Harrison-Principals of Internal Medicine 20th. Ed. Prt.7-11

Harrisons_20e_Part6_p1649-p1942.
indd 1942 6/1/18 12:55 PM

Disorders of the Respiratory System PART 7
analysis, a variety of serologic or microbiologic studies, and diagnostic
Section 1 Diagnosis of Respiratory Disorders procedures, such as bronchoscopy. This stepwise approach is discussed
in detail below.
278
■■HISTORY
Approach to the Patient
Dyspnea and Cough The cardinal symptoms of respiratory dis-
with Disease of the ease are dyspnea and cough (Chaps. 33 and 34). Dyspnea has many
Respiratory System causes, some of which are not predominantly due to lung pathology.
The words a patient uses to describe shortness of breath can suggest
Patricia A. Kritek, Bruce D. Levy certain etiologies for dyspnea. Patients with obstructive lung disease
often complain of “chest tightness” or “inability to get a deep breath,”
whereas patients with congestive heart failure more commonly report
“air hunger” or a sense of suffocation.
The majority of diseases of the respiratory system present with cough
The tempo of onset and the duration of a patient’s dyspnea are
and/or dyspnea and fall into one of three major categories: (1) obstruc-
likewise helpful in determining the etiology. Acute shortness of breath
tive lung diseases; (2) restrictive disorders; and (3) abnormalities of the
is usually associated with sudden physiological changes, such as
vasculature. Obstructive lung diseases are most common and primarily
laryngeal edema, bronchospasm, myocardial infarction, pulmonary
disorders of the airways, such as asthma, chronic obstructive pulmo-
embolism, or pneumothorax. Patients with COPD and idiopathic pul-
nary disease (COPD), bronchiectasis, and bronchiolitis. Diseases result-
monary fibrosis (IPF) experience a gradual progression of dyspnea on
ing in restrictive pathophysiology include parenchymal lung diseases,
exertion, punctuated by acute exacerbations of shortness of breath. In
abnormalities of the chest wall and pleura, and neuromuscular dis-
contrast, most asthmatics do not have daily symptoms, but experience
ease. Pulmonary embolism, pulmonary hypertension, and pulmonary
intermittent episodes of dyspnea, cough, and chest tightness that are
venoocclusive disease are all disorders of the pulmonary vasculature.
usually associated with specific triggers, such as an upper respiratory
Although many specific diseases fall into these major categories, both
tract infection or exposure to allergens.
infective and neoplastic processes can affect the respiratory system and
Specific questioning should focus on factors that incite dyspnea as
result in myriad pathologic findings, including those listed in the three
well as on any intervention that helps resolve the patient’s shortness of
categories above (Table 278-1).
breath. Asthma is commonly exacerbated by specific triggers, although
Disorders can also be grouped according to gas exchange abnor-
this can also be true of COPD. Many patients with lung disease report
malities, including hypoxemic, hypercarbic, or combined impairment;
dyspnea on exertion. Determining the degree of activity that results in
however, many respiratory disorders do not manifest as gas exchange
shortness of breath gives the clinician a gauge of the patient’s degree of
abnormalities.
disability. Many patients adapt their level of activity to accommodate
As with the evaluation of most patients, the approach to a patient
progressive limitation. For this reason, it is important, particularly in
with a respiratory system disorder begins with a thorough history
older patients, to delineate the activities in which they engage and how
and a focused physical examination. Many patients will subsequently
these activities have changed over time. Dyspnea on exertion is often
undergo pulmonary function testing, chest imaging, blood and sputum
an early symptom of underlying lung or heart disease and warrants a
thorough evaluation.
TABLE 278-1 Categories of Respiratory Disease For cough, the clinician should inquire about the duration of the
CATEGORY EXAMPLES
cough, whether or not it is associated with sputum production, and any
specific triggers that induce it. Acute cough productive of phlegm is
Obstructive lung disease Asthma
often a symptom of infection of the respiratory system, including pro-
Chronic obstructive pulmonary disease
cesses affecting the upper airway (e.g., sinusitis, tracheitis), the lower
(COPD)
airways (e.g., bronchitis, bronchiectasis), and the lung parenchyma (e.g.,
Bronchiectasis
pneumonia). Both the quantity and quality of the sputum, including
Bronchiolitis
whether it is blood-streaked or frankly bloody, should be determined.
Restrictive pathophysiology— Idiopathic pulmonary fibrosis (IPF) Hemoptysis warrants urgent evaluation as delineated in Chap. 35.
parenchymal disease Asbestosis Chronic cough (defined as that persisting for >8 weeks) is com-
Desquamative interstitial pneumonitis (DIP) monly associated with obstructive lung diseases, particularly asthma,
Sarcoidosis COPD and chronic bronchiectasis, as well as “nonrespiratory” diseases,
Restrictive pathophysiology— Amyotrophic lateral sclerosis (ALS) such as gastroesophageal reflux and postnasal drip. Diffuse parenchy-
neuromuscular weakness Guillain-Barré syndrome mal lung diseases, including IPF, frequently present as a persistent,
Myasthenia gravis nonproductive cough. All causes of cough are not respiratory in origin,
Restrictive pathophysiology— Kyphoscoliosis and assessment should encompass a broad differential, including car-
chest wall/pleural disease Ankylosing spondylitis
diac and gastrointestinal diseases as well as psychogenic causes.
Chronic pleural effusions Additional Symptoms Patients with respiratory disease may
Pulmonary vascular disease Pulmonary embolism report wheezing, which is suggestive of airways disease, particularly
Pulmonary arterial hypertension (PAH) asthma. Hemoptysis can be a symptom of a variety of lung diseases,
Pulmonary venoocclusive disease including infections of the respiratory tract, bronchogenic carcinoma,
Vasculitis and pulmonary embolism. In addition, chest pain or discomfort can be
Malignancy Bronchogenic carcinoma (non-small-cell and respiratory in origin. As the lung parenchyma is not innervated with
small-cell lung cancer) pain fibers, pain in the chest from respiratory disorders usually results
Metastatic disease from either diseases of the parietal pleura (e.g., pneumothorax) or
Infectious diseases Pneumonia
pulmonary vascular diseases (e.g., pulmonary hypertension). As many
diseases of the lung can result in strain on the right side of the heart,
Bronchitis
patients may also present with symptoms of cor pulmonale, including
Tracheitis
abdominal bloating or distention and pedal edema (Chap. 252).
Harrisons_20e_Part7_p1943-p2022.indd 1943 6/1/18 1:00 PM

1944 Additional History A thorough social history is an essential are generally more prominent at the bases. Interestingly, diseases that
component of the evaluation of patients with respiratory disease. All result in fibrosis of the interstitium (e.g., IPF) also result in crackles that
patients should be asked about current or previous cigarette smoking, sound like Velcro being ripped apart. Although some clinicians make a
as this exposure is associated with many diseases of the respiratory sys- distinction between “wet” and “dry” crackles, this distinction has not
tem, including COPD, bronchogenic lung cancer, and select parenchy- been shown to be a reliable way to differentiate among etiologies of
mal lung diseases (e.g., desquamative interstitial pneumonitis and respiratory disease.
pulmonary Langerhans cell histiocytosis). For most of these disorders, One way to help distinguish between crackles associated with alve-
increased cigarette smoke exposure (i.e., cigarette pack-years) increases olar fluid and those associated with interstitial fibrosis is to assess for
the risk of disease. “Secondhand smoke” also increases risk for some egophony. Egophony is the auscultation of the sound “AH” instead of
respiratory disorders, so patients should also be asked about parents, “EEE” when a patient phonates “EEE.” This change in note is due to
spouses, or housemates who smoke. Possible inhalational exposures abnormal sound transmission through consolidated parenchyma and
at work (e.g., asbestos, silica) or home (e.g., wood smoke, excrement is present in pneumonia but not in IPF. Similarly, areas of alveolar
PART 7
from pet birds) should be explored (Chap. 283). Travel predisposes to filling have increased whispered pectoriloquy as well as transmission
certain infections of the respiratory tract, most notably tuberculosis. of larger-airway sounds (i.e., bronchial breath sounds in a lung zone
Potential exposure to fungi is increased in specific geographic regions where vesicular breath sounds are expected).
or climates (e.g., Histoplasma capsulatum), so exposures to these regions The lack or diminution of breath sounds can also help determine the
Disorders of the Respiratory System
should be determined. etiology of respiratory disease. Patients with emphysema often have a
Associated symptoms of fever and chills should raise the suspicion quiet chest with diffusely decreased breath sounds. A pneumothorax
of infective etiologies, both pulmonary and systemic. A comprehensive or pleural effusion may present with an area of absent breath sounds.
review of systems may suggest rheumatologic or autoimmune disease
presenting with respiratory tract manifestations. Questions should
Other Systems Pedal edema, if symmetric, may suggest cor pul-
monale; if asymmetric, it may be due to deep venous thrombosis and
focus on joint pain or swelling, rashes, dry eyes, dry mouth, or consti-
associated pulmonary embolism. Jugular venous distention may also
tutional symptoms. In addition, carcinomas from a variety of primary
be a sign of volume overload associated with right heart failure. Pulsus
sources commonly metastasize to the lung and cause respiratory symp-
paradoxus is an ominous sign in a patient with obstructive lung disease,
toms. Finally, therapy for other conditions, including both irradiation
as it is associated with significant negative intrathoracic (pleural) pres-
and medications, can result in diseases of the chest.
sures required for ventilation and impending respiratory failure.
Physical Examination The clinician’s suspicion of respiratory As stated earlier, rheumatologic disease may manifest primarily as
disease often begins with patient’s vital signs. The respiratory rate is lung disease. Owing to this association, particular attention should be
informative, whether elevated (tachypnea) or depressed (hypopnea). paid to joint and skin examination. Clubbing can be found in many
In addition, pulse oximetry should be measured, as many patients with lung diseases, including cystic fibrosis, IPF, and lung cancer. Cyanosis
respiratory disease have hypoxemia, either at rest or with exertion. is seen in hypoxemic respiratory disorders that result in >5 g of deoxy-
The first step of the physical examination is inspection. Patients genated hemoglobin/dL.
with respiratory disease may be in distress, using accessory muscles
■■DIAGNOSTIC EVALUATION
of respiration to breathe. Severe kyphoscoliosis can result in restrictive
The sequence of studies is dictated by the clinician’s differential
pathophysiology. Inability to complete a sentence in conversation is
diagnosis, as determined by the history and physical examination.
generally a sign of severe impairment and should result in an expe-
Acute respiratory symptoms are often evaluated with multiple tests
dited evaluation of the patient.
performed at the same time in order to diagnose any life-threatening
Percussion of the chest is used to establish diaphragm excursion
diseases rapidly (e.g., pulmonary embolism or multilobar pneumonia).
and lung size. In the setting of decreased breath sounds, percussion is
In contrast, chronic dyspnea and cough can be evaluated in a more
used to distinguish between pleural effusions (dull to percussion) and
protracted, stepwise fashion.
pneumothorax (hyper-resonant note).
The role of palpation is limited in the respiratory examination. Pal- Pulmonary Function Testing (See also Chap. 280) The
pation can demonstrate subcutaneous air in the setting of barotrauma. initial pulmonary function test obtained is spirometry. This study is an
It can also be used as an adjunctive assessment to determine whether effort-dependent test used to assess for obstructive pathophysiology as
an area of decreased breath sounds is due to consolidation (increased seen in asthma, COPD, and bronchiectasis. A diminished-forced expi-
tactile fremitus) or a pleural effusion (decreased tactile fremitus). To ratory volume in 1 s (FEV1)/forced vital capacity (FVC) (often defined
detect unilateral disorders of ventilation, the symmetry and degree as <70%) is diagnostic of obstruction. In addition to measuring FEV1
of chest wall expansion can be assessed during a deep inspiration by and FVC, the clinician should examine the flow-volume loop (which
placing one’s thumbs together at the midline over the lower posterior is less effort-dependent). A plateau of the inspiratory and expiratory
chest while grasping the lateral rib cage. curves suggests large-airway obstruction in extrathoracic and intratho-
The majority of the manifestations of respiratory disease present as racic locations, respectively.
abnormalities of auscultation. Wheezes are a manifestation of airway Spirometry with symmetric decreases in FEV1 and FVC warrants
obstruction. While most commonly a sign of asthma, peribronchial further testing, including measurement of lung volumes and the
edema in the setting of congestive heart failure can also result in dif- diffusion capacity of the lung for carbon monoxide (DlCO). A total
fuse wheezes, as can any other process that causes narrowing of small lung capacity <80% of the patient’s predicted value defines restrictive
airways. Wheezes can be polyphonic, involving multiple different size pathophysiology. Restriction can result from parenchymal disease, neu-
airways (e.g., asthma) or monophonic, involving one size airway (e.g., romuscular weakness, or chest wall or pleural diseases (Table 278-1).
bronchogenic carcinoma). For these reasons, clinicians must take care Restriction with impaired gas exchange, as indicated by a decreased
not to attribute all wheezing to asthma. DlCO, suggests parenchymal lung disease. Additional testing, such as
Rhonchi are a manifestation of obstruction of medium-sized air- measurements of maximal inspiratory and expiratory pressures, can
ways, most often with secretions. In the acute setting, this manifes- help diagnose neuromuscular weakness. Normal spirometry, normal
tation may be a sign of viral or bacterial bronchitis. Chronic rhonchi lung volumes, and a low DlCO should prompt further evaluation for
suggest bronchiectasis or COPD. In contrast to expiratory wheezes and pulmonary vascular disease.
rhonchi, stridor is a high-pitched, focal inspiratory wheeze, usually Arterial blood gas testing is often helpful in assessing respiratory
heard over the neck as a manifestation of upper airway obstruction. disease. Hypoxemia, while usually apparent with pulse oximetry, can
Crackles, or rales, are commonly a sign of alveolar disease. Pro- be further evaluated with the measurement of arterial PO2 and the cal-
cesses that fill the alveoli with fluid may result in crackles, including culation of an alveolar gas and arterial blood oxygen tension difference
pulmonary edema and pneumonia. Crackles in pulmonary edema ([A–a]DO2). Patients with diseases that cause ventilation-perfusion

mismatch or shunt physiology have an increased (A–a)DO2 at rest. by an extremely thin membrane of flattened endothelial and epithelial 1945
Arterial blood gas testing also allows the measurement of arterial Pco . cells, across which respiratory gases diffuse and equilibrate. Blood flow
2
Hypercarbia can accompany disorders of ventilation, as seen in severe through the lung is unidirectional via a continuous vascular path along
airway obstruction (e.g., COPD) or progressive restrictive physiology. which venous blood absorbs oxygen from and loses CO2 to inspired
gas. The path for airflow, in contrast, reaches a dead end at the alveolar
Chest Imaging (See Chap. A12) Most patients with disease walls; thus the alveolar space must be ventilated tidally, with inflow
of the respiratory system undergo imaging of the chest as part of the
of fresh gas and outflow of alveolar gas alternating periodically at the
initial evaluation. Clinicians should generally begin with ultrasound
respiratory rate (RR). To provide an enormous alveolar surface area
of the chest or a plain chest radiograph, preferably posterior-anterior
(typically 70 m2) for blood-gas diffusion within the modest volume
and lateral films. Ultrasound is often readily available and can help of a thoracic cavity (typically 7 L), nature has distributed both blood
rapidly diagnose pneumothorax, pleural effusion, and consolidation flow and ventilation among millions of tiny alveoli through multigen-
CHAPTER 279 Disturbances of Respiratory Function

of lung parenchyma. Chest radiographs give additional detail and can erational branching of both pulmonary arteries and bronchial airways.
reveal findings including opacities of the parenchyma, blunting of the As a consequence of variations in tube lengths and calibers along these
costophrenic angles, mass lesions, and volume loss. However, many pathways as well as the effects of gravity, tidal pressure fluctuations,
diseases of the respiratory system, particularly those of the airways and and anatomic constraints from the chest wall, the alveoli vary in their
pulmonary vasculature, are associated with a normal chest radiograph. relative ventilations and perfusions. Not surprisingly, for the lung to
CT scan of the chest can also be useful to delineate parenchymal be most efficient in exchanging gas, the fresh gas ventilation of a given
processes, pleural disease, masses or nodules, and large airways. If the alveolus must be matched to its perfusion.
test includes administration of contrast, the pulmonary vasculature For the respiratory system to succeed in oxygenating blood and
can be assessed with particular utility for determination of pulmonary eliminating CO2, it must be able to ventilate the lung tidally and thus
emboli. Intravenous contrast also allows lymph nodes to be examined to freshen alveolar gas; it must provide for perfusion of the individual
in greater detail. When coupled with positron emission testing (PET), alveolus in a manner proportional to its ventilation; and it must allow
lesions of the chest can be assessed for metabolic activity; helping dif- adequate diffusion of respiratory gases between alveolar gas and cap-
ferentiate between malignancy and scar. illary blood. Furthermore, it must accommodate several-fold increases
■■FURTHER STUDIES in the demand for oxygen uptake or CO2 elimination imposed by met-
Depending on the clinician’s suspicion, a variety of other studies may abolic needs or acid-base derangement. Given these multiple require-
be done. Concern about large-airway lesions may warrant bronchos- ments for normal operation, it is not surprising that many diseases
copy. This procedure may also be used to sample the alveolar space disturb respiratory function. This chapter considers in some detail the
with bronchoalveolar lavage or to obtain nonsurgical lung biopsies. physiologic determinants of lung ventilation and perfusion, elucidates
Blood testing may include assessment for hypercoagulable states in the how the matching distributions of these processes and rapid gas diffu-
setting of pulmonary vascular disease, serologic testing for infectious sion allow normal gas exchange, and discusses how common diseases
or rheumatologic disease, or assessment of inflammatory markers or derange these normal functions, thereby impairing gas exchange—or
leukocyte counts (e.g., eosinophils). Genetic testing is increasingly used at least increasing the work required by the respiratory muscles or
for heritable lung diseases such as cystic fibrosis. Sputum evaluation heart to maintain adequate respiratory function.
for malignant cells or microorganisms may be appropriate. An echocar-
diogram to assess right- and left-sided heart function is often obtained. ■■VENTILATION
Finally, at times, a surgical lung biopsy is needed to diagnose certain It is useful to conceptualize the respiratory system as three indepen-
diseases of the respiratory system. All of these studies will be guided dently functioning components: the lung, including its airways; the neu-
by the preceding history, physical examination, pulmonary function romuscular system; and the chest wall, which includes everything that
testing, and chest imaging. is not lung or active neuromuscular system. Accordingly, the mass of the
respiratory muscles is part of the chest wall, while the force these mus-
■■FURTHER READING cles generate is part of the neuromuscular system; the abdomen (espe-
Achilleos A: Evidence-based evaluation and management of chronic cially an obese abdomen) and the heart (especially an enlarged heart) are,
cough. Med Clin North Am 100:1033, 2016. for these purposes, part of the chest wall. Each of these three components
Bohadana A et al: Fundamentals of lung auscultation. N Engl J Med has mechanical properties that relate to its enclosed volume (or—in the
370:744, 2014. case of the neuromuscular system—the respiratory system volume at
Koenig SJ et al: Thoracic ultrasonography for the pulmonary specialist. which it is operating) and to the rate of change of its volume (i.e., flow).
Chest 140:1332, 2011.
Parshall MB et al: An official American Thoracic Society statement: Volume-Related Mechanical Properties—Statics Figure 279-1
Update on the mechanisms, assessment, and management of dysp- shows the volume-related properties of each component of the respira-
nea. Am J Respir Crit Care Med 185:435, 2012. tory system. Because of both surface tension at the air-liquid interface
Pellegrino R et al: Interpretive strategies for lung function tests. Eur between alveolar wall lining fluid and alveolar gas and elastic recoil
Respir J 26:948, 2005. of the lung tissue itself, the lung requires a positive transmural pres-
sure difference between alveolar gas and its pleural surface to stay
inflated; this difference is called the elastic recoil pressure of the lung,
and it increases with lung volume. The lung becomes rather stiff at high
volumes, so that relatively small volume changes are accompanied
279 Respiratory
Disturbances of
Function
by large changes in transpulmonary pressure; in contrast, the lung is
compliant at lower volumes, including those at which tidal breathing
normally occurs. At zero inflation pressure, even normal lungs retain
some air in the alveoli. Because the small peripheral airways are
Edward T. Naureckas, Julian Solway tethered open by outward radial pull from inflated lung parenchyma
attached to adventitia, as the lung deflates during exhalation, those
small airways are pulled open progressively less, and eventually close,
The primary functions of the respiratory system—to oxygenate blood trapping some gas in the alveoli. This effect can be exaggerated with
and eliminate carbon dioxide—require virtual contact between blood age and especially with obstructive airway diseases, resulting in gas
and fresh air, which facilitates diffusion of respiratory gases between trapping at quite large lung volumes.
blood and gas. This process occurs in the lung alveoli, where blood The elastic behavior of the passive chest wall (i.e., in the absence
flowing through alveolar wall capillaries is separated from alveolar gas of neuromuscular activation) differs markedly from that of the lung.

1946 Volume
TLC
Passive
Respiratory System Inspiratory Muscles
FRC
Expiratory Muscles Chest Wall
Lungs
RV
PART 7
–80 –60 –40 –20 0 20 40 60 80

Pressure (cmH2O)
FIGURE 279-1 Pressure-volume curves of the isolated lung, isolated chest wall, combined respiratory system, inspiratory muscles, and expiratory muscles. FRC,
functional residual capacity; RV, residual volume; TLC, total lung capacity.
Whereas the lung tends toward full deflation with no distending stiffness extremes—one determined by the lung (TLC) and the other by
(transmural) pressure, the chest wall encloses a large volume when the chest wall or airways (RV). Thus, although VC is easy to measure
pleural pressure equals body surface (atmospheric) pressure. Further- (see below), it provides little information about the intrinsic properties
more, the chest wall is compliant at high enclosed volumes, readily of the respiratory system. As will become clear, it is much more useful
expanding even further in response to increases in transmural pressure. for the clinician to consider TLC and RV individually.
The chest wall also remains compliant at small negative transmural
pressures (i.e., when pleural pressure falls slightly below atmospheric Flow-Related Mechanical Properties—Dynamics The
pressure), but as the volume enclosed by the chest wall becomes quite passive chest wall and active neuromuscular system both exhibit
small in response to large negative transmural pressures, the passive mechanical behaviors related to the rate of change of volume, but
chest wall becomes stiff due to squeezing together of ribs and intercos- these behaviors become quantitatively important only at markedly
tal muscles, diaphragm stretch, displacement of abdominal contents, supraphysiologic breathing frequencies (e.g., during high-frequency
and straining of ligaments and bony articulations. Under normal cir- mechanical ventilation), and thus will not be addressed here. In con-
cumstances, the lung and the passive chest wall enclose essentially the trast, the dynamic airflow properties of the lung substantially affect its
same volume, the only difference being the volumes of the pleural fluid ability to ventilate and contribute importantly to the work of breathing,
and of the lung parenchyma (normally both quite small in the absence and these properties are often deranged by disease. Understanding
of disease). For this reason and because the lung and chest wall function dynamic airflow properties is, therefore, worthwhile.
in mechanical series, the pressure required to displace the passive respi- As with the flow of any fluid (gas or liquid) in any tube, mainte-
ratory system (lungs plus chest wall) at any volume is simply the sum nance of airflow within the pulmonary airways requires a pressure
of the elastic recoil pressure of the lungs and the transmural pressure gradient that falls along the direction of flow, the magnitude of which
across the chest wall. When plotted against respiratory system volume, is determined by the flow rate and the frictional resistance to flow. Dur-
this relationship assumes a sigmoid shape, exhibiting stiffness at high ing quiet tidal breathing, the pressure gradients driving inspiratory or
lung volumes (imparted by the lung), stiffness at low lung volumes expiratory flow are small owing to the very low frictional resistance of
(imparted by the chest wall or sometimes by airway closure), and com- normal pulmonary airways (Raw, normally <2 cmH2O/L/s). However,
pliance in the middle range of lung volumes where normal tidal breath- during rapid exhalation, another phenomenon reduces flow below that
ing occurs. In addition, a passive resting point of the respiratory system which would have been expected if frictional resistance were the only
is attained when alveolar gas pressure equals body surface pressure impediment to flow. This phenomenon is called dynamic airflow lim-
(i.e., when the transrespiratory system pressure is zero). At this vol- itation, and it occurs because the bronchial airways through which air
ume (called the functional residual capacity [FRC]), the outward recoil of is exhaled are collapsible rather than rigid (Fig. 279-3). An important
the chest wall is balanced exactly by the inward recoil of the lung. anatomic feature of the pulmonary airways is its treelike branching
As these recoils are transmitted through the pleural fluid, the lung is structure. While the individual airways in each successive generation,
pulled both outward and inward simultaneously at FRC, and thus its from most proximal (trachea) to most distal (respiratory bronchioles),
pressure falls below atmospheric pressure (typically, −5 cmH2O). are smaller than those of the parent generation, their number increases
The normal passive respiratory system would equilibrate at the FRC exponentially such that the summed cross-sectional area of the air-
and remain there were it not for the actions of the respiratory muscles. ways becomes very large toward the lung periphery. Because flow
The inspiratory muscles act on the chest wall to generate the equivalent
of positive pressure across the lungs and passive chest wall, while the
expiratory muscles generate the equivalent of negative transrespiratory
pressure. The maximal pressures these sets of muscles can generate
Total
vary with the lung volume at which they operate. This variation is Tidal Vital Lung
due to length-tension relationships in striated muscle sarcomeres and Volume Capacity Capacity
to changes in mechanical advantage as the angles of insertion change
with lung volume (Fig. 279-1). Nonetheless, under normal conditions, Expiratory
the respiratory muscles are substantially “overpowered” for their roles Reserve
and generate more than adequate force to drive the respiratory system Functional Volume
to its stiffness extremes, as determined by the lung (total lung capacity Residual
Capacity
[TLC]) or by chest wall or airway closure (residual volume [RV]); the Residual
airway closure always prevents the adult lung from emptying com- Volume
pletely under normal circumstances. The excursion between full and
minimal lung inflation is called vital capacity (VC; Fig. 279-2) and is FIGURE 279-2 Spirogram demonstrating a slow vital capacity maneuver and
readily seen to be the difference between volumes at two unrelated various lung volumes.

Luminal Area because of the dependence of lung recoil pressure on lung volume 1947
(Fig. 279-1). In pulmonary fibrosis, lung recoil pressure is increased at
any lung volume, and thus the maximal expiratory flow is elevated
when considered in relation to lung volume. Conversely, in emphy-
sema, lung recoil pressure is reduced; this reduction is a principal
mechanism by which maximal expiratory flows fall. Diseases that
narrow the airway lumen at any transmural pressure (e.g., asthma or
chronic bronchitis) or that cause excessive airway collapsibility (e.g.,
tracheomalacia) also reduce maximal expiratory flow.
The Bernoulli effect also applies during inspiration, but the more
_ negative pleural pressures during inspiration lower the pressure

Transmural Pressure +
outside of the airways, thereby increasing transmural pressure and
FIGURE 279-3 Luminal area versus transmural pressure relationship. Transmural
pressure represents the pressure difference across the airway wall from inside
promoting airway expansion. Thus, inspiratory airflow limitation
to outside. seldom occurs due to diffuse pulmonary airway disease. Conversely,
extrathoracic airway narrowing (e.g., due to a tracheal adenoma or
post-tracheostomy stricture) can lead to inspiratory airflow limitation
(volume/time) is constant along the airway tree, the velocity of airflow (Fig. 279-4).
(flow/summed cross-sectional area) is much greater in the central air-
ways than in the peripheral airways. During exhalation, gas leaving the The Work of Breathing In health, the elastic (volume change-
alveoli must, therefore, gain velocity as it proceeds toward the mouth. related) and dynamic (flow-related) loads that must be overcome
The energy required for this “convective” acceleration is drawn from to ventilate the lungs at rest are small, and the work required of the
the component of gas energy manifested as its local pressure, which respiratory muscles is minimal. However, the work of breathing can
reduces intraluminal gas pressure, airway transmural pressure, airway increase considerably due to a metabolic requirement for substantially
size (Fig. 279-3), and flow. This phenomenon is the Bernoulli effect, increased ventilation, an abnormally increased mechanical load, or
the same effect that keeps an airplane airborne, generating a lifting both. As discussed below, the rate of ventilation is primarily set by
force by decreasing pressure above the curved upper surface of the the need to eliminate carbon dioxide, and thus ventilation increases
wing due to acceleration of air flowing over the wing. If an individual during exercise (sometimes by >20-fold) and during metabolic acido-
tries to exhale more forcefully, the local velocity increases further and sis as a compensatory response. Naturally, the work rate required to
reduces airway size further, resulting in no net increase in flow. Under overcome the elasticity of the respiratory system increases with both
these circumstances, flow has reached its maximum possible value, or the depth and the frequency of tidal breaths, while the work required
its flow limit. Lungs normally exhibit such dynamic airflow limitation. to overcome the dynamic load increases with total ventilation. A mod-
This limitation can be assessed by spirometry, in which an individual est increase of ventilation is most efficiently achieved by increasing
inhales fully to TLC and then forcibly exhales to RV. One useful spiro- tidal volume but not RR, which is the normal ventilatory response to
metric measure is the volume of air exhaled during the forced expira- lower-level exercise. At higher levels of exercise, deep breathing per-
tory volume 1 s (FEV1), as discussed later. Maximal expiratory flow at sists, but RR also increases.
any lung volume is determined by gas density, airway cross-section The work of breathing also increases when disease reduces the com-
and distensibility, elastic recoil pressure of the lung, and frictional pliance of the respiratory system or increases the resistance to airflow.
pressure loss to the flow-limiting airway site. Under normal conditions, The former occurs commonly in diseases of the lung parenchyma (inter-
maximal expiratory flow falls with lung volume (Fig. 279-4), primarily stitial processes or fibrosis, alveolar filling diseases such as pulmonary
edema or pneumonia, or substantial
C lung resection), and the latter occurs
A B
in obstructive airway diseases such
Expiratory
Expiratory
Expiratory
as asthma, chronic bronchitis, emphy-

sema, and cystic fibrosis. Further-
more, severe airflow obstruction can
functionally reduce the compliance of
TLC TLC the respiratory system by leading to
TLC
Flow
Flow
Flow
dynamic hyperinflation. In this sce-

RV Volume RV Volume RV Volume nario, expiratory flows slowed by the
obstructive airways disease may be
Inspiratory
Inspiratory
Inspiratory
insufficient to allow complete exha-

lation during the expiratory phase
of tidal breathing; as a result, the
“functional residual capacity (FRC)”
D E from which the next breath is inhaled
is greater than the static FRC. With
Expiratory
Expiratory
repetition of incomplete exhalations

of each tidal breath, the operating
FRC becomes dynamically elevated,
TLC TLC
sometimes to a level that approaches
Inspiratory Flow
Inspiratory Flow
TLC. At these high lung volumes,

the respiratory system is much less
RV
RV compliant than at normal breathing
volumes, and thus the elastic work
of each tidal breath is also increased.
The dynamic pulmonary hyperinfla-
FIGURE 279-4 Flow-volume loops. A. Normal. B. Airflow obstruction. C. Fixed central airway obstruction (either above tion that accompanies severe airflow
or below the thoracic inlet). D. Variable upper airway obstruction (above the thoracic inlet) E. Variable lower airway obstruction causes patients to sense
obstruction (below the thoracic inlet); RV, residual volume; TLC, total lung capacity. difficulty in inhaling—even though

1948 the root cause of this pathophysiologic abnormality is expiratory air- blood cell becomes fully oxygen saturated by the time the cell has trav-
flow obstruction. eled just one-third the length of the alveolar capillary. Thus, the uptake
of alveolar oxygen is ordinarily limited by the amount of blood tran-
Adequacy of Ventilation As noted above, the respiratory control siting the alveolar capillaries rather than by the rapidity with which
system that sets the rate of ventilation responds to chemical signals,
oxygen can diffuse across the membrane; consequently, oxygen uptake
including arterial CO2 and oxygen tensions and blood pH, and to
from the lung is said to be “perfusion limited” rather than diffusion
volitional needs, such as the need to inhale deeply before playing a
limited. CO2 also equilibrates rapidly across the alveolar membrane.
long phrase on the trumpet. Disturbances in ventilation are discussed Therefore, the oxygen and CO2 tensions in capillary blood leaving a
in Chap. 290. The focus of this chapter is on the relationship between normal alveolus are essentially equal to those in alveolar gas. Only
ventilation of the lung and CO2 elimination. in rare circumstances (e.g., at high altitude or in high-performance
At the end of each tidal exhalation, the conducting airways are filled
athletes exerting maximal effort) is oxygen uptake from normal lungs
with alveolar gas that did not reach the mouth when expiratory flow
diffusion limited. Diffusion limitation can also occur in interstitial lung
PART 7
stopped. During the ensuing inhalation, fresh gas immediately enters

disease if substantially thickened alveolar walls remain perfused.
the airway tree at the mouth, but the gas first entering the alveoli at the
start of inhalation is that same alveolar gas in the conducting airways Ventilation/Perfusion Heterogeneity As noted above, for gas
that had just left the alveoli. Accordingly, fresh gas does not enter the exchange to be most efficient, ventilation to each individual alveolus
alveoli until the volume of the conducting airways has been inspired. (among the millions of alveoli) should match perfusion to its accompa-
This volume is called the anatomic dead space (VD). Quiet breathing nying capillaries. Because of the differential effects of gravity on lung
with tidal volumes smaller than the anatomic dead space introduces mechanics and blood flow throughout the lung and because of differ-
no fresh gas into the alveoli at all; only that part of the inspired tidal ences in airway and vascular architecture among various respiratory
volume (VT) that is greater than the VD introduces fresh gas into the paths, there is minor ventilation/perfusion heterogeneity even in the
. .
alveoli. The dead space can be further increased functionally if some normal lung; however, V/Q heterogeneity can be particularly marked
of the inspired tidal volume is delivered to a part of the lung that in disease. Two extreme examples are (1) ventilation of unperfused
receives no pulmonary blood flow and thus cannot contribute to gas lung distal to a pulmonary embolus, in which ventilation of the phys-
exchange (e.g., the portion of the lung distal to a large . pulmonary iologic dead space is “wasted” in the sense that it does not contribute
embolus). In this situation, exhaled minute ventilation. ( VE = VT × RR) to gas exchange; and (2) perfusion of nonventilated lung (a “shunt”),
includes a component of dead space ventilation.( VD = VD × RR) and which allows venous blood to pass through the lung unaltered. When
a component of fresh gas alveolar ventilation ( .VA = [VT − VD] × RR). mixed with fully oxygenated blood leaving other well-ventilated lung
CO2 elimination from the alveoli is equal to VA times the difference units, shunted venous blood disproportionately lowers the mixed
in CO2 fraction between inspired air (essentially zero) and alveolar arterial Pao as a result of the nonlinear oxygen content versus Po2
gas (typically ~5.6% after correction for humidification of inspired 2
relationship of hemoglobin (Fig. 279-5). Furthermore, the resulting
air, corresponding to 40 mmHg). In the steady state, the alveolar frac- arterial hypoxemia is refractory to supplemental inspired oxygen. The
tion of CO2 is equal to metabolic CO2 production divided by alveolar reason is that (1) raising the inspired Fio has no effect on alveolar gas
ventilation. Because, as discussed below, alveolar and arterial CO2 2
tensions in nonventilated alveoli and (2) while raising inspired Fio
tensions are equal, and because the respiratory controller normally increases Paco in ventilated alveoli, the oxygen content of blood exit-
2
strives to maintain arterial Pco (Paco ) at ~40 mmHg, the adequacy of 2

ing ventilated units increases only slightly, as hemoglobin will already
2 2
alveolar ventilation is reflected in Paco . If the Paco falls much below have been nearly fully saturated and the solubility of oxygen in plasma
2 2
40 mmHg, alveolar hyperventilation is present; if the Paco exceeds is quite small.
2
40 mmHg, alveolar hypoventilation is present. Ventilatory failure is A more common occurrence than the two extreme examples given
characterized by extreme alveolar hypoventilation. above is
. a.widening of the distribution of ventilation/perfusion ratios;
As a consequence of oxygen uptake of alveolar gas into capillary such V/Q heterogeneity is a common consequence of lung disease.
blood, alveolar oxygen tension falls below that of inspired gas. The rate In this circumstance, perfusion of relatively underventilated alveoli
of oxygen uptake (determined by the body’s metabolic oxygen con- results in the incomplete oxygenation of exiting . .blood. When mixed
sumption) is related to the average rate of metabolic. . 2 production,
CO with well-oxygenated blood leaving higher V/Q regions, this par-
and their ratio—the “respiratory quotient” (R = VCO 2/ VO 2 )—depends tially reoxygenated blood disproportionately lowers arterial Pao ,
largely on the fuel being metabolized. For a typical American diet, R is although to a lesser extent than does a similar perfusion fraction of
2
usually around 0.85. Together, these phenomena allow the estimation blood leaving regions of pure shunt. In addition, in contrast to shunt
of alveolar oxygen tension, according to the following relationship, regions, inhalation of supplemental
. . oxygen raises the Pao2, even in rel-
known as the alveolar gas equation: atively underventilated
. . low V/Q regions, and so the arterial hypox-
emia induced by V/Q heterogeneity is typically responsive to oxygen
Pao = Fio × (Pbar − PH O) − Paco /R therapy (Fig. 279-5).
2 2 2 2
The alveolar gas equation also highlights the influences of inspired oxy- In sum, arterial hypoxemia can be caused by substantial reduction
gen fraction (Fio2), barometric pressure (Pbar), and vapor pressure of water of inspired oxygen tension, severe alveolar
. . hypoventilation, perfusion
(PH O = 47 mmHg at 37°C) in addition to alveolar ventilation (which sets of relatively underventilated (low V/Q ) or completely unventilated
2
Paco ) in determining Pao . An implication of the alveolar gas equation (shunt) lung regions, and, in very unusual circumstances, by limitation
2 2
is that severe arterial hypoxemia rarely occurs as a pure consequence of gas diffusion.
of alveolar hypoventilation at sea level while an individual is breathing
air. The potential for alveolar hypoventilation to induce severe hypox- ■■PATHOPHYSIOLOGY
emia with otherwise normal lungs increases as Pbar falls with increasing Although many diseases injure the respiratory system, this system
altitude. responds to injury in relatively few ways. For this reason, the pattern
of physiologic abnormalities may or may not provide sufficient infor-
mation by which to discriminate among conditions.
■■GAS EXCHANGE
Figure 279-6 lists abnormalities in pulmonary function testing that
Diffusion For oxygen to be delivered to the peripheral tissues, it are typically found in a number of common respiratory disorders and
must pass from alveolar gas into alveolar capillary blood by diffusing highlight the simultaneous occurrence of multiple physiologic abnor-
through alveolar membrane. The aggregate alveolar membrane is malities. The coexistence of some of these respiratory disorders results
highly optimized for this process, with a very large surface area and in more complex superposition of these abnormalities. Methods to
minimal thickness. Diffusion through the alveolar membrane is so effi- measure respiratory system function clinically are described later in
cient in the human lung that in most circumstances hemoglobin of a red this chapter.

Shunt FIO2 = 0.21 FIO2 = 1 1949
40 99 40 650
mmHg mmHg mmHg mmHg

40 mmHg 40 mmHg
40 mmHg (75%) 40 mmHg
(75%)
(75%) (75%)
40 mmHg 99 mmHg 40 mmHg 650 mmHg
(75%) (100%) (75%) (100%)
55 mmHg 56 mmHg
(87.5%) (88%)
. . FIO2 = 0.21 FIO2 = 1

V/Q
Heterogeneity
40 99 200 650
mmHg mmHg mmHg mmHg
40 mmHg 40 mmHg
(75%) 40 mmHg (75%) 40 mmHg
(75%) (75%)
45 mmHg 99 mmHg 200 mmHg 650 mmHg
(79%) (100%) (100%)
(100%)
58 mmHg 350 mmHg

(89.5%) (100%)
FIGURE 279-5 Influence of air versus oxygen breathing on mixed arterial oxygenation in shunt and ventilation/perfusion heterogeneity. Partial pressure of oxygen
(mmHg) and oxygen. . saturations are shown for mixed venous blood, for end capillary blood (normal vs affected alveoli), and for mixed arterial blood. Fio2, fraction of
inspired oxygen; V/Q, ventilation/perfusion.
Restriction due to Restriction due to Restriction due to Obstruction Obstruction due to

increased lung chest wall respiratory muscle due to airway decreased
elastic recoil abnormality weakness narrowing elastic recoil
(pulmonary (moderate (myasthenia (acute (severe
fibrosis) obesity) gravis) asthma) emphysema)
TLC 60% 95% 75% 100% 130%

FRC 60% 65% 100% 104% 220%
RV 60% 100% 120% 120% 310%
FVC 60% 92% 60% 90% 60%
35% pre-b.d. 35% pre-b.d.
FEV1 75% 92% 60%
75% post-b.d. 38% post-b.d.
Raw 1.0 1.0 1.0 2.5 1.5
DLCO 60% 95% 80% 120% 40%

Flow
Flow
Flow
Flow
Flow
Volume Volume Volume Volume Volume
FIGURE 279-6 Common abnormalities of pulmonary function (see text). Pulmonary function values are expressed as a percentage of normal predicted values, except
for Raw, which is expressed as cmH2O/L/s (normal, <2 cmH2O/L/s). The figures at the bottom of each column show the typical configuration of flow-volume loops in
each condition, including the flow-volume relationship during tidal breathing. b.d., bronchodilator; Dlco, diffusion capacity of lung for carbon monoxide; FEV1, forced
expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced vital capacity; Raw, airways resistance; RV, residual volume; TLC, total lung capacity.

1950 Ventilatory Restriction due to Increased Elastic Recoil— elevated TLC is the hallmark. FRC is more severely elevated due to
Example: Idiopathic Pulmonary Fibrosis Idiopathic pulmo- both loss of lung elastic recoil and dynamic hyperinflation—the same
nary fibrosis raises lung recoil at all lung volumes, thereby lowering phenomenon as auto-PEEP (auto–positive end-expiratory pressure),
TLC, FRC, and RV as well as forced vital capacity (FVC). Maximal which is the positive end-expiratory alveolar pressure that occurs
expiratory flows are also reduced from normal values but are elevated when a new breath is initiated before the lung volume is allowed to
when considered in relation to lung volumes. Increased flow occurs return to FRC. RV is very severely elevated because of airway closure
both because the increased lung recoil drives greater maximal flow at and because exhalation toward RV may take so long that RV cannot be
any lung volume and because airway diameters are relatively increased reached before the patient must inhale again. Both FVC and FEV1 are
due to greater radially outward traction exerted on bronchi by the stiff markedly decreased, the former because of the severe elevation of RV
lung parenchyma. For the same reason, airway resistance is also nor- and the latter because loss of lung elastic recoil reduces the pressure
mal. Destruction of the pulmonary capillaries by the fibrotic process driving maximal expiratory flow and also reduces tethering open of
results in a marked reduction in diffusing capacity (see below). Oxy- small intrapulmonary airways. The flow-volume loop demonstrates
PART 7
genation is often severely reduced by persistent perfusion of alveolar marked scooping, with an initial transient spike of flow attributable
units that are relatively underventilated due to fibrosis of nearby (and largely to expulsion of air from collapsing central airways at the onset
mechanically linked) lung. The flow-volume loop (see below) looks of forced exhalation. Otherwise, the central airways remain relatively
like a miniature version of a normal loop but is shifted toward lower unaffected, so Raw is normal in “pure” emphysema. Loss of alveolar
absolute lung volumes and displays maximal expiratory flows that are surface and capillaries in the alveolar walls reduces DlCO; however,
increased for any given volume over the normal tracing. because poorly ventilated emphysematous acini are also poorly per-
fused (due to loss of their capillaries), arterial hypoxemia usually is not
Ventilatory Restriction due to Chest Wall Abnormality— seen at rest until emphysema becomes very severe. However, during
Example: Moderate Obesity As the size of the average American exercise, Pao may fall precipitously if extensive destruction of the
2
continues to increase, this pattern may become the most common of pulmonary vasculature prevents a sufficient increase in cardiac output
pulmonary function abnormalities. In moderate obesity, the outward and mixed venous oxygen content falls substantially. . . Under these
recoil of the chest wall is blunted by the weight of chest wall fat and circumstances, any venous admixture through low V/Q units has a
the space occupied by intra-abdominal fat. In this situation, preserved particularly marked effect in lowering mixed arterial oxygen tension.
inward recoil of the lung overbalances the reduced outward recoil of
the chest wall, and FRC falls. Because respiratory muscle strength and
lung recoil remain normal, TLC is typically unchanged (although it
■■FUNCTIONAL MEASUREMENTS
may fall in massive obesity) and RV is normal (but may be reduced Measurement of Ventilatory Function • LUNG VOLUMES
in massive obesity). Mild hypoxemia may be present due to perfusion Figure 279-2 demonstrates a spirometry tracing in which the volume
of alveolar units that are poorly ventilated because of airway closure of air entering or exiting the lung is plotted over time. In a slow
in dependent portions of the lung during breathing near the reduced vital capacity maneuver, the patient inhales from FRC, fully inflating
FRC. Flows remain normal, as does the diffusion capacity of the lung the lungs to TLC, and then exhales slowly to RV; VC, the difference
for carbon monoxide (DlCO), unless obstructive sleep apnea (which between TLC and RV, represents the maximal excursion of the respi-
often accompanies obesity) and associated chronic intermittent hypox- ratory system. Spirometry discloses relative volume changes during
emia have induced pulmonary arterial hypertension, in which case these maneuvers but cannot reveal the absolute volumes at which
DlCO may be low. they occur. To determine absolute lung volumes, two approaches are
commonly used: inert gas dilution and body plethysmography. In the
Ventilatory Restriction due to Reduced Muscle Strength— former, a known amount of a nonabsorbable inert gas (usually helium
Example: Myasthenia Gravis In this circumstance, FRC or neon) is inhaled in a single large breath or is rebreathed from a
remains normal, as both lung recoil and passive chest wall recoil are closed circuit; the inert gas is diluted by the gas resident in the lung at
normal. However, TLC is low and RV is elevated because respiratory the time of inhalation, and its final concentration reveals the volume of
muscle strength is insufficient to push the passive respiratory system resident gas contributing to the dilution. A drawback of this method
fully toward either volume extreme. Caught between the low TLC and is that regions of the lung that ventilate poorly (e.g., due to airflow
the elevated RV, FVC, and FEV1 are reduced as “innocent bystanders.” obstruction) may not receive much inspired inert gas and so do not
As airway size and lung vasculature are unaffected, both Raw and DlCO contribute to its dilution. Therefore, inert gas dilution (especially in the
are normal. Oxygenation is normal unless weakness becomes so severe single-breath method) often underestimates true lung volumes.
that the patient has insufficient strength to reopen collapsed alveoli In the second approach, FRC is determined by measuring the com-
during sighs, with resulting atelectasis. pressibility of gas within the chest, which is proportional to the volume
Airflow Obstruction due to Decreased Airway Diameter— of gas being compressed. The patient sits in a body plethysmograph (a
Example: Acute Asthma During an episode of acute asthma, chamber usually made of transparent plastic to minimize claustropho-
luminal narrowing due to smooth muscle constriction as well as bia) and, at the end of a normal tidal breath (i.e., when lung volume
inflammation and thickening within the small- and medium-sized is at FRC), is instructed to pant against a closed shutter, thus period-
bronchi raise frictional resistance and reduce airflow. “Scooping” of the ically compressing air within the lung slightly. Pressure fluctuations
flow-volume loop is caused by reduction of airflow, especially at lower at the mouth and volume fluctuations within the body box (equal but
lung volumes. Often, airflow obstruction can be reversed by inhalation opposite to those in the chest) are determined, and from these mea-
of β2-adrenergic agonists acutely or by treatment with inhaled steroids surements, the thoracic gas volume is calculated by means of Boyle’s
chronically. TLC usually remains normal (although elevated TLC is law. Once FRC is obtained, TLC and RV are calculated by adding the
sometimes seen in long-standing asthma), but FRC may be dynami- value for inspiratory capacity and subtracting the value for expiratory
cally elevated. RV is often increased due to exaggerated airway closure reserve volume, respectively (both values having been obtained during
at low lung volumes, and this elevation of RV reduces FVC. Because spirometry) (Fig. 279-2). The most important determinants of healthy
central airways are narrowed, Raw is usually elevated. Mild arterial individuals’ lung volumes are height, age, and sex, but there is consid-
hypoxemia is often present due to perfusion of relatively underventi- erable additional normal variation beyond that accounted for by these
lated alveoli distal to obstructed airways (and is responsive to oxygen parameters. In addition, race influences lung volumes; on average, TLC
supplementation), but DlCO is normal or mildly elevated. values are ~12% lower in African Americans and 6% lower in Asian
Americans than in Caucasian Americans. In practice, a mean “normal”
Airflow Obstruction due to Decreased Elastic Recoil— value is predicted by multivariate regression equations using height,
Example: Severe Emphysema Loss of lung elastic recoil in age, and sex, and the patient’s value is divided by the predicted value
severe emphysema results in pulmonary hyperinflation, of which (often with “race correction” applied) to determine “percent predicted.”

For most measures of lung function, 85–115% of the predicted value can hypertension), or reduce alveolar capillary hemoglobin (e.g., anemia). 1951
be normal; however, in health, the various lung volumes tend to scale Single-breath diffusing capacity may be elevated in acute congestive
together. For example, if one is “normal big” with a TLC 110% of the heart failure, asthma, polycythemia, and pulmonary hemorrhage.
predicted value, all other lung volumes and spirometry values will also
approximate 110% of their respective predicted values. This pattern is
Arterial Blood Gases The effectiveness of gas exchange can be
assessed by measuring the partial pressures of oxygen and CO2 in a
particularly helpful in evaluating airflow, as discussed below.
sample of blood obtained by arterial puncture. The oxygen content
AIR FLOW As noted above, spirometry plays a key role in lung vol- of blood (Cao ) depends on arterial saturation (%O2Sat), which is set
ume determination. Even more often, spirometry is used to measure 2
by Pao , pH, and Paco according to the oxyhemoglobin dissociation
airflow, which reflects the dynamic properties of the lung. During an 2 2
curve. Cao can also be measured by oximetry (see below):
FVC maneuver, the patient inhales to TLC and then exhales rapidly 2
CHAPTER 280 Diagnostic Procedures in Respiratory Disease

and forcefully to RV; this method ensures that flow limitation has been Cao (mL/dL) = 1.39 (mL/dL) × [hemoglobin](g) × % O2 Sat +
2
achieved, so that the precise effort made has little influence on actual 0.003 (mL/dL/mmHg) × Pao (mmHg)
2
flow. The total amount of air exhaled is the FVC, and the amount of air If hemoglobin saturation alone needs to be determined, this task can
exhaled in the first second is the FEV1; the FEV1 is a flow rate, revealing be accomplished noninvasively with pulse oximetry.
volume change per time. Like lung volumes, an individual’s maximal
expiratory flows should be compared with predicted values based on Acknowledgment
height, age, and sex. While the FEV1/FVC ratio is typically reduced The authors wish to acknowledge the contributions of Drs. Steven E.
in airflow obstruction, this condition can also reduce FVC by raising Weinberger and Irene M. Rosen to this chapter in previous editions.
RV, sometimes rendering the FEV1/FVC ratio “artifactually normal”
with the erroneous implication that airflow obstruction is absent. To ■■FURTHER READING
circumvent this problem, it is useful to compare FEV1 as a fraction of its Bates JH: Systems physiology of the airways in health and obstructive
predicted value with TLC as a fraction of its predicted value. In health, pulmonary disease. Wiley Interdiscip Rev Sys Biol Med 8:423, 2016.
the results are usually similar. In contrast, even an FEV1 value that is Hughes JM et al: Effect of lung volume on the distribution of pulmo-
95% of its predicted value may actually be relatively low if TLC is 110% nary blood flow in man. Respir Physiol 4:58, 1968.
of its respective predicted value. In this case, airflow obstruction may Levitsky MG et al: Pulmonary Physiology, 8th ed. New York,
be present, despite the “normal” value for FEV1. McGraw Hill, 2013; http://accessmedicine.mhmedical.com/book.aspx?
The relationships among volume, flow, and time during spirometry bookid=575. Accessed June 6, 2017.
are best displayed in two plots—the spirogram (volume vs time) and Macklem PT, Murphy BR: The forces applied to the lung in health and
the flow-volume loop (flow vs volume) (Fig. 279-4). In conditions disease. Am J Med 57:371, 1974.
that cause airflow obstruction, the site of obstruction is sometimes Pederson OF, Ingram RH: Configuration of maximal expiratory
correlated with the shape of the flow-volume loop. In diseases that flow-volume curve: Model experiments with physiologic implica-
cause lower airway obstruction, such as asthma and emphysema, tions. J Appl Physiol 58:1305, 1985.
flows decrease more rapidly with declining lung volumes, leading to Prange HD: Respiratory Physiology: Understanding Gas Exchange.
a characteristic scooping of the flow-volume loop. In contrast, fixed New York, Chapman and Hill, 1996.
upper-airway obstruction typically leads to inspiratory and/or expira- Weibel ER: Morphometric estimation of pulmonary diffusion capacity,
tory flow plateaus (Fig. 279-4). I. Model and method. Respir Physiol 11:54, 1970.
AIRWAYS RESISTANCE The total resistance of the pulmonary and upper
West JB: Respiratory Physiology, The Essentials, 9th ed. Philadelphia,
airways is measured in the same body plethysmograph used to mea- Lippincott Williams & Wilkins, 2012.
sure FRC. The patient is asked once again to pant, but this time against Wiley Online Library: Comprehensive Physiology: The Respi-
a closed and then opened shutter. Panting against the closed shutter ratory System. Available from http://www.comprehensivephysiology
reveals the thoracic gas volume as described above. When the shutter is .com/WileyCDA/Section/id-420557.html. Accessed August 12, 2016.
opened, flow is directed to and from the body box, so that volume fluc-
tuations in the box reveal the extent of thoracic gas compression, which
280 Diagnostic
in turn reveals the pressure fluctuations driving flow. Simultaneous
measurement of flow allows the calculation of lung resistance (as flow Procedures in
divided by pressure). In health, Raw is very low (<2 cmH2O/L/s), and
half of the detected resistance resides within the upper airway. In the
Respiratory Disease
lung, most resistance originates in the central airways. For this reason, Anne L. Fuhlbrigge, Augustine M.K. Choi
airways resistance measurement tends to be insensitive to peripheral
airflow obstruction.
RESPIRATORY MUSCLE STRENGTH To measure respiratory muscle The diagnostic modalities available for assessing the patient with
strength, the patient is instructed to exhale or inhale with maximal suspected or known respiratory system disease include imaging stud-
effort against a closed shutter while pressure is monitored at the ies and techniques for acquiring biologic specimens, some of which
mouth. Pressures >±60 cmH2O at FRC are considered adequate and involve direct visualization of part of the respiratory system. Methods
make it unlikely that respiratory muscle weakness accounts for any to characterize the functional changes developing as a result of dis-
other resting ventilatory dysfunction that is identified. ease, including pulmonary function tests and measurements of gas
exchange, are discussed in Chap. 279.
Measurement of Gas Exchange • DIFFUSING CAPACITY (DlCO)
This test uses a small (and safe) amount of carbon monoxide (CO) IMAGING STUDIES
to measure gas exchange across the alveolar membrane during a
10-s breath hold. CO in exhaled breath is analyzed to determine the ■■ROUTINE RADIOGRAPHY
quantity of CO crossing the alveolar membrane and combining with Routine chest radiography, including both posteroanterior (PA) and
hemoglobin in red blood cells. This “single-breath diffusing capacity” lateral views, is an integral part of the diagnostic evaluation of diseases
(Dlco), value increases with the surface area available for diffusion and involving the pulmonary parenchyma, the pleura, and, to a lesser
the amount of hemoglobin within the capillaries, and it varies inversely extent, the airways and the mediastinum (see Chaps. 278 and A12).
with alveolar membrane thickness. Thus, Dlco decreases in diseases Lateral decubitus views are useful for determining whether pleural
that thicken or destroy alveolar membranes (e.g., pulmonary fibrosis, abnormalities represent freely flowing fluid, whereas apical lordotic
emphysema), curtail the pulmonary vasculature (e.g., pulmonary views can visualize disease at the lung apices better than the standard

1952 PA view. Portable equipment is often used for acutely ill patients who
cannot be transported to a radiology suite but are more difficult to
interpret owing to several limitations: (1) the single anteroposterior
(AP) projection obtained; (2) variability in over- and underexposure
of film; (3) a shorter focal spot-film distance leading to lack of edge
sharpness and loss of fine detail; and (4) magnification of the cardiac
silhouette and other anterior structures by the AP projection. Common
radiographic patterns and their clinical correlates are reviewed in
Chap. A12.
Advances in computer technology have allowed the development
of digital or computed radiography, which has several benefits:
(1) immediate availability of the images; (2) significant postprocessing
PART 7
analysis of images to improve diagnostic information; and (3) ability

to store images electronically and to transfer them within or between
health care systems.
■■ULTRASOUND
Diagnostic ultrasound (US) produces images using echoes or reflection

of the US beam from interfaces between tissues with differing acoustic
properties. US is nonionizing and safe to perform on pregnant patients
and children. It can detect and localize pleural abnormalities, guide
percutaneous needle biopsy of peripheral lung, pleural, or chest wall
lesions and identify septations within loculated pleural collections (i.e.,
for thoracentesis), improving the yield and safety of the procedure.
Real-time imaging can be used to assess the movement of the dia-
phragm and can demonstrate changes in clinical condition. Availability A
of portable machines has allowed point of care (POC) ultrasound
to provide rapid and accurate bedside diagnosis and monitoring of
several common respiratory conditions, including pneumothorax, and
pleural effusions. In experienced hands, POC ultrasound has higher
sensitivity and specificity than chest radiography in detecting pleural
effusions and pneumothorax, with an accuracy approaching computed
tomography (CT). Pulmonary congestion may be quantified using
lung US monitoring pulmonary congestion in heart failure patients in
response to therapy.
■■NUCLEAR MEDICINE TECHNIQUES

Nuclear imaging depends on the selective uptake of various com-
pounds by organs of the body. In thoracic imaging, these compounds
are concentrated by one of three mechanisms: blood pool or compart-
mentalization (e.g., within the heart), physiologic incorporation (e.g.,
bone or thyroid) and capillary blockage (e.g., lung scan). Radioactive
isotopes can be administered by either the IV or inhaled routes or
both. When injected intravenously, albumin macroaggregates labeled
with technetium-99m (99mTc) become lodged in pulmonary capillaries;
the distribution of the trapped radioisotope follows the distribution
of blood flow. When inhaled, radiolabeled xenon gas can be used to
demonstrate the distribution of ventilation. Using these techniques,
ventilation-perfusion lung scanning was a commonly used technique
for the evaluation of pulmonary embolism. Pulmonary thromboembo-
lism produces one or more regions of ventilation-perfusion mismatch
(i.e., regions in which there is a defect in perfusion that follows the B
distribution of a vessel and that is not accompanied by a correspond-
FIGURE 280-1 Chest x-ray (A) and computed tomography (CT) scan (B) from a
ing defect in ventilation [Chap. 273]). However, with advances in patient with emphysema. The extent and distribution of emphysema are not well
CT scanning, scintigraphic imaging has been largely replaced by CT appreciated on plain film but clearly evident on the CT scan obtained.
angiography in patients with suspected pulmonary embolism.
Another common use of ventilation-perfusion scans is in patients
with impaired lung function, who are being considered for lung
plain radiographs. Second, CT is far better than routine radiographic
resection. Many patients with bronchogenic carcinoma have coexisting
studies at characterizing tissue density and providing accurate size
chronic obstructive pulmonary disease (COPD), and the question arises
assessment of lesions.
as to whether or not a patient can tolerate lung resection. The distribu-
CT is particularly valuable in assessing hilar and mediastinal disease
tion of the isotope(s) can be used to assess the regional distribution of
(often poorly characterized by plain radiography), in identifying and
blood flow and ventilation, allowing the physician to estimate the level
characterizing disease adjacent to the chest wall or spine (including
of postoperative lung function.
pleural disease), and in identifying areas of fat density or calcification
in pulmonary nodules (Fig. 280-2). Its utility in the assessment of medi-
■■COMPUTED TOMOGRAPHY astinal disease has made CT an important tool in the staging of lung
CT offers several advantages over routine chest radiography cancer (Chap. 74). With the additional use of contrast material, CT also
(Figs. 280-1A, B and 280-2A, B). First, the use of cross-sectional images makes it possible to distinguish vascular from nonvascular structures,
allows distinction between densities that would be superimposed on which is particularly important in distinguishing lymph nodes and

Data from the imaging procedure can be reconstructed in coronal or 1953
sagittal planes (Fig. 280-3A), as well as the traditional cross-sectional
(axial) view.
Further refinements in detector technology have allowed production
of scanners with additional detectors along the scanning axis (z-axis).
These multidetector CT (MDCT) scanners can obtain multiple slices in a
single rotation that are thinner and can be acquired in a shorter period
of time. This results in enhanced resolution and increased image recon-
struction ability. As the technology has progressed, higher numbers
(currently up to 64) of detectors allow submillimeter spatial resolution

A
B
FIGURE 280-2 Chest x-ray (A) and computed tomography (CT) scan
(B) demonstrating a right lower-lobe mass. The mass is not well appreciated
on the plain film because of the hilar structures and known calcified adenopathy.
CT is superior to plain radiography for the detection of abnormal mediastinal
densities and the distinction of masses from adjacent vascular structures.
masses from vascular structures primarily in the mediastinum, and

vascular disorders such as pulmonary embolism.
B
Helical CT and Multidetector CT Helical scanning is currently
the standard method for thoracic CT. Helical CT technology results in FIGURE 280-3 Spiral computed tomography (CT) with reconstruction of images
in planes other than axial view. Spiral CT in a lung transplant patient with a
faster scans with improved contrast enhancement and thinner colli-
dehiscence and subsequent aneurysm of the anastomosis. CT images were
mation. Images are obtained during a single breath-holding maneuver reconstructed in the sagittal view (A) and using digital subtraction to view images
that allows less motion artifact and collection of continuous data of the airways only (B), which demonstrate the exact location and extent of the
over a larger volume of lung than is possible with conventional CT. abnormality.

1954 to produce clearer final images, allowing this technique to essentially Virtual bronchoscopy has been proposed as an adjunct to conven-
replace high-resolution CT (HRCT) in the evaluation of lung disease. tional bronchoscopy in several clinical situations: It can allow accurate
The pattern of usual interstitial pneumonia (UIP) seen on MDCT assessment of the extent and length of an airway stenosis, including
(peripheral, basilar predominant honeycomb structure, and traction the airway distal to the narrowing; it can provide useful information
bronchiectasis), together with typical clinical presentation, and other about the relationship of the airway abnormality to adjacent medias-
causes are ruled out, the diagnosis of idiopathic pulmonary fibrosis (IPF) tinal structures; and it allows preprocedure planning for therapeutic
can be reliably diagnosed without histological confirmation. MDCT bronchoscopy to help ensure the appropriate equipment is available
allows for even shorter breath holds, which are beneficial for all patients for the procedure.
but especially children, the elderly, and the critically ill. It should be Electromagnetic navigational bronchoscopy systems (EMN or ENB),
noted that despite the advantages of MDCT, there is an increase in using virtual bronchoscopy, have been developed to allow accurate
radiation dose compared to single-detector CT to consider. However, navigation to peripheral pulmonary target lesions. Electromagnetic
using iterative reconstruction techniques, there is continued progress navigation bronchoscopy (ENB) uses technology similar to a car global
PART 7
in reducing the radiation dose reported for CT scans of the thorax. positioning system (GPS) unit, which allows precise tracking of both
Low dose MDCT is now a recommended screening procedure for lung position and orientation through the use of electromagnetic fields.
cancer among persons who are aged 55–80 years with 30 pack year
smoking history and currently smoke or quit within the past 15 years. ■■POSITRON EMISSION TOMOGRAPHIC SCANNING
In MDCT, the additional detectors along the z-axis result in Positron emission tomographic (PET) scanning involves injection of
improved use of the contrast bolus. This and the faster scanning a radiolabeled glucose analogue, [18F]-fluoro-2-deoxyglucose (FDG),
times and increased resolution have all led to improved imaging of which is taken up by metabolically active malignant cells. This tech-
the pulmonary vasculature and the ability to detect segmental and nique has been used in the evaluation of solitary pulmonary nodules
subsegmental emboli. CT pulmonary angiography (CTPA) also allows and in staging lung cancer. Detection or exclusion of mediastinal
simultaneous detection of parenchymal abnormalities that may be con- lymph node involvement and identification of extrathoracic disease
tributing to a patient’s clinical presentation. Secondary to these advan- can be achieved. The development of hybrid imaging allows the super-
tages and increasing availability, CTPA has rapidly become the test of imposition of PET and CT images, a technique known as functional–
choice for many clinicians in the evaluation of pulmonary embolism; anatomical mapping. Hybrid PET/CT scans provide images that help
compared with pulmonary angiography, it is considered equal in terms pinpoint the abnormal metabolic activity to anatomical structures seen
of accuracy and with less associated risks. A further development is on CT and provide more accurate diagnoses than the two scans per-
the dual-source CT (DSCT), which uses two x-ray tubes and their cor- formed separately. FDG-PET can differentiate benign from malignant
responding detectors offset by 90°. These scanners can emphasize par- lesions as small as 1 cm and can be very useful in detection of distant
ticular tissue characteristics and combine functional and morphological metastases. However, false-negative findings can occur in lesions with
information, which may allow better detection of perfusion defects in low metabolic activity such as carcinoid tumors and bronchioloalveolar
the lung parenchyma. In addition, the newer generation DSCT systems cell carcinomas, or in lesions <1 cm in which the required threshold of
allow high resolution scans of the thorax to be performed in <1 s, of metabolically active malignant cells is not present for PET diagnosis.
particular interest for dyspneic patients who are unable to comply with False-positive results can be seen due to FDG uptake in inflammatory
breath hold instructions. conditions such as pneumonia and granulomatous diseases.
■■VIRTUAL BRONCHOSCOPY ■■MAGNETIC RESONANCE IMAGING

The three-dimensional (3D) image of the thorax obtained by MDCT can Magnetic resonance (MR) provides poorer spatial resolution and
be digitally stored, reanalyzed, and displayed as 3D reconstructions less detail of the pulmonary parenchyma and, for these reasons, is
of the airways down to the sixth to seventh generation. Using these not currently considered a substitute for CT in imaging the thorax.
reconstructions, a “virtual” bronchoscopy can be performed (Fig. 280-4). However, because of the high soft tissue contract available with MRI,
this technology may be used to distinguish tumor from post-stenotic
atelectasis and assess infiltration of the chest wall and/or mediasti-
num. In addition, for superior sulcus tumors, MRI can be valuable in
preoperative planning to better visualize if/where the tumor is in con-
tact with the spine. Further, “diffusion-weighted” MRI is an emerging
technique that has been used to differentiate metastatic lymph nodes
from healthy lymph nodes with sensitivity, specificity, and positive
predictive values higher than PET/CT or CT alone. Finally, the use of
hyperpolarized gas in conjunction with MR has led to the investiga-
tional use of MR for imaging the lungs, particularly in obstructive lung
disease. Imaging performed during an inhalation and exhalation can
provide dynamic information on lung function.
An advantage of MR is the use of nonionizing electromagnetic
radiation. Additionally, MR is well suited to distinguish vascular from
nonvascular structures without the need for contrast. Blood vessels
appear as hollow tubular structures because flowing blood does not
produce a signal on MRI. Therefore, MR can be useful in demonstrat-
ing pulmonary emboli, defining aortic lesions such as aneurysms or
dissection, or other vascular abnormalities (Fig. 280-5) if radiation
and IV contrast medium cannot be used. Gadolinium can be used as
an intravascular contrast agent for MR angiography (MRA); however,
synchronization of data acquisition with the peak arterial bolus is one
of the major challenges of MRA. The flow of contrast medium from the
peripheral injection site to the vessel of interest is affected by a num-
ber of factors including heart rate, stroke volume, and the presence of
FIGURE 280-4 Virtual bronchoscopic image of the trachea. The view projected is proximal stenotic lesions.
one that would be obtained from the trachea looking down to the carina. The left Disadvantages of MRI include less spatial resolution and longer
and right main stem airways are seen bifurcating from the carina. study acquisition times compared with CT. MR examinations are

■■COLLECTION OF SPUTUM 1955
Sputum can be collected either by spontaneous expectoration or
induced (after inhalation of an irritating aerosol such as hypertonic
saline). Sputum induction is used either because sputum is not spon-
taneously being produced or because of an expected higher yield of
certain types of findings. Because sputum consists mainly of secretions
from the tracheobronchial tree rather than the upper airway, the find-
ing of alveolar macrophages and other inflammatory cells is consis-
tent with a lower respiratory tract origin of the sample, whereas the
presence of squamous epithelial cells in a “sputum” sample indicates
contamination by secretions from the upper airways.

In addition to processing for routine bacterial pathogens by Gram’s
method and culture, sputum can be processed for a variety of other
pathogens, including staining and culture for mycobacteria or fungi,
culture for viruses, and staining for Pneumocystis jiroveci. In the specific
case of sputum obtained for evaluation of P. jiroveci pneumonia, for
example, sputum should be collected by induction rather than sponta-
neous expectoration, and an immunofluorescent stain should be used
to detect the organisms. Traditional stains and cultures are now also
being supplemented in some cases by immunologic techniques and
by molecular biologic methods, including the use of polymerase chain
reaction (PCR) amplification and DNA probes. Cytologic staining of
sputum for malignant cells, using the traditional Papanicolaou method,
allows noninvasive evaluation for suspected lung cancer.
FIGURE 280-5 Magnetic resonance angiography image of the vasculature of a
patient after lung transplant. The image demonstrates the detailed view of the ■■PERCUTANEOUS NEEDLE ASPIRATION
vasculature that can be obtained using digital subtraction techniques. Images from (TRANSTHORACIC)
a patient after lung transplant show the venous and arterial anastomosis on the A needle can be inserted through the chest wall into a pulmonary
right; a slight narrowing is seen at the site of the anastomosis, which is considered lesion to obtain an aspirate or tissue core for cytologic/histologic or
within normal limits and not suggestive of obstruction.
microbiologic analysis. Aspiration can be performed to obtain a diag-
nosis or to decompress and/or drain a fluid collection. The procedure
difficult to obtain among patients who cannot lie still or who cannot lay is usually carried out under CT or US guidance to assist positioning of
on their backs. MRI is generally avoided in unstable and/or ventilated the needle and assure localization in the lesion. The low potential risk
patients and those with severe trauma because of the hazards of the of this procedure (intrapulmonary bleeding or creation of a pneumot-
MR environment and the difficulties in monitoring patients within the horax with collapse of the underlying lung) in experienced hands is
MR room. The presence of metallic foreign bodies, pacemakers, and usually acceptable compared with the information obtained. However,
intracranial aneurysm clips also preclude use of MRI. a limitation of the technique is sampling error due to the small size
of the tissue sample. Thus, findings other than a specific cytologic or
■■PULMONARY ANGIOGRAPHY
microbiologic diagnosis are of limited clinical value.
The pulmonary arterial system can be visualized by pulmonary angi-
ography, in which radiopaque contrast medium is injected through ■■THORACENTESIS
a catheter placed in the pulmonary artery. When performed in cases Sampling of pleural liquid by thoracentesis is commonly performed
of pulmonary embolism, pulmonary angiography demonstrates the for diagnostic purposes or, in the case of a large effusion, for palliation
consequences of an intravascular thrombus—either a defect in the of dyspnea. Diagnostic sampling, either by blind needle aspiration or
lumen of a vessel (a filling defect) or an abrupt termination (cutoff) of after localization by US, allows the collection of liquid for microbio-
the vessel. Other, less common indications for pulmonary angiography logic and cytologic studies. Analysis of the fluid obtained for its cellular
include visualization of a suspected pulmonary arteriovenous malfor- composition and chemical constituents allows classification of the effu-
mation and assessment of pulmonary arterial invasion by a neoplasm. sion and can help with diagnosis and treatment (Chap. 288).
The risks associated with modern arteriography are small, generally
of greatest concern in patients with severe pulmonary hypertension ■■BRONCHOSCOPY
or chronic kidney disease. With advances in CT scanning, MDCT Bronchoscopy is the process of direct visualization of the tracheo-
angiography (MDCTA) is replacing conventional angiography for the bronchial tree. Although bronchoscopy is now performed almost
diagnosis of pulmonary embolism. exclusively with flexible fiberoptic instruments, rigid bronchoscopy,
generally performed in an operating room on a patient under general
MEDICAL TECHNIQUES FOR OBTAINING anesthesia, still has a role in selected circumstances, primarily because
BIOLOGIC SPECIMENS of a larger suction channel and the fact that the patient can be venti-
lated through the bronchoscope channel. These situations include the
■■COLLECTION OF BLOOD AND SERUM retrieval of a foreign body and the suctioning of a massive hemor-
Testing of blood and/or serum can be useful in situations where respi- rhage, for which the small suction channel of the bronchoscope may
ratory diseases are secondary to systemic illness. Collagen vascular be insufficient.
disease is a frequent cause of diffuse interstitial lung disease (DILD) and
serologic tests for autoantibodies may be helpful in determining if an ■■FLEXIBLE FIBEROPTIC BRONCHOSCOPY
autoimmune disorder is affecting the lungs. In addition, blood tests for This outpatient procedure is usually performed in an awake but
inherited respiratory diseases are available. In patients presenting with sedated patient (conscious sedation). The bronchoscope is passed
COPD, a low level of α1-antitrypsin (α1AT) confirms α1AT deficiency and through either the mouth or the nose, between the vocal cords, and
further assessment with α1AT protein phenotyping and/or α1AT geno- into the trachea. The ability to flex the scope makes it possible to visu-
typing can be carried if needed. Beyond emphysema, next-generation alize virtually all airways to the level of subsegmental bronchi. The
sequencing has allowed development of respiratory gene panels that bronchoscopist is able to identify endobronchial pathology, including
identify genes implicated in several different lung syndromes includ- tumors, granulomas, bronchitis, foreign bodies, and sites of bleed-
ing cystic, fibrotic, and bronchiectatic diseases. ing. Samples from airway lesions can be taken by several methods,

1956 including washing, brushing, and biopsy. Washing involves instillation evaluating nodules that have a ground glass appearance on CT scan
of sterile saline through a channel of the bronchoscope and onto the and a high reliance on the bronchoscopist’s ability to navigate the
surface of a lesion. A portion of the liquid is collected by suctioning branching architecture of the airways to position the probe near the
through the bronchoscope, and the recovered material can be analyzed nodule.
for cells (cytology) or organisms (by standard stains and cultures).
Brushing or biopsy of the surface of the lesion, using a small brush or ■■EMERGING BRONCHOSCOPIC TECHNIQUES
biopsy forceps at the end of a long cable inserted through a channel Additional techniques that can be performed using bronchoscopy
of the bronchoscope, allows recovery of cellular material or tissue for include video/autofluorescence bronchoscopy (AFB), narrow band
analysis by standard cytologic and histopathologic methods. imaging (NBI), optical coherence tomography (OCT), and endomi-
The bronchoscope can be used to sample material not only from croscopy using confocal fluorescent laser microscopy (CFM). AFB
the regions that can be directly visualized (i.e., the airways), but also uses bronchoscopy with an additional light source to screen high-risk
from the more distal pulmonary parenchyma. With the bronchoscope individuals and identify premalignant lesions (airway dysplasia) and
PART 7
wedged into a subsegmental airway, aliquots of sterile saline can be carcinoma in situ. NBI capitalizes on the increased absorption of blue
instilled through the scope, allowing sampling of cells and organisms and green wavelengths of light by hemoglobin to enhance the visibility
from alveolar spaces. This procedure, called bronchoalveolar lavage of vessels of the mucosa and differentiate between inflammatory ver-
(BAL), has been particularly useful for the recovery of fluid for cul- sus malignant mucosal lesions. CFM uses a blue laser to induce fluo-
rescence, and its high degree of resolution provides a real-time view of
ture. In addition, immunofluorescent staining with antibodies and/or

nucleic acid analysis via PCR can facilitate more rapid diagnosis than living tissue at an almost histologic resolution. OCT uses near-infrared
culture techniques for some organisms. Cytology, cellular analysis, and light source and has spatial resolution advantages over CT and MRI. It
examination of acellular components such as cytokines, viral particles, can penetrate the airway wall up to three times deeper than CFM and is
and microbial signatures are commonly performed. less susceptible to motion artifacts from cardiac pulsation and respira-
Brushing and biopsy of the distal lung parenchyma can also be tory movements. However, careful assessment is required before these
performed with the same instruments that are used for endobronchial methods find a place in the evaluation strategy of early lung cancer and
sampling. These instruments can be passed through the scope into other lung diseases.
small airways. When biopsies are performed, the forceps penetrate
the airway wall, allowing biopsy of peribronchial alveolar tissue. This MEDICAL THORACOSCOPY
procedure, called transbronchial biopsy, is used when there is either rel- Medical thoracoscopy (or pleuroscopy) focuses on the diagnosis of
atively diffuse disease or a localized lesion of adequate size. With the pleural-based problems. The procedure is performed with a conven-
aid of fluoroscopic imaging, the bronchoscopist is able to determine not tional rigid or a semi-rigid pleuroscope (similar in design to a broncho-
only whether and when the instrument is in the area of abnormality, scope and enabling the operator to inspect the pleural surface, sample
but also the proximity of the instrument to the pleural surface. If the and/or drain pleural fluid, or perform targeted biopsies of the parietal
forceps are too close to the pleural surface, there is a risk of violating pleura). Medical thoracoscopy can be performed in the endoscopy suite
the visceral pleura and creating a pneumothorax; the other potential or operating room with the patient under conscious sedation and local
complication of transbronchial biopsy is pulmonary hemorrhage. The anesthesia. In contrast, video-assisted thoracoscopic surgery (VATS)
incidence of these complications is less than several percent. requires general anesthesia and is only performed in the operating
room. A common diagnostic indication for medical thoracoscopy is the
■■TRANSBRONCHIAL NEEDLE ASPIRATION evaluation of a pleural effusion or biopsy of presumed parietal pleural
Another procedure involves use of a hollow-bore needle passed carcinomatosis. It can also be used to place a chest tube under visual
through the bronchoscope for sampling of tissue adjacent to the tra- guidance, or perform chemical or talc pleurodesis, a therapeutic inter-
chea or a large bronchus. The needle is passed through the airway vention to prevent a recurrent pleural effusion (usually malignant) or
wall (transbronchial), and cellular material can be aspirated from mass recurrent pneumothorax.
lesions or enlarged lymph nodes, generally in a search for malignant The increasing availability of advanced bronchoscopic and pleu-
cells. Mediastinoscopy has been considered the gold standard for roscopic techniques has motivated the development of IP programs.
mediastinal staging; however, transbronchial needle aspiration (TBNA) IP can be defined as “the art and science of medicine as related to the
allows sampling from the lungs and surrounding lymph nodes without performance of diagnostic and invasive therapeutic procedures, that
the need for surgery or general anesthesia. which require additional training and expertise beyond that which
required in a standard pulmonary medicine training program.” IP phy-
■■ENDOBRONCHIAL ULTRASOUND (EBUS)– sicians provide alternatives to surgery for patients with a wide variety
TRANSBRONCHIAL NEEDLE ASPIRATION (TBNA) of thoracic disorders and problems, including therapeutic interventions
Further advances in needle aspiration techniques have been accom- (see further reading).
plished with the development of endobronchial ultrasound (EBUS).
The technology uses an ultrasonic bronchoscope fitted with a probe SURGICAL TECHNIQUES FOR OBTAINING
that allows for needle aspiration of mediastinal and hilar lymph nodes BIOLOGIC SPECIMENS
guided by real-time US images. EBUS allows sampling of mediastinal Evaluation and diagnosis of disorders of the chest commonly involve
lymph nodes and masses under direct vision to better identify and collaboration between pulmonologists and thoracic surgeons. Although
localize peribronchial and mediastinal pathology and offers access to procedures such as mediastinoscopy, VATS, and thoracotomy are
more difficult-to-reach areas and smaller lymph nodes in the staging of performed by thoracic surgeons, there is overlap in many minimally
malignancies. EBUS-TBNA has the potential to access the same paratra- invasive techniques that can be performed by a pulmonologist, an
cheal and subcarinal lymph node stations as mediastinoscopy, but also interventional pulmonologist, or a thoracic surgeon.
extends out to the hilar lymph nodes (levels 10 and 11).
Radial probe endobronchial ultrasound (RP-EBUS) produces a ■■MEDIASTINOSCOPY AND MEDIASTINOTOMY
360-degree ultrasound image of the surrounding lung parenchyma Proper staging of lung cancer is of paramount concern when determin-
and has significantly improved the bronchoscopic diagnostic yield for ing a treatment regimen. Although CT and PET scanning are useful
peripheral pulmonary nodules, particularly for larger lesions (>2 cm). for determining the size and nature of mediastinal lymph nodes as
RP-EBUS can be combined with ENB (described above), to provide part of the staging of lung cancer, tissue biopsy and histopathologic
accurate navigational assistance to localize peripheral nodules and examination are often critical for the diagnosis of mediastinal masses or
increase the diagnostic yield. enlarged mediastinal lymph nodes. The two major surgical procedures
RP-EBUS has a superior safety profile compared with transtho- used to obtain specimens from masses or nodes in the mediastinum are
racic approach, but limitations include a poor ultrasound signal for mediastinoscopy (via a suprasternal approach) and mediastinotomy

(via a parasternal approach). Both procedures are performed under ■■FURTHER READING 1957
general anesthesia by a qualified surgeon. In the case of suprasternal Bahmer T et al: The use of auto-antibody testing in the evaluation
mediastinoscopy, a rigid mediastinoscope is inserted at the supraster- of interstitial lung disease (ILD)—A practical approach for the pul-
nal notch and passed into the mediastinum along a pathway just ante- monologist. Respir Med 113:80, 2016.
rior to the trachea. Tissue can be obtained with biopsy forceps passed Flohr TG, Schmidt B: CT technology for imaging the thorax: State
through the scope, sampling masses or nodes that are in a paratracheal of the art, in Multidetector-Row CT of the Thorax, Medical Radiology,
or pretracheal position (levels 2R, 2L, 3, 4R, 4L). Aortopulmonary Schoepf UJ, Meinel FG (eds). Springer International Publishing, 2016,
lymph nodes (levels 5, 6) are not accessible by this route and thus are pp. 3–28.
commonly sampled by parasternal mediastinotomy (the Chamberlain Hirsch FR et al: New and emerging targeted treatments in advanced
procedure). This approach involves a parasternal incision and dissec- non-small-cell lung cancer. Lancet 388(10048):1012, 2016.
tion directly down to a mass or node that requires biopsy. Hoffman EA et al: For the IWPFI Investigators. Pulmonary CT and
CHAPTER 281 Asthma

As an alternative to surgery, a bronchoscope can be used to perform MRI phenotypes that help explain chronic pulmonary obstruction
TBNA to obtain tissue from the mediastinum, and, when combined disease pathophysiology and outcomes J Magn Reson Imaging
with EBUS, can allow access to the same lymph node stations asso- 43:544, 2016.
ciated with mediastinoscopy, but also extend access out to the hilar Irwin Z, Cook JO: Advances in point-of-care thoracic ultrasound.
lymph nodes (levels 10, 11). Finally, endoscopic ultrasound (EUS)– Emerg Med Clin North Am 34:151, 2016.
fine-needle aspiration (FNA) is a second procedure that complements Meyer KC et al: American Thoracic Society Committee on BAL in
EBUS-FNA in the staging of lung cancer. EUS-FNA is performed via Interstitial Lung Disease. An official American Thoracic Society clin-
the esophagus and is ideally suited for sampling lymph nodes in the ical practice guideline: The clinical utility of bronchoalveolar lavage
posterior mediastinum (levels 7, 8, 9). Because US imaging cannot pen- cellular analysis in interstitial lung disease. Am J Respir Crit Care
etrate air-filled spaces, the area directly anterior to the trachea cannot Med 185:1004, 2012.
accurately be assessed and is a “blind spot” for EUS-FNA. However, Mirsadraee S, van Beek EJ: Functional imaging: Computed tomogra-
EBUS-FNA can visualize the anterior lymph nodes and can comple- phy and MRI. Clin Chest Med 36:349, 2015.
ment EUS-FNA. The combination of EUS-FNA and EBUS-FNA with The National Lung Screening Trial Research Team: Reduced
the use of radial probes has made these techniques a clear nonoperative lung-cancer mortality with low-dose computed tomographic screen-
alternative for staging the mediastinum in thoracic malignancies. ing. N Engl J Med 365:395, 2011.
Walters DM, Wood DE: Operative endoscopy of the airway. J Thorac
■■VIDEO-ASSISTED THORACOSCOPIC SURGERY Dis 8(Suppl 2):S130, 2016.
VATS is the operative technique for the diagnosis and management
of pleural as well as parenchymal lung disease. This procedure is
performed in the operating room using single-lung ventilation with
double-lumen endotracheal intubation and involves the passage of a
rigid scope with a distal lens through a trocar inserted into the pleura.
A high-quality image is shown on a monitor screen, allowing the oper-
Section 2 Diseases of the Respiratory System
ator to manipulate instruments passed into the pleural space through
separate small intercostal incisions. With these instruments the opera-
tor can biopsy lesions of the pleura under direct visualization. In addi-
tion, this procedure is now used commonly to biopsy peripheral lung
tissue or to remove peripheral nodules for both diagnostic and thera-
281 Asthma Peter J. Barnes
peutic purposes. This much less invasive procedure has largely sup-
planted the traditional “open lung biopsy” performed via thoracotomy.
The decision to use medical thorascopy versus VATS technique is based Asthma is a syndrome characterized by airflow obstruction that varies
on the clinical scenario with input from the consulting pulmonary and markedly, both spontaneously and with treatment. Asthmatics harbor
thoracic surgery providers. If a surgical technique is preferred, the deci- a special type of inflammation in the airways that makes them more
sion to use a VATS technique versus performing an open thoracotomy responsive than nonasthmatics to a wide range of triggers, leading
is made by the thoracic surgeon and based on whether a patient can to excessive narrowing with consequent reduced airflow and symp-
tolerate the single-lung ventilation that is required to allow adequate tomatic wheezing and dyspnea. Narrowing of the airways is usually
visualization of the lung. With further advances in instrumentation reversible, but in some patients with chronic asthma there may be an
and experience, VATS can be used to perform procedures previously element of irreversible airflow obstruction. Asthma is a heterogeneous
requiring thoracotomy, including stapled lung biopsy, resection of disease with several phenotypes recognized, but thus far these do not
pulmonary nodules, lobectomy, pneumonectomy, pericardial window, correspond well to specific pathogenic mechanisms (endotypes) or
or other standard thoracic surgical procedures, but allows them to be responses to therapy. The increasing global prevalence of asthma, the
performed in a minimally invasive manner. large burden it now imposes on patients, and the high health care costs
■■THORACOTOMY have led to extensive research into its mechanisms and treatment.
Although frequently replaced by VATS, thoracotomy remains an
option for the diagnostic sampling of lung tissue. It provides the largest ■■PREVALENCE
amount of material, and it can be used to biopsy and/or excise lesions Asthma is one of the most common chronic diseases globally and
that are too deep or too close to vital structures for removal by VATS. currently affects ~300 million people worldwide, with ~250,000 deaths
The choice between VATS and thoracotomy needs to be made on a annually. The prevalence of asthma has risen in affluent countries over
case-by-case basis. the last 30 years but now appears to have stabilized, with ~10–12%
of adults and 15% of children affected by the disease. In developing
TECHNIQUES ON BIOLOGIC SPECIMENS countries where the prevalence of asthma had been much lower, there
Histopathologic examination of tissue samples and cytologic exami- is a rising prevalence, which is associated with increased urbanization.
nation of aspirates or fluid are critical components in the diagnosis The prevalence of atopy and other allergic diseases has also increased
of many respiratory disorders. In the area of lung cancer, improved over the same time, suggesting that the reasons for the increase are
understanding of molecular changes and genetic mutations that drive likely to be systemic rather than confined to the lungs. Most patients
cancer has allowed development of specific molecular tests that guide with asthma in affluent countries are atopic, with allergic sensitization
therapy (e.g., epidermal growth factor receptor [EGFR] mutations and to the house dust mite Dermatophagoides pteronyssinus and other envi-
anaplastic lymphoma kinase [ALK] fusions). ronmental allergens, such as animal fur and pollens.

1958 Asthma can present at any age, with a peak age of 3 years. In child- are usually proteins that have protease activity, and the most common
hood, twice as many males as females are asthmatic, but by adulthood allergens are derived from house dust mites, cat and dog fur, cock-
the sex ratio has equalized. Long-term studies that have followed chil- roaches (in inner cities), grass and tree pollens, and rodents (in labora-
dren until they reach the age of 40 years suggest that many with asthma tory workers). Atopy is due to the genetically determined production
become asymptomatic during adolescence but that asthma returns in of specific IgE antibody, with many patients showing a family history
some during adult life, particularly in those with persistent symptoms of allergic diseases.
and severe asthma. Adults with asthma, including those with onset
during adulthood, rarely become permanently asymptomatic. The Genetic Predisposition The familial association of asthma
severity of asthma does not vary significantly within a given patient; and a high degree of concordance for asthma in identical twins
those with mild asthma rarely progress to more severe disease, whereas indicate a genetic predisposition to the disease; however, whether
those with severe asthma usually have severe disease at the onset. or not the genes predisposing to asthma are similar or in addition to
Deaths from asthma are relatively uncommon, and in many affluent those predisposing to atopy is not yet clear. It now seems likely that
PART 7
countries have been steadily declining over the last decade. A rise different genes may also contribute to asthma specifically, and there is
in asthma mortality seen in several countries during the 1960s was increasing evidence that the severity of asthma is also genetically deter-
associated with increased use of short-acting inhaled β2-adrenergic mined. Genetic screens with classical linkage analysis and single-
agonists (as rescue therapy), but there is now compelling evidence that nucleotide polymorphisms of various candidate genes indicate that
asthma is polygenic, with each gene identified having a small effect
the more widespread use of inhaled corticosteroids (ICS) in patients

with persistent asthma is responsible for the decrease in mortality in that is often not replicated in different populations. This observation
recent years. Major risk factors for asthma deaths are poorly controlled suggests that the interaction of many genes is important, and these may
disease with frequent use of bronchodilator inhalers, lack of or poor differ in different populations. The most consistent findings have been
compliance with ICS therapy, and previous admissions to hospital with associations with polymorphisms of genes on chromosome 5q, includ-
near-fatal asthma. ing the T helper 2 (Th2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13,
It has proved difficult to agree on a definition of asthma, but there which are associated with atopy. There is increasing evidence for a
is good agreement on the description of the clinical syndrome and complex interaction between genetic polymorphisms and environmen-
disease pathology. Until the etiologic mechanisms of the disease are tal factors that will require very large population studies to unravel.
better understood, it will be difficult to provide an accurate definition. Novel genes that have been associated with asthma, including ADAM-33,
DPP-10, and ORMDL3, have also been identified by positional cloning,
■■RISK FACTORS AND TRIGGERS but their function in disease pathogenesis is not yet clear. Recent
Asthma is a heterogeneous disease with interplay between genetic and genome-wide association studies have identified further novel genes,
environmental factors. Several risk factors that predispose to asthma such as ORMDL3, although their functional role is not yet clear. Genetic
have been identified (Table 281-1). These should be distinguished from polymorphisms may also be important in determining the response to
triggers, which are environmental factors that worsen asthma in a asthma therapy. For example, the Arg-Gly-16 variant in the β2-receptor
patient with established asthma. has been associated with reduced response to β2-agonists, and repeats
of an Sp1 recognition sequence in the promoter region of 5-lipoxygen-
Atopy Atopy is the major risk factor for asthma, and non-atopic ase may affect the response to antileukotrienes. However, these effects
individuals have a very low risk of developing asthma. Patients with are small and inconsistent and do not yet have any implications for
asthma commonly suffer from other atopic diseases, particularly asthma therapy.
allergic rhinitis, which may be found in >80% of asthmatic patients, It is likely that environmental factors in early life determine which
and atopic dermatitis (eczema). Atopy may be found in 40–50% of atopic individuals become asthmatic. The increasing prevalence of
the population in affluent countries, but only a proportion of atopic asthma, particularly in developing countries, over the last few decades
individuals becoming asthmatic. This observation suggests that some also indicates the importance of environmental mechanisms interacting
other environmental or genetic factor(s) predispose to the development with a genetic predisposition.
of asthma in atopic individuals. The allergens that lead to sensitization
Epigenetic Mechanisms There is increasing evidence that
epigenetic mechanisms may be important, particularly in the early
TABLE 281-1 Risk Factors and Triggers Involved in Asthma development of asthma. DNA methylation and histone modification
ENDOGENOUS FACTORS ENVIRONMENTAL FACTORS patterns may be influenced by diet, cigarette smoke exposure, and
Genetic predisposition Indoor allergens air pollution, and may affect genes involved in the pathogenesis of
Atopy Outdoor allergens
asthma. These epigenetic changes may occur in the fetus as a result of
maternal environmental exposure.
Airway hyperresponsiveness Occupational sensitizers
Gender Passive smoking Infections Although viral infections (especially Rhinovirus) are
Ethnicity Respiratory infections common as triggers of asthma exacerbations, it is uncertain whether
Obesity Air pollution (diesel particulates, they play a role in etiology. There is some association between respira-
Early viral infections nitrogen oxides) tory syncytial virus infection in infancy and the development of asthma,
Diet but the specific pathogenesis is difficult to elucidate, as this infection
Dampness and mold exposure
is very common in children. Atypical bacteria, such as Mycoplasma
and Chlamydophila, have been implicated in the mechanism of severe
Acetaminophen (paracetamol)
asthma, but thus far, the evidence is not very convincing of a true
Triggers association. Living in damp houses with exposure to mold spores is
Allergens now recognized to be a risk factor, and removal of these factors may
Upper respiratory tract viral infections improve asthma.
Exercise and hyperventilation The observation that allergic sensitization and asthma were less
Cold air common in children with older siblings first suggested that lower levels
Sulfur dioxide and irritant gases of infection may be a factor in affluent societies that increase the risks of
Drugs (β-blockers, aspirin) asthma. This “hygiene hypothesis” proposes that lack of infections in
early childhood preserves the Th2 cell bias at birth, whereas exposure
Stress
to infections and endotoxin results in a shift toward a predominant pro-
Irritants (household sprays, paint
tective Th1 immune response. Children brought up on farms who are
fumes)
exposed to a high level of endotoxin are less likely to develop allergic

sensitization than children raised on dairy farms. Intestinal parasite about mechanism, but the immunopathology in bronchial biopsies and 1959
infection, such as hookworm, may also be associated with a reduced sputum appears to be identical to that found in atopic asthma. There
risk of asthma. While there is considerable epidemiologic support for is recent evidence for increased local production of IgE in the airways,
the hygiene hypothesis, it cannot account for the parallel increase in suggesting that there may be common IgE-mediated mechanisms;
Th1-driven diseases such as diabetes mellitus over the same period. staphylococcal enterotoxins, which serve as “superantigens,” have
been implicated. Type-2 innate lymphoid cells (ILC2) may drive the
Diet The role of dietary factors is controversial. Observational stud- eosinophilic inflammation in these non-allergic patients.
ies have shown that diets low in antioxidants such as vitamin C and
vitamin A, magnesium, selenium, and omega-3 polyunsaturated fats Asthma Triggers Several stimuli trigger airway narrowing,
(fish oil) or high in sodium and omega-6 polyunsaturates are associated wheezing, and dyspnea in asthmatic patients. While the previous view
with an increased risk of asthma. Vitamin D deficiency may also pre- held that these should be avoided, it is now seen as evidence for poor
CHAPTER 281 Asthma

dispose to the development of asthma. However, interventional studies control and an indicator of the need to increase controller (preventive)
with supplementary diets have not supported an important role for therapy.
these dietary factors. Obesity is also an independent risk factor for
asthma, particularly in women, but the mechanisms are not yet clear. ALLERGENS Inhaled allergens activate mast cells with bound IgE
directly leading to the immediate release of bronchoconstrictor media-
Air Pollution Air pollutants such as sulfur dioxide, ozone, and die- tors, resulting in the early response that is reversed by bronchodilators.
sel particulates may trigger asthma symptoms, but the role of different Often, an experimental allergen challenge is followed by a late response
air pollutants in the etiology of the disease is not yet clear. Asthma had when there is airway edema and an acute inflammatory response with
a much lower prevalence in East Germany compared to West Germany increased eosinophils and neutrophils that are not very reversible with
despite a much higher level of air pollution, but since reunification bronchodilators. The most common allergens to trigger asthma are
these differences have decreased as Eastern Germany has become more Dermatophagoides species, and environmental exposure leads to low-
affluent. There is increasing evidence that exposure to road traffic pol- grade chronic symptoms that are perennial. Other perennial allergens
lution is associated with increased asthma symptoms, with the main are derived from cats and other domestic pets, as well as cockroaches.
culprits being diesel particulates and nitrogen dioxide. Indoor air pol- Other allergens, including grass pollen, ragweed, tree pollen, and fun-
lution is also important with exposure to nitrogen oxides from cooking gal spores, are seasonal. Pollens usually cause allergic rhinitis rather
stoves and exposure to passive cigarette smoke. There is some evidence than asthma, but in thunderstorms the pollen grains are disrupted and
that maternal smoking is a risk factor for asthma, but it is difficult to dis- the particles that may be released can trigger severe asthma exacerba-
sociate this association from an increased risk of respiratory infections. tions (thunderstorm asthma).
Allergens Inhaled allergens are common triggers of asthma symp- VIRUS INFECTIONS Upper respiratory tract virus infections such as
toms and have also been implicated in allergic sensitization. Exposure rhinovirus, respiratory syncytial virus, and coronavirus are the most
to house dust mites in early childhood is a risk factor for allergic sen- common triggers of acute severe exacerbations and may invade epi-
sitization and asthma, but rigorous allergen avoidance has not shown thelial cells of the lower as well as the upper airways. The mechanism
any evidence for a reduced risk of developing asthma. The increase in whereby these viruses cause exacerbations is poorly understood, but
house dust mites in centrally heated poorly ventilated homes with fit- there is an increase in airway inflammation with increased numbers of
ted carpets has been implicated in the increasing prevalence of asthma eosinophils and neutrophils. There is evidence for reduced production
in affluent countries. Domestic pets, particularly cats, have also been of type I interferons by epithelial cells from asthmatic patients, result-
associated with allergic sensitization, but early exposure to cats in the ing in increased susceptibility to these viral infections and a greater
home may be protective through the induction of tolerance. inflammatory response.
Occupational Exposure Occupational asthma is relatively com- PHARMACOLOGIC AGENTS Several drugs may trigger asthma. Beta-
mon and may affect up to 10% of young adults. Over 300 sensitizing adrenergic blockers commonly acutely worsen asthma, and their use may
agents have been identified. Chemicals such as toluene diisocyanate be fatal. The mechanisms are not clear but are likely mediated through
and trimellitic anhydride, may lead to sensitization independent of increased cholinergic bronchoconstriction. All beta blockers need to be
atopy. Individuals may also be exposed to allergens in the workplace avoided and even selective β, β2 blockers, or topical application (e.g.,
such as small animal allergens in laboratory workers and fungal amy- timolol eye drops) may be dangerous. Angiotensin-converting enzyme
lase in wheat flour in bakers. Cleaners commonly develop occupational inhibitors are theoretically detrimental as they inhibit breakdown of
asthma owing to exposure to aerosols of cleaning liquids. Occupational kinins, which are bronchoconstrictors; however, they rarely worsen
asthma may be suspected when symptoms improve during weekends asthma, and the characteristic cough is no more frequent in asthmatics
and holidays. than in non-asthmatics. Aspirin may worsen asthma in some patients
(aspirin-sensitive asthma is discussed under “Special Considerations”).
Obesity Asthma occurs more frequently in obese people (BMI
>30 kg/m2) and is often more difficult to control. Although mechanical EXERCISE Exercise is a common trigger of asthma, particularly in
factors may contribute, it may also be linked to the pro-inflammatory children. The mechanism is linked to hyperventilation, which results
adipokines and reduced anti-inflammatory adipokines that are released in increased osmolality in airway lining fluid and triggers mast cell
from fat cells. mediator release, resulting in bronchoconstriction. Exercise-induced
asthma (EIA) typically begins after exercise has ended, and recovers
Other Factors Several other factors have been implicated in the spontaneously within about 30 min. EIA is worse in cold, dry climates
etiology of asthma, including lower maternal age, duration of breast- than in hot, humid conditions. It is, therefore, more common in sports
feeding, prematurity and low birthweight, and inactivity, but are such as cross-country running in cold weather, overland skiing, and ice
unlikely to contribute to the recent global increase in asthma preva- hockey than in swimming. It may be prevented by prior administration
lence. There is also an association with acetaminophen (paracetamol) of β2-agonists and antileukotrienes, but is best prevented by regular
consumption in childhood, which may be linked to increased oxidative treatment with ICS, which reduce the population of surface mast cells
stress. required for this response.
Intrinsic Asthma A minority of asthmatic patients (~10%) have PHYSICAL FACTORS Cold air and hyperventilation may trigger asthma
negative skin tests to common inhalant allergens and normal serum through the same mechanisms as exercise. Laughter may also be a
concentrations of IgE. These patients, with non-atopic or intrinsic trigger. Many patients report worsening of asthma in hot weather
asthma, usually show later onset of disease (adult-onset asthma), com- and when the weather changes. Some asthmatics become worse when
monly have concomitant nasal polyps, and may be aspirin-sensitive. exposed to strong smells or perfumes, but the mechanism of this
They usually have more severe, persistent asthma. Little is understood response is uncertain.

1960 FOOD AND DIET There is little evidence that allergic
reactions to food lead to increased asthma symptoms,
despite the belief of many patients that their symp-
toms are triggered by particular food constituents.
Exclusion diets are usually unsuccessful at reduc-
ing the frequency of episodes. Some foods such as
shellfish and nuts may induce anaphylactic reactions
that may include wheezing. Patients with aspirin-
induced asthma may benefit from a salicylate-free
diet, but these are difficult to maintain. Certain food
additives may trigger asthma. Metabisulfite, which
is used as a food preservative, may trigger asthma
PART 7
through the release of sulfur dioxide gas in the stom-

ach. Tartrazine, a yellow food-coloring agent, was
believed to be a trigger for asthma, but there is little
convincing evidence for this.
AIR POLLUTION Increased ambient levels of sul-

fur dioxide, ozone, diesel particulates and nitro- FIGURE 281-1 Histopathology of a small airway in fatal asthma. The lumen is occluded with a mucous
gen oxides are associated with increased asthma plug, there is goblet cell metaplasia, and the airway wall is thickened, with an increase in basement
symptoms. membrane thickness and airway smooth muscle. (Courtesy of Dr. J. Hogg, University of British Colombia.)
OCCUPATIONAL FACTORS Several substances found
in the workplace may act as sensitizing agents, as discussed above, but of the airway lumen by a mucous plug, which is comprised of mucous
may also act as triggers of asthma symptoms. Occupational asthma glycoproteins secreted from goblet cells and plasma proteins from
is characteristically associated with symptoms at work with relief on leaky bronchial vessels (Fig. 281-1). There is also vasodilation and
weekends and holidays. If removed from exposure within the first increased numbers of blood vessels (angiogenesis). Direct observation
6 months of symptoms, there is usually complete recovery. More per- by bronchoscopy indicates that the airways may be narrowed, ery-
sistent symptoms lead to irreversible airway changes, and, thus, early thematous, and edematous. The pathology of asthma is remarkably
detection and avoidance are important. uniform in different phenotypes of asthma, including atopic (extrinsic),
non-atopic (intrinsic), occupational, aspirin-sensitive, and pediatric
HORMONES Some women show premenstrual worsening of asthma,
asthma. These pathologic changes are found in all airways, but do
which can occasionally be very severe. The mechanisms are not
not extend to the lung parenchyma; peripheral airway inflammation
completely understood, but are related to a fall in progesterone and
is found particularly in patients with severe asthma. The involvement
in severe cases may be improved by treatment with high doses of
of airways may be patchy and this is consistent with bronchographic
progesterone or gonadotropin-releasing factors. Thyrotoxicosis and
findings of uneven narrowing of the airways.
hypothyroidism can both worsen asthma, although the mechanisms
are uncertain. Airway Inflammation There is inflammation in the respiratory
GASTROESOPHAGEAL REFLUX Gastroesophageal reflux is common in mucosa from the trachea to terminal bronchioles, but with a predom-
asthmatic patients as it is increased by bronchodilators. Although acid inance in the bronchi (cartilaginous airways), but it is still uncertain
reflux might trigger reflex bronchoconstriction, it rarely causes asthma how inflammatory cells interact and how inflammation translates into
symptoms, and antireflux therapy usually fails to reduce asthma symp- the symptoms of asthma (Fig. 281-2). There is good evidence that the
toms in most patients. specific pattern of airway inflammation in asthma is associated with
airway hyperresponsiveness (AHR), the physiologic abnormality of
STRESS Many asthmatics report worsening of symptoms with stress. asthma, which is correlated with variable airflow obstruction. The
Psychological factors can induce bronchoconstriction through cholinergic pattern of inflammation in asthma is characteristic of allergic diseases,
reflex pathways. Paradoxically, very severe stress such as bereavement with similar inflammatory cells seen in the nasal mucosa in rhinitis.
usually does not worsen, and may even improve, asthma symptoms. However, an indistinguishable pattern of inflammation is found
in intrinsic asthma, and this may reflect local rather than systemic
■■PATHOPHYSIOLOGY IgE production. Although most attention has focused on the acute
Asthma is associated with a specific chronic inflammation of the
mucosa of the lower airways. One of the main aims of treatment is to
reduce this inflammation.
Allergens
Sensitizers
Pathology The pathology of asthma has been revealed through Viruses
examining the lungs of patients who have died of asthma and from Air pollutants?
bronchial biopsies. The airway mucosa is infiltrated with activated
eosinophils and T lymphocytes, and there is activation of mucosal mast
cells. The degree of inflammation is poorly related to disease severity Inflammation Airway
and may even be found in atopic patients without asthma symptoms. Chronic eosinophilic hyperresponsiveness
bronchitis
This inflammation is usually reduced by treatment with ICS. There are
also structural changes in the airways (often termed remodeling). A
characteristic finding is thickening of the basement membrane due to
Symptoms Triggers
subepithelial collagen deposition. This feature is also found in patients Cough Allergens
with eosinophilic bronchitis presenting as cough who do not have Wheeze Exercise
asthma and is, therefore, likely to be a marker of eosinophilic inflam- Chest tightness Cold air
mation in the airway as eosinophils release fibrogenic mediators. The Dyspnea SO2
epithelium is often shed or friable, with reduced attachments to the Particulates
airway wall and increased numbers of epithelial cells in the lumen.
The airway wall itself may be thickened and edematous, particularly FIGURE 281-2 Inflammation in the airways of asthmatic patients leads to airway
in fatal asthma. Another common finding in fatal asthma is occlusion hyperresponsiveness and symptoms. SO2, sulfur dioxide.

inflammatory changes seen in asthma, this is a chronic condition, the release of a certain pattern of cytokines, but these cells also release 1961
with inflammation persisting over many years in most patients. The anti-inflammatory mediators (e.g., IL-10) and, thus, their roles in
mechanisms involved in persistence of inflammation in asthma are still asthma are uncertain. Dendritic cells are specialized macrophage-like
poorly understood. Superimposed on this chronic inflammatory state cells in the airway epithelium, which are the major antigen-presenting
are acute inflammatory episodes, which correspond to exacerbations cells. Dendritic cells take up allergens, process them to peptides, and
of asthma. Although the common pattern of inflammation in asthma migrate to local lymph nodes where they present the allergenic pep-
is characterized by eosinophil infiltration, some patients with severe tides to uncommitted T lymphocytes to program the production of
asthma show a neutrophilic pattern of inflammation that is less sensi- allergen-specific T cells. Immature dendritic cells in the respiratory tract
tive to corticosteroids. However, many inflammatory cells are involved promote Th2 cell differentiation and require cytokines such as IL-12 and
in asthma with no key cell that is predominant (Fig. 281-3). tumor necrosis factor α (TNF-α), to promote the normally preponder-
ant Th1 response. The cytokine thymic stromal lymphopoietin (TSLP)
CHAPTER 281 Asthma

MAST CELLS Mast cells are important in initiating the acute bronchocon-
strictor responses to allergens and several other indirectly acting stimuli, released from epithelial cells in asthmatic patients instructs dendritic
such as exercise and hyperventilation (via osmolality changes), as well cells to release chemokines that attract Th2 cells into the airways.
as fog. Activated mucosal mast cells are found at the airway surface in
EOSINOPHILS Eosinophil infiltration is a characteristic feature of
asthma patients and also in the airway smooth-muscle layer, whereas
asthmatic airways. Allergen inhalation results in a marked increase
this is not seen in normal subjects or patients with eosinophilic bron-
in activated eosinophils in the airways at the time of the late reaction.
chitis. Mast cells are activated by allergens through an IgE-dependent
Eosinophils are linked to the development of AHR through the release
mechanism, and binding of specific IgE to mast cells renders them more
of basic proteins and oxygen-derived free radicals. Eosinophil recruit-
sensitive to activation by physical stimuli such as osmolality. The impor-
ment involves adhesion of eosinophils to vascular endothelial cells in
tance of IgE in the pathophysiology of asthma has been highlighted by
the airway circulation due to interaction between adhesion molecules,
clinical studies with humanized anti-IgE antibodies, which inhibit IgE-
migration into the submucosa under the direction of chemokines, and
mediated effects, reduce asthma symptoms, and reduce exacerbations.
their subsequent activation and prolonged survival. Blocking antibod-
There are, however, uncertainties about the role of mast cells in more
ies to IL-5 causes a profound and prolonged reduction in circulating
chronic allergic inflammatory events. Mast cells release several bron-
and sputum eosinophils, but is not associated with reduced AHR or
choconstrictor mediators, including histamine, prostaglandin D2, and
asthma symptoms, although in selected patients with steroid-resistant
cysteinyl-leukotrienes, but also several cytokines, chemokines, growth
airway eosinophils, there is a reduction in exacerbations. Eosinophils
factors, and neurotrophins.
may be important in release of growth factors involved in airway
MACROPHAGES AND DENDRITIC CELLS Macrophages, which are derived remodeling and in exacerbations but probably not in AHR.
from blood monocytes, may traffic into the airways in asthma and may
be activated by allergens via low-affinity IgE receptors (FcεRII). Macro- NEUTROPHILS Increased numbers of activated neutrophils are found in
phages have the capacity to initiate a type of inflammatory response via sputum and airways of some patients with severe asthma and during
exacerbations, although there is a propor-
Allergen tion of patients even with mild or mod-
erate asthma who have a predominance
of neutrophils. The roles of neutrophils
in asthma that are resistant to the anti-
inflammatory effects of corticosteroids
are currently unknown.
Dendritic cell Mast cell
LYMPHOCYTES T lymphocytes play a
very important role in coordinating the
inflammatory response in asthma through
the release of specific patterns of cytok-
ines, resulting in the recruitment and
TH2 cell survival of eosinophils and in the mainte-
Eosinophil Neutrophil nance of a mast cell population in the air-
ways. The naïve immune system and the
immune system of asthmatics are skewed
Mucous plug to express the Th2 phenotype, whereas in
Epithelial
shedding normal airways Th1 cells predominate.
Th2 cells, through the release of IL-5, are
Nerve activation associated with eosinophilic inflammation
and, through the release of IL-4 and IL-13,
are associated with increased IgE forma-
Subepithelial fibrosis tion. Natural killer CD4+ T lymphocytes
that express high levels of IL-4 have been
Plasma described in some studies. Regulatory
Mucus leak Myofibroblast T cells (Treg) play an important role in
hypersecretion determining the expression of other T
Edema
Hyperplasia Vasodilation Sensory nerve cells, and there is evidence for a reduction
New vessels in a certain subset of Tregs (CD4+CD25+)
that express the transcription factor
Cholinergic reflex FOXP3 in asthma that is associated with
Airway smooth m
uscle cells increased Th2 cells. Recently innate T cells
(ILC2) without T cell receptors have been
Brochoconstriction identified that release TH2 cytokines and
Hypertrophy/hyperplasia are regulated by epithelial cytokines such
FIGURE 281-3 The pathophysiology of asthma is complex with participation of several interacting inflammatory as IL-25 and IL-33 and may be predomi-
cells, which result in acute and chronic inflammatory effects on the airway. nant in non-allergic asthma.

1962 STRUCTURAL CELLS Structural cells of the airways, including epithelial
Allergens Viruses
cells, fibroblasts, and airway smooth-muscle cells, are also important
sources of inflammatory mediators such as cytokines and lipid mediators,
in asthma. Indeed, because structural cells far outnumber inflammatory
cells, they may become the major sources of mediators driving chronic
inflammation in asthmatic airways. In addition, epithelial cells may have
key roles in translating inhaled environmental signals into an airway
inflammatory response, and are probably major target cells for ICS.
Inflammatory Mediators Multiple inflammatory mediators

have been implicated in asthma, and they may have a variety of effects
on the airways that account for the pathologic features of asthma
PART 7
(Fig. 281-4). Mast cell-derived mediators, such as histamine, pros- TSLP IL-25, IL-33
taglandin D2, and cysteinyl-leukotrienes, contract airway smooth mus- Dendritic
cle, increase microvascular leakage, increase airway mucus secretion, cell
and attract other inflammatory cells. Because each mediator has many
effects, the role of individual mediators in the pathophysiology of

asthma is not yet clear. Although the multiplicity of mediators makes CCL17, CCL22 CCL11
it unlikely that preventing the synthesis or action of a single mediator
will have a major impact in clinical asthma, recent clinical studies with
antileukotrienes suggest that cysteinyl-leukotrienes have clinically TH2 ILC2
important effects.
CYTOKINES Multiple cytokines regulate the chronic inflammation of
asthma. The TH2 cytokines IL-4, IL-5, IL-9, and IL-13 mediate allergic IL-5 IL-5
inflammation, whereas proinflammatory cytokines such as TNF-α
and IL-1β amplify the inflammatory response and play a role in more
severe disease. TSLP is an upstream cytokine released from epithelial
cells of asthmatics that orchestrates the release of chemokines that
selectively attract Th2 cells. Some cytokines such as IL-10 and IL-12 are
anti-inflammatory and may be deficient in asthma.
Eosinophils
CHEMOKINES Chemokines are involved in attracting inflammatory
cells from the bronchial circulation into the airways. Eotaxin (CCL11) is FIGURE 281-5 T lymphocytes in asthma. Allergen interacts with dendritic cells
selectively attractant to eosinophils via CCR3 and is expressed by epi- and releases thymus stimulated lymphopoietin (TSLP) which stimulate activated
dendritic cells to release the chemokines CCL17 and CCL22, which attract T
thelial cells of asthmatics, whereas CCL17 (TARC) and CCL22 (MDC)
helper 2 (TH2) lymphocytes. Allergens and viral infection may release interleukins
from epithelial cells attract Th2 cells via CCR4 (Fig. 281-5). (IL)-25 and -33 which recruit and activate type 2 innate lymphoid cells (ILC2).
OXIDATIVE STRESS Activated inflammatory cells such as macrophages, Both TH2 and ILC2 cells release IL-5 and epithelial cells CCL11 (eotaxin), which
together lead to recruitment of eosinophils into the airways.
eosinophils, and neutrophils produce reactive oxygen species. Evidence
for increased oxidative stress in asthma is provided by the increased
concentrations of 8-isoprostane (a product of oxidized arachidonic diagnosis and monitoring of asthmatic inflammation, although it is not
acid) in exhaled breath condensates and increased ethane (a product of yet used routinely in clinical practice.
lipid peroxidation) in the expired air of asthmatic patients. Increased TRANSCRIPTION FACTORS Proinflammatory transcription factors such
oxidative stress is related to disease severity, it may amplify the inflam- as nuclear factor-κB (NF-κB) and activator protein-1, are activated in
matory response, and may reduce responsiveness to corticosteroids. asthmatic airways and orchestrate the expression of multiple inflam-
NITRIC OXIDE Nitric oxide (NO) is produced by NO synthases in matory genes. More specific transcription factors that are involved
several cells in the airway, particularly airway epithelial cells and mac- include nuclear factor of activated T cells and GATA-3, which regulate
rophages. The level of NO in the expired air of patients with asthma the expression of Th2 cytokines in Th2 and ILC2 cells.
is higher than normal and is related to the eosinophilic inflammation. Effects of Inflammation The chronic inflammatory response
Increased NO may contribute to the bronchial vasodilation observed has several effects on the target cells of the airways, resulting in the
in asthma. Fractional exhaled NO (FENO) is increasingly used in the characteristic pathophysiologic and remodeling changes associated
with asthma. Asthma may be regarded as a disease with continuous
inflammation and repair proceeding simultaneously, although the
Inflammatory cells Mediators relationship between chronic inflammatory processes and asthma
Mast cells Histamine symptoms is often obscure.
Eosinophils Leukotrienes
AIRWAY EPITHELIUM Airway epithelial shedding may be important in
TH2 cells Prostanoids Effects
Basophils PAF Bronchospasm
contributing to AHR and may explain how several mechanisms, such as
Neutrophils Kinins Plasma exudation ozone exposure, virus infections, chemical sensitizers, and allergens (usu-
Platelets Adenosine Mucus secretion ally proteases), can lead to its development, as all of these stimuli may
Structural cells Endothelins AHR lead to epithelial disruption. Epithelial damage may contribute to AHR
Epithelial cells Nitric oxide Structural changes in a number of ways, including loss of its barrier function to allow pen-
Smooth muscle cells Cytokines
etration of allergens; loss of enzymes (such as neutral endopeptidase/
Endothelial cells Chemokines
Growth factors
neprilysin) that degrade certain peptide inflammatory mediators like
Fibroblasts
Nerves bradykinin; loss of a relaxant factor (so-called epithelial-derived relax-
ant factor); and exposure of sensory nerves, which may lead to reflex
neural effects on the airway.
FIGURE 281-4 Many cells and mediators are involved in asthma and lead to
several effects on the airways. AHR, airway hyperresponsiveness; PAF, platelet- FIBROSIS In all asthmatic patients, the basement membrane is appar-
activating factor. ently thickened due to subepithelial fibrosis with deposition of types III

and V collagen below the true basement membrane and is associated in a reduction in forced expiratory volume in 1 second (FEV1), FEV1/ 1963
with eosinophil infiltration, presumably through the release of pro- forced vital capacity (FVC) ratio, and peak expiratory flow (PEF), as
fibrotic mediators such as transforming growth factor-β. Mechanical well as an increase in airway resistance. Early closure of peripheral air-
manipulations can alter the phenotype of airway epithelial cells in a way results in lung hyperinflation (air trapping) and increased residual
profibrotic fashion. In more severe patients, there is also fibrosis within volume, particularly during acute exacerbations and in severe persis-
the airway wall, which may contribute to irreversible narrowing of the tent asthma. In more severe asthma, reduced ventilation and increased
airways. pulmonary blood flow result in mismatching of ventilation and perfu-
AIRWAY SMOOTH MUSCLE In vitro airway smooth muscle from asth- sion and in bronchial hyperemia. Ventilatory failure is very uncommon,
matic patients usually shows no increased responsiveness to constric- even in patients with severe asthma, and arterial PCO tends to be low
2
tors. Reduced responsiveness to β-agonists has also been reported in due to increased ventilation.
CHAPTER 281 Asthma

postmortem or surgically removed bronchi from asthmatics, although Airway Hyperresponsiveness AHR is the characteristic physi-
the number of β-receptors is not reduced, suggesting that β-receptors ologic abnormality of asthma and describes the excessive bronchocon-
have been uncoupled. These abnormalities of airway smooth muscle strictor response to multiple inhaled triggers that would have no effect
may be secondary to the chronic inflammatory process. Inflammatory on normal airways. The increase in AHR is linked to the frequency
mediators may modulate the ion channels that serve to regulate the of asthma symptoms, and, thus, an important aim of therapy is to
resting membrane potential of airway smooth-muscle cells, thus alter- reduce AHR. Increased bronchoconstrictor responsiveness is seen with
ing the level of excitability of these cells. In asthmatic airways there is direct bronchoconstrictors such as histamine and methacholine, which
also a characteristic hypertrophy and hyperplasia of airway smooth contract airway smooth muscle, but is characteristically also seen with
muscle, which is presumably the result of stimulation of airway many indirect stimuli, which release bronchoconstrictors from mast
smooth-muscle cells by various growth factors such as platelet-derived cells or activate sensory nerves. Most of the triggers for asthma symp-
growth factor (PDGF) or endothelin-1 released from inflammatory or toms appear to act indirectly, including allergens, exercise, hyperven-
epithelial cells. Airway smooth-muscle cells from asthmatic patients tilation, fog (via mast cell activation), irritant dusts, and sulfur dioxide
also release multiple inflammatory mediators, particularly cytokines (via a cholinergic reflex).
and chemokines.
VASCULAR RESPONSES There is increased airway mucosal blood flow ■■CLINICAL FEATURES AND DIAGNOSIS
in asthma, which may contribute to airway narrowing. There is an The characteristic symptoms of asthma are wheezing, dyspnea, and
increase in the number of blood vessels in asthmatic airways as a coughing, which are variable, both spontaneously and with therapy.
result of angiogenesis in response to growth factors, particularly Symptoms may be worse at night and patients typically awake in the
vascular-endothelial growth factor. Microvascular leakage from post- early morning hours. Patients may report difficulty in filling their lungs
capillary venules in response to inflammatory mediators is observed with air. There is increased mucus production in some patients, with
in asthma, resulting in airway edema and plasma exudation into the typically tenacious mucus that is difficult to expectorate. There may
airway lumen. be increased ventilation and use of accessory muscles of ventilation.
MUCUS HYPERSECRETION Increased mucus secretion contributes to
Prodromal symptoms may precede an attack, with itching under the
the viscid mucous plugs that occlude asthmatic airways, particularly chin, discomfort between the scapulae, or inexplicable fear (impending
in fatal asthma. There is hyperplasia of submucosal glands that are doom).
confined to large airways and of increased numbers of epithelial goblet Typical physical signs are inspiratory, and to a greater extent expi-
cells. IL-13 induces mucus hypersecretion in experimental models of ratory, rhonchi throughout the chest, and there may be hyperinflation.
asthma. Some patients, particularly children, may present with a predominant
nonproductive cough (“cough-variant asthma”). There may be no
NEURAL REGULATION Various defects in autonomic neural control may abnormal physical findings when asthma is under control.
contribute to AHR in asthma, but these are likely to be secondary to the
disease, rather than primary defects. Cholinergic pathways, through ■■DIAGNOSIS
the release of acetylcholine acting on muscarinic receptors, cause bron- The diagnosis of asthma is usually apparent from the symptoms of
choconstriction and may be activated reflexly in asthma. Inflammatory variable and intermittent airways obstruction, but must be confirmed
mediators may activate sensory nerves, resulting in reflex choliner- by objective measurements of lung function.
gic bronchoconstriction or release of inflammatory neuropeptides.
Inflammatory products may also sensitize sensory nerve endings Lung Function Tests Simple spirometry confirms airflow lim-
in the airway epithelium such that the nerves become hyperalgesic. itation with a reduced FEV1, FEV1/FVC ratio, and PEF (Fig. 281-6).
Neurotrophins, which may be released from various cell types in air- Reversibility is demonstrated by a >12% and 200-mL increase in
ways, including epithelial cells and mast cells, may cause proliferation FEV1 15 min after an inhaled short-acting β2-agonist (SABA; such as
and sensitization of airway sensory nerves. Airway nerves may also inhaled albuterol 400 μg) or in some patients by a 2–4 week trial of oral
release neurotransmitters, such as substance P, which may have inflam- corticosteroids (OCS) (prednisone or prednisolone 30–40 mg daily).
matory effects. Measurements of PEF twice daily may confirm the diurnal varia-
tions in airflow obstruction. Flow-volume loops show reduced peak
Airway Remodeling Several changes in the structure of the flow and reduced maximum expiratory flow. Further lung function
airway are characteristically found in asthma, and these may lead to tests are rarely necessary, but whole body plethysmography shows
irreversible narrowing of the airways. Population studies have shown a increased airway resistance and may show increased total lung capac-
greater decline in lung function over time than in normal subjects; how- ity and residual volume. Gas diffusion, measured by carbon monoxide
ever, most patients with asthma preserve normal or near-normal lung transfer, is usually normal, but there may be a small increase in some
function throughout life if appropriately treated. This suggests that the patients.
accelerated decline in lung function occurs in a smaller proportion of
Airway Responsiveness The increased AHR is normally mea-
asthmatics, and these are usually patients with more severe disease.
sured by methacholine or histamine challenge with calculation of the
There is some evidence that the early use of ICS may reduce the decline
provocative concentration that reduces FEV1 by 20% (PC20). This is
in lung function. The characteristic structural changes are increased
rarely useful in clinical practice, but can be used in the differential diag-
airway smooth muscle, fibrosis, angiogenesis, and mucus hyperplasia.
nosis of chronic cough and when the diagnosis is in doubt in the setting
Physiology Limitation of airflow is due mainly to bronchoconstric- of normal pulmonary function tests. Occasionally exercise testing is
tion (from mast cell mediators), but airway edema, vascular conges- done to demonstrate the post-exercise bronchoconstriction if there is
tion, and luminal occlusion with exudate may contribute. This results a predominant history of EIA. Allergen challenge is rarely necessary

1964 Spirometry Flow-volume loop
Normal
FEV1 = 3.5 L FVC = 4.0 L 10
4 PEF
Expired volume (liters)

3 FVC = 3.6 L
Flow (liters/min)
Asthma
FEV1/FVC = 61% Normal
2 5
FEV1 = 2.2 L
PART 7
1 Asthma
0 0
0 1 2 3 4 0 1 2 3 4
Time (seconds) Volume (liters)

FIGURE 281-6 Spirometry and flow-volume loop in asthmatic compared to normal subject. There is a reduction in forced expiratory volume in 1 second (FEV1) but
less reduction in forced vital capacity (FVC), giving a reduced FEV1/FVC ratio (<70%). The flow-volume loop shows reduced peak expiratory flow and a typical scalloped
appearance indicating widespread airflow obstruction.
and should only be undertaken by a specialist if specific occupational remit, and show much less (or no) reversibility to bronchodilators.
agents are to be identified. Approximately 15% of COPD patients have features of asthma, with
increased sputum eosinophils and a response to OCS; these patients
Hematologic Tests Blood tests are not usually helpful. Total probably have both diseases concomitantly.
serum IgE and specific IgE to inhaled allergens (radioallergosorbent
test [RAST]) may be measured in some patients.
TREATMENT
Imaging Chest roentgenography is usually normal but in more
severe patients may show hyperinflated lungs. In exacerbations, there Asthma
may be evidence of a pneumothorax. Lung shadowing usually indi-
cates pneumonia or eosinophilic infiltrates in patients with broncho- The treatment of asthma is straightforward, with the majority
pulmonary aspergillosis (BPA). High-resolution CT may show areas of patients now managed by internists and family doctors with
of bronchiectasis in patients with severe asthma, and there may be effective and safe therapies. There are several aims of therapy
thickening of the bronchial walls, but these changes are not diagnostic (Table 281-2). Most of the emphasis has been placed on drug ther-
of asthma. apy, but several non-pharmacologic approaches have also been
used. The main drugs for asthma can be divided into bronchodila-
Skin Tests Skin prick tests to common inhalant allergens (house tors, which give rapid relief of symptoms mainly through relaxation
dust mite, cat fur, grass pollen) are positive in allergic asthma and neg- of airway smooth muscle, and controllers, which inhibit the under-
ative in intrinsic asthma, but are not helpful in diagnosis. Positive skin lying inflammatory process.
responses may be useful in persuading patients to undertake allergen
avoidance measures. BRONCHODILATOR THERAPIES
Bronchodilators act primarily on airway smooth muscle to reverse
Exhaled NO Fractional exhaled nitric oxide (FENO) is now being the bronchoconstriction of asthma. This gives rapid relief of symp-
used as a noninvasive test to measure eosinophilic airway inflamma- toms but has little or no effect on the underlying inflammatory
tion. The typically elevated levels in asthma are reduced by ICS, so process. Thus, bronchodilators are not sufficient to control asthma in
this may be a test of compliance with therapy. It may also be useful in patients with persistent symptoms. There are three classes of bron-
demonstrating insufficient anti-inflammatory therapy and may be use- chodilator in current use: β2-adrenergic agonists, anticholinergics,
ful in down-titrating ICS. However, studies in unselected patients have and theophylline; of these, β2-agonists are by far the most effective.
not convincingly demonstrated improved clinical outcomes and it may
be necessary to select patients who are poorly controlled. a2-Agonists β2-Agonists activate β2-adrenergic receptors, which are
widely expressed in the airways. β2-Receptors are coupled through
Differential Diagnosis It is usually not difficult to differenti- a stimulatory G protein to adenylyl cyclase, resulting in increased
ate asthma from other conditions that cause wheezing and dyspnea. intracellular cyclic adenosine monophosphate (AMP), which relaxes
Upper airway obstruction by a tumor or laryngeal edema can mimic smooth muscle cells and inhibits certain inflammatory cells, partic-
severe asthma, but patients typically present with stridor localized to ularly mast cells.
large airways. The diagnosis is confirmed by a flow-volume loop that
shows a reduction in inspiratory as well as expiratory flow, and bron-
choscopy to demonstrate the site of upper airway narrowing. Persistent TABLE 281-2 Aims of Asthma Therapy
wheezing in a specific area of the chest may indicate endobronchial • Minimal (ideally no) chronic symptoms, including nocturnal
obstruction with a foreign body. Left ventricular failure may mimic • Minimal (infrequent) exacerbations
the wheezing of asthma but basilar crackles are present in contrast to • No emergency visits
asthma. Vocal cord dysfunction may mimic asthma and is thought to • Minimal (ideally no) use of a required β2-agonist
be a hysterical conversion syndrome.
• No limitations on activities, including exercise
Eosinophilic pneumonias and systemic vasculitis, including Churg-
• Peak expiratory flow circadian variation <20%
Strauss syndrome (eosinophilic granulomatosis with polyangiitis)
and polyarteritis nodosa, may be associated with wheezing. Chronic • (Near) normal PEF
obstructive pulmonary disease (COPD) is usually easy to differentiate • Minimal (or no) adverse effects from medicine
from asthma as symptoms show less variability, never completely Abbreviation: PEF, peak expiratory flow.

Mode of Action The primary action of β2-agonists is to relax air- be given by nebulizer in treating acute severe asthma but should 1965
way smooth-muscle cells of all airways, where they act as func- only be given following β2-agonists, as they have a slower onset of
tional antagonists, reversing and preventing contraction of airway bronchodilation.
smooth-muscle cells by all known bronchoconstrictors. This gen- Side effects are not usually a problem as there is little or no
eralized action is likely to account for their great efficacy as bron- systemic absorption. The most common side effect is dry mouth;
chodilators in asthma. There are also additional non-bronchodilator in elderly patients, urinary retention and glaucoma may also be
effects that may be clinically useful, including inhibition of mast observed.
cell mediator release, reduction in plasma exudation, and inhibi-
Theophylline Theophylline was widely prescribed as an oral bron-
tion of sensory nerve activation. Inflammatory cells express small
chodilator several years ago, especially as it was inexpensive. It has
numbers of β2-receptors, but these are rapidly down-regulated with
now fallen out of favor as side effects are common, and inhaled
β2-agonist activation so that, in contrast to corticosteroids, there
CHAPTER 281 Asthma

β2-agonists are much more effective as bronchodilators. The bron-
are no effects on inflammatory cells in the airways and there is no
chodilator effect is due to inhibition of phosphodiesterases in airway
reduction in AHR.
smooth-muscle cells, which increases cyclic AMP, but doses required
Clinical Use β2-Agonists are usually given by inhalation to reduce for bronchodilatation commonly cause side effects that are medi-
side effects. SABA, such as albuterol and terbutaline, have a dura- ated mainly by phosphodiesterase inhibition. There is increasing
tion of action of 3–6 h. They have a rapid onset of bronchodilatation evidence that theophylline at lower doses has anti-inflammatory
and are, therefore, used as needed for symptom relief (relievers). effects, and these are likely to be mediated through different molec-
Increased use of SABA indicates that asthma is not controlled. They ular mechanisms. Theophylline activates the key nuclear enzyme
are also useful in preventing EIA if taken prior to exercise. SABA histone deacetylase-2 (HDAC2), which is a critical mechanism for
are used in high doses by nebulizer or via a metered-dose inhaler switching off activated inflammatory genes and may therefore
(MDI) with a spacer. Long-acting β2-agonists (LABA) include salme- reduce corticosteroid insensitivity in severe asthma.
terol and formoterol, both of which have a duration of action over
Clinical Use Oral theophylline is usually given as a slow-release
12 h and are given twice daily by inhalation; and indacaterol,
preparation once or twice daily as this gives more stable plasma
olodaterol, and vilanterol, which are given once daily. LABA have
concentrations than normal theophylline tablets. It may be used as
replaced the regular use of SABA, but LABA should not be given
an additional bronchodilator in patients with severe asthma when
in the absence of ICS therapy as they do not control the underlying
plasma concentrations of 10–20 mg/L are required, although these
inflammation. They do, however, improve asthma control and
concentrations are often associated with side effects. Low doses of
reduce exacerbations when added to ICS, which allows asthma
theophylline, giving plasma concentrations of 5–10 mg/L, have
to be managed with lower doses of corticosteroids. This observa-
additive effects to ICS and are particularly useful in patients with
tion has led to the widespread use of fixed combination inhalers
severe asthma. Indeed, withdrawal of theophylline from these
that contain a corticosteroid and a LABA, which have proved
patients may result in marked deterioration in asthma control. At
to be highly effective in the control of asthma and prevention of
low doses, the drug is well tolerated. IV aminophylline (a soluble
exacerbations.
salt of theophylline) was used for the treatment of severe asthma
Side Effects Adverse effects are not usually a problem with β2- but has now been largely replaced by high doses of inhaled SABA,
agonists when given by inhalation. The most common side effects which are more effective and have fewer side effects. Aminophyl-
are muscle tremor and palpitations, which are seen more commonly line is occasionally used (via slow IV infusion) in patients with
in elderly patients. There is a small fall in plasma potassium due to severe exacerbations that are refractory to SABA.
increased uptake by skeletal muscle cells, but this effect does not
Side Effects Oral theophylline is well absorbed and is largely inac-
usually cause any clinical problem.
tivated in the liver. Side effects are related to plasma concentrations;
Tolerance Tolerance is a potential problem with any agonist given measurement of plasma theophylline may be useful in determining
chronically, but while there is down-regulation of β2-receptors, this the correct dose. The most common side effects are nausea, vomit-
does not reduce the bronchodilator response as there is a large ing, and headaches and are due to phosphodiesterase inhibition.
receptor reserve in airway smooth-muscle cells. By contrast, mast Diuresis and palpitations may also occur, and at high concentra-
cells become rapidly tolerant, but their tolerance may be prevented tions cardiac arrhythmias, epileptic seizures, and death may occur
by concomitant administration of ICS. due to adenosine A1-receptor antagonism. Theophylline side effects
Safety The safety of β2-agonists has been an important issue. are related to plasma concentration and are rarely observed at
There is an association between asthma mortality and the amount plasma concentrations <10 mg/L. Theophylline is metabolized by
of SABA used, but careful analysis demonstrates that the increased CYP450 (CYP1A2) in the liver, and, thus, plasma concentrations
use of rescue SABA reflects poor asthma control, which is a risk may be elevated by drugs that block CYP450 such as erythromy-
factor for asthma death. The slight excess in mortality that has been cin and allopurinol. Other drugs may also reduce clearance by
associated with the use of LABA is related to the lack of use of con- other mechanisms leading to increased plasma concentrations
comitant ICS, as the LABA therapy fails to suppress the underlying (Table 281-3).
inflammation. This highlights the importance of always using an
ICS when LABAs are given, which is most conveniently achieved CONTROLLER THERAPIES
by using a combination inhaler. Recent large safety studies have Inhaled Corticosteroids ICS are by far the most effective controllers
shown no adverse effects of LABA in adults or children. for asthma, and their early use has revolutionized asthma therapy.
Anticholinergics Muscarinic receptor antagonists, such as ipratro- Mode of Action ICS are the most effective anti-inflammatory agents
pium bromide, prevent cholinergic nerve-induced bronchoconstric- used in asthma therapy, reducing inflammatory cell numbers and
tion and mucus secretion. They are less effective than β2-agonists their activation in the airways. ICS reduce eosinophils in the air-
in asthma therapy as they inhibit only the cholinergic reflex com- ways and sputum, and numbers of activated T lymphocytes and
ponent of bronchoconstriction, whereas β2-agonists prevent all surface mast cells in the airway mucosa. These effects may account
bronchoconstrictor mechanisms. Long-acting muscarinic antago- for the reduction in AHR that is seen with chronic ICS therapy.
nists (LAMA), including tiotropium bromide or glycopyrronium The molecular mechanism of action of corticosteroids involves
bromide, may be used as an additional bronchodilator in patients several effects on the inflammatory process. The major effect of
with asthma that is not controlled by maximal doses of ICS-LABA corticosteroids is to switch off the transcription of multiple acti-
combinations, and improve lung function and further reduce vated genes that encode inflammatory proteins such as cytok-
exacerbations. High doses of short-acting anticholinergics may ines, chemokines, adhesion molecules, and inflammatory enzymes.

1966 TABLE 281-3 Factors Affecting Clearance of Theophylline Side Effects Local side effects include hoarseness (dysphonia) and
Increased Clearance
oral candidiasis, which may be reduced with the use of a large-
volume spacer device. There has been concern about systemic side
• Enzyme induction (rifampicin, phenobarbitone, ethanol)
effects from lung absorption, but many studies have demonstrated
• Smoking (tobacco, marijuana) that ICS have minimal systemic effects (Fig. 281-7). At the highest
• High-protein, low-carbohydrate diet recommended doses, there may be some suppression of plasma and
• Barbecued meat urinary cortisol concentrations, but there is no convincing evidence
• Childhood that long-term treatment leads to impaired growth in children or to
Decreased Clearance osteoporosis in adults. Indeed effective control of asthma with ICS
• Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, reduces the number of courses of OCS that are needed and, thus,
zafirlukast) reduces systemic exposure to ICS.
PART 7
• Congestive heart failure

Systemic Corticosteroids Corticosteroids are used intravenously
• Liver disease (hydrocortisone or methylprednisolone) for the treatment of acute
• Pneumonia severe asthma, although several studies now show that OCS are as
• Viral infection and vaccination effective and easier to administer. A course of OCS (usually pred-
• High carbohydrate diet nisone or prednisolone 30–45 mg once daily for 5–10 days) is used
• Old age to treat acute exacerbations of asthma; no tapering of the dose is

needed. Approximately 1% of asthma patients may require main-
tenance treatment with OCS; the lowest dose necessary to maintain
This effect involves several mechanisms, including inhibition of the control needs to be determined. Systemic side effects, including
transcription factors NF-κB, but an important mechanism is recruit- truncal obesity, bruising, osteoporosis, diabetes, hypertension, gas-
ment of HDAC2 to the inflammatory gene complex, which reverses tric ulceration, proximal myopathy, depression, and cataracts, may
the histone acetylation associated with increased gene transcrip- be a major problem, and steroid-sparing therapies may be consid-
tion. Corticosteroids also activate anti-inflammatory genes such as ered if side effects are a significant problem. If patients require main-
mitogen-activated protein (MAP) kinase phosphatase-1, and tenance treatment with OCS, it is important to monitor bone density
increase the expression of β2-receptors. Most of the metabolic and so that preventive treatment with bisphosphonates or estrogen in
endocrine side effects of corticosteroids are also mediated through postmenopausal women may be initiated if bone density is low.
transcriptional activation. Intramuscular triamcinolone acetonide is a depot preparation that is
occasionally used in noncompliant patients, but proximal myopathy
Clinical Use ICS are by far the most effective controllers in the is a major problem with this therapy.
management of asthma and are beneficial in treating asthma of any
severity and age. ICS are usually given twice daily, but some may Antileukotrienes Cysteinyl-leukotrienes are potent bronchocon-
be effective once daily in mildly symptomatic patients. ICS rapidly strictors; they cause microvascular leakage and increase eosinophilic
improve the symptoms of asthma, and lung function improves over inflammation through the activation of cys-LT1-receptors. These
several days. They are effective in preventing asthma symptoms, inflammatory mediators are produced predominantly by mast cells
such as EIA and nocturnal exacerbations, but also prevent severe and, to a lesser extent, eosinophils in asthma. Antileukotrienes, such
exacerbations. ICS reduce AHR, but maximal improvement may as montelukast and zafirlukast, block cys-LT1-receptors and provide
take several months of therapy. Early treatment with ICS appears modest clinical benefit in asthma. They are less effective than ICS
to prevent irreversible changes in airway function that occur with in controlling asthma and have less effect on airway inflammation,
chronic asthma. Withdrawal of ICS results in slow deterioration of but are useful as an add-on therapy in some patients not controlled
asthma control, indicating that they suppress inflammation and with low doses of ICS, although less effective than a LABA. They
symptoms, but do not cure the underlying condition. ICS are now are given orally once or twice daily and are well tolerated. Some
given as first-line therapy for patients with persistent asthma, but patients show a better response than others to antileukotrienes, but
if they do not control symptoms at low doses, it is usual to add a this has not been convincingly linked to any genomic differences in
LABA as the next step. the leukotriene pathway.
MDI
~10–20% inhaled
Mouth and Lungs

pharynx
Systemic
Absorption circulation
~80–90% swallowed from GI tract
( spacer/mouth wash) Liver
GI tract
Inactivation
in liver Systemic
“first pass” side effects
FIGURE 281-7 Pharmacokinetics of inhaled corticosteroids.

Cromones Cromolyn sodium and nedocromil sodium are asthma TABLE 281-4 Asthma Control 1967
controller drugs that appear to inhibit mast cell and sensory nerve CONTROLLED
activation and are, therefore, effective in blocking trigger-induced (ALL OF PARTLY
asthma such as EIA and allergen- and sulfur dioxide-induced CHARACTERISTIC FOLLOWING) CONTROLLED UNCONTROLLED
symptoms. Cromones have relatively little benefit in the long-term Daytime symptoms None (≤2/week) >2/week Three of more
control of asthma due to their short duration of action (at least four features of partly
times daily by inhalation). They are very safe and were popular in controlled
the treatment of childhood asthma, although now low doses of ICS Limitation of None Any
are preferred as they are far more effective and have a proven safety activities
profile. Nocturnal None Any
symptoms/
CHAPTER 281 Asthma

Steroid-Sparing Therapies Various immunomodulatory treatments awakening
have been used to reduce the requirement for OCS in patients with Need for reliever/ None (≤2/week) >2/week
severe asthma, who have serious side effects with this therapy. rescue treatment
Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma Lung function (PEF Normal <80%
globulin have all been used as steroid-sparing therapies, but none or FEV1) predicted or
of these treatments has any long-term benefit and each is associated personal best
with a relatively high risk of side effects. (if known)
Anti-IgE Omalizumab is a blocking antibody that neutralizes cir-

culating IgE without binding to cell-bound IgE and, thus, inhibits
IgE-mediated reactions. This treatment has been shown to reduce phosphodiesterase-4, NF-κB, and p38 MAP kinase. However, these
the number of exacerbations in patients with severe asthma and drugs, which act on signal transduction pathways common to many
may improve asthma control. However, the treatment is very cells, have troublesome side effects, which may necessitate their
expensive and is only suitable for highly selected patients who delivery by inhalation. Safer and more effective immunotherapy
are not controlled on maximal doses of inhaler therapy and have a using T cell peptide fragments of allergens or DNA vaccination are
circulating IgE within a specified range. Patients should be given a also being investigated. Bacterial products, such as CpG oligonucle-
3- to 4-month trial of therapy to show objective benefit. Omalizumab otides that stimulate Th1 immunity or Treg, are also currently under
is usually given as a subcutaneous injection every 2–4 weeks and evaluation.
appears not to have significant side effects, although anaphylaxis is MANAGEMENT OF CHRONIC ASTHMA
very occasionally seen.
There are several aims of chronic therapy in asthma (Table 281-2). It
Anti-IL-5 Antibodies that block IL-5 (mepolizumab, reslizumab) or is important to establish the diagnosis objectively using spirometry
its receptor (benralizumab) markedly reduce blood and tissue eos- or PEF measurements at home. Triggers that worsen asthma con-
inophils and reduce exacerbations in patients who have persistently trol, such as allergens or occupational agents, should be avoided,
increased sputum eosinophils despite maximal ICS therapy. whereas triggers, such as exercise and fog, which result in transient
Immunotherapy Specific immunotherapy using injected extracts of symptoms, provide an indication that more controller therapy is
pollens or house dust mites has not been very effective in controlling needed. It is important to assess asthma control, assessed by symp-
asthma and may cause anaphylaxis. Side effects may be reduced by toms, night awakening, need for reliever inhalers, limitation of
sublingual dosing. It is not recommended in most asthma treatment activity and lung function (Table 281-4). Avoidance of side effects
guidelines because of lack of evidence of clinical efficacy and poten- and expense of medications are also important. There are several
tial anaphylaxis. validated questionnaires for quantifying asthma control, such as the
Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control
Alternative Therapies Nonpharmacologic treatments, including Test (ACT).
hypnosis, acupuncture, chiropraxis, breathing control, yoga, and
speleotherapy, may be popular with some patients. However, Stepwise Therapy For patients with mild, intermittent asthma, a
placebo-controlled studies have shown that each of these treatments SABA is all that is required (Fig. 281-8). However, use of a reliever
lacks efficacy and cannot be recommended. However, they are not medication more than twice a week indicates the need for regular con-
detrimental and may be used as long as conventional pharmacologic troller therapy. The treatment of choice for all patients is an ICS given
therapy is continued. twice daily. It is usual to start with an intermediate dose (e.g., 200
[μg] bid of [beclomethasone dipropionate] BDP) or equivalent and
Bronchial Thermoplasty Bronchial thermoplasty is a bronchoscopic to decrease the dose if symptoms are controlled after three months.
treatment using thermal energy to ablate airway smooth muscle If symptoms are not controlled, a LABA should be added, which
in accessible bronchi. It may reduce exacerbations and improve is most conveniently given by switching to a combination inhaler.
asthma control in highly selected patients not controlled on max-
imal inhaler therapy, particularly when there is no increase in
inflammation.
OCS
Future Therapies It has proved very difficult to discover novel
pharmaceutical therapies, particularly as current therapy with cor-
LABA LABA
ticosteroids and β2-agonists is so effective in the majority of patients.
There is, however, a need for the development of new therapies for LABA
patients with refractory asthma who have side effects with systemic ICS ICS
corticosteroids. Antagonists of specific mediators have little or no ICS ICS High dose High dose
benefit in asthma, apart from antileukotrienes, which have rather Low dose Low dose
weak effects, presumably reflecting the fact that multiple media- Short-acting β2-agonist as required for symptom relief
tors are involved. Anti-TNF-α antibodies are not effective in severe
asthma. Anti-IL-13 blocking antibodies have little clinical effect, but Mild Mild Moderate Severe Very severe
an antibody (dupilumab) against the common receptor for IL-4 and intermittent persistent persistent persistent persistent
IL-13 (IL-4Rα) is more promising in reducing exacerbations and FIGURE 281-8 Stepwise approach to asthma therapy according to the severity
improving asthma control in severe asthma. Novel anti-inflammatory of asthma and ability to control symptoms. ICS, inhaled corticosteroids; LABA,
treatments that are in clinical development include inhibitors of long-acting β2-agonist; OCS, oral corticosteroid.

1968 The dose of controller should be adjusted accordingly, as judged ■■SPECIAL CONSIDERATIONS
by the need for a rescue inhaler. Low doses of theophylline or an
antileukotriene may also be considered as an add-on therapy, but Refractory Asthma Although most patients with asthma are
these are less effective than LABA. In patients with severe asthma, easily controlled with appropriate medication, a small proportion of
low-dose oral theophylline is also helpful, and when there is irre- patients (~5%) are difficult to control despite maximal inhaled therapy.
versible airway narrowing, the long-acting anticholinergic may be It is important to check adherence to therapy and inhaler technique.
tried. If asthma is not controlled despite the maximal recommended Some of these patients will require maintenance treatment with OCS.
dose of inhaled therapy, it is important to check adherence and In managing these patients, it is important to investigate and correct
inhaler technique. In these patients, maintenance treatment with any mechanisms that may be aggravating asthma. There are two major
an OCS may be needed and the lowest dose that maintains control patterns of difficult asthma: some patients have persistent symptoms
should be used. Occasionally omalizumab and anti-IL-5 may be and poor lung function, despite appropriate therapy, whereas others
tried in steroid-dependent asthmatics who are not well controlled. may have normal or near normal lung function but intermittent, severe
PART 7
Once asthma is controlled, it is important to slowly decrease therapy (sometimes life-threatening) exacerbations.
in order to find the optimal dose to control symptoms. MECHANISMS The most common reason for poor control of asthma is
Education Patients with asthma need to understand how to use poor adherence with medication, particularly ICS. Compliance with
their medications and the difference between reliever and controller ICS may be low because patients do not feel any immediate clinical
therapies. Education may improve adherence, particularly with ICS. benefit or may be concerned about side effects. Adherence with ICS is
All patients should be taught how to use their inhalers correctly. In difficult to monitor as there are no useful plasma measurements that
particular, they need to understand how to recognize worsening can be made but measuring FENO may identify the problem. Compli-
of asthma and how to step up therapy accordingly. Written action ance may be improved by giving the ICS as a combination with a LABA
plans have been shown to reduce hospital admissions and morbid- that gives symptom relief. Adherence with OCS may be measured
ity rates in adults and children, and are recommended particularly by suppression of plasma cortisol and the expected concentration of
in patients with unstable disease who have frequent exacerbations. prednisone/prednisolone in the plasma. There are several factors that
may make asthma more difficult to control, including exposure to
high, ambient levels of allergens or unidentified occupational agents.
■■ACUTE SEVERE ASTHMA Severe rhinosinusitis may make asthma more difficult to control; upper
Exacerbations of asthma are feared by patients and may be life airway disease should be vigorously treated. Drugs such as beta-
threatening. One of the main aims of controller therapy is to prevent adrenergic blockers, aspirin, and other cyclooxygenase (COX) inhibi-
exacerbations; in this respect, ICS and combination inhalers are very tors may worsen asthma. Some women develop severe premenstrual
effective. worsening of asthma, which is unresponsive to corticosteroids and
requires treatment with progesterone or gonadotropin-releasing fac-
Clinical Features Patients are aware of increasing chest tight- tors. Few systemic diseases make asthma more difficult to control,
ness, wheezing, and dyspnea that are often not or poorly relieved but hyper- and hypothyroidism may increase asthma symptoms and
by their usual reliever inhaler. In severe exacerbations patients may should be investigated if suspected.
be so breathless that they are unable to complete sentences and may Bronchial biopsy studies in refractory asthma may show the typical
become cyanotic. Examination usually shows increased ventilation, eosinophilic pattern of inflammation, whereas others have a predomi-
hyperinflation, and tachycardia. Pulsus paradoxus may be present, but nantly neutrophilic pattern. There may be an increase in Th1 cells, TH17
this is rarely a useful clinical sign. There is a marked fall in spirometric cells, and CD8 lymphocytes compared to mild asthma and increased
values and PEF. Arterial blood gases on air show hypoxemia, and PCO2 expression of TNF-α. Structural changes in the airway, including
is usually low due to hyperventilation. A normal or rising PCO2 is an fibrosis, angiogenesis, and airway smooth muscle thickening, are more
indication of impending respiratory failure and requires immediate commonly seen in these patients.
monitoring and therapy. A chest roentgenogram is not usually infor-
mative, but may show pneumonia or pneumothorax.
Corticosteroid-Resistant Asthma A few patients with asthma
show a poor response to corticosteroid therapy and may have various
molecular abnormalities that impair the anti-inflammatory action of
corticosteroids. Complete resistance to corticosteroids is extremely
TREATMENT uncommon and affects <1 in 1000 patients. It is defined by a failure
Acute Severe Asthma to respond to a high dose of oral prednisone/prednisolone (40 mg
once daily over 2 weeks), ideally with a 2-week run-in with matched
A high concentration of oxygen should be given by face mask to placebo. More common is reduced responsiveness to corticosteroids
achieve oxygen saturation of >90%. The mainstay of treatment are where control of asthma requires OCS (corticosteroid-dependent
high doses of SABA given either by nebulizer or via a MDI with a asthma). In patients with poor responsiveness to corticosteroids, there
spacer. In severely ill patients with impending respiratory failure, is a reduction in the response of circulating monocytes and lympho-
IV β2-agonists may be given. A nebulized anticholinergic may be cytes to the anti-inflammatory effects of corticosteroids in vitro and
added if there is not a satisfactory response to β2-agonists alone, as reduced skin blanching in response to topical corticosteroids. There are
there are additive effects. In patients who are refractory to inhaled several mechanisms that have been described, including an increase in
therapies, a slow infusion of aminophylline may be effective, but the alternatively spliced form of the glucocorticoid receptor (GR)-β, an
it is important to monitor blood levels, especially if patients have abnormal pattern of histone acetylation in response to corticosteroids,
already been treated with oral theophylline. Magnesium sulfate a defect in IL-10 production, and a reduction in HDAC2 activity (as in
given intravenously or by nebulizer is effective when added to COPD). These observations suggest that there are likely to be heteroge-
inhaled β2-agonists, and is relatively well tolerated but is not rou- neous mechanisms for corticosteroid resistance; whether these mecha-
tinely recommended. Prophylactic intubation may be indicated nisms are genetically determined has yet to be decided.
for impending respiratory failure, when the PCO is normal or rises.
2
For patients with respiratory failure, it is necessary to intubate and Brittle Asthma Some patients show chaotic variations in lung
institute ventilation. These patients may benefit from a general function despite taking appropriate therapy. Some show a persistent
anesthetic, such as halothane, if they have not responded to conven- pattern of variability and may require OCS or, at times, continuous
tional bronchodilators. Sedatives should never be given as they may infusion of β2-agonists (type I brittle asthma), whereas others have
depress ventilation. Antibiotics should not be used routinely unless generally normal or near-normal lung function but precipitous, unpre-
there are signs of pneumonia. dictable falls in lung function that may result in death (type 2 brittle
asthma). These latter patients are difficult to manage as they do not

respond well to corticosteroids, and the worsening of asthma does not the corticosteroid. There is no contraindication to breast-feeding when 1969
reverse well with inhaled bronchodilators. The most effective therapy patients are using these drugs.
is subcutaneous epinephrine, which suggests that the worsening is
likely to be a localized airway anaphylactic reaction with edema. In
Cigarette Smoking Approximately 20% of asthmatics smoke,
which may adversely affect asthma in several ways. Smoking asth-
some of these patients, there may be allergy to specific foods. These
matics have more severe disease, more frequent hospital admissions, a
patients should be taught to self-administer epinephrine and should
faster decline in lung function, and a higher risk of death from asthma
carry a medical warning accordingly.
than nonsmoking asthmatics. There is evidence that smoking inter-
feres with the anti-inflammatory actions of corticosteroids by reducing
TREATMENT HDAC2, necessitating higher doses for asthma control. Smoking ces-
sation improves lung function and reduces the steroid resistance, and,
Refractory Asthma
CHAPTER 281 Asthma

thus, vigorous smoking cessation strategies should be used. LABA
Refractory asthma is difficult to control, by definition. It is important and theophylline appear to overcome some of the steroid resistance;
to check adherence and the correct use of inhalers and to identify so, ICS-LABA combination therapy and low dose theophylline should
and eliminate any underlying triggers. Low doses of theophylline be used. Some patients report a temporary worsening of asthma when
may be helpful in some patients, and theophylline withdrawal has they first stop smoking, possibly due to the loss of the bronchodilating
been found to worsen in many patients. Many of these patients will effect of NO in cigarette smoke.
require maintenance treatment with OCS, and the minimal dose
that achieves satisfactory control should be determined by careful
Surgery If asthma is well controlled, there is no contraindication to
general anesthesia and intubation. Patients who are treated with OCS will
dose titration. Steroid-sparing therapies are rarely effective. In some
have adrenal suppression and should be treated with an increased dose
patients with allergic asthma, omalizumab is effective, particularly
of OCS immediately prior to surgery. Patients with FEV1 <80% of their
when there are frequent exacerbations. Anti-IL-5 may be useful if
normal levels should also be given a boost of OCS prior to surgery. High-
sputum eosinophils persist despite maximal ICS or OCS therapy.
maintenance doses of corticosteroids may be a contraindication to sur-
Anti-TNF therapy is not effective in severe asthma and should not
gery because of increased risks of infection and delayed wound healing.
be used. A few patients may benefit from infusions of β2-agonists.
New therapies are needed for these patients, who currently consume Bronchopulmonary Aspergillosis BPA is uncommon and
a disproportionate amount of health care spending. results from an allergic pulmonary reaction to inhaled spores of
Aspergillus fumigatus and, occasionally, other Aspergillus species. A skin
Aspirin-Sensitive Asthma A small proportion (1–5%) of asth- prick test to A. fumigatus is always positive, whereas serum Aspergillus
matics become worse with aspirin and other COX inhibitors, although precipitins are low or undetectable. Characteristically, there are fleeting
this is much more commonly seen in severe cases and in those patients eosinophilic infiltrates in the lungs, particularly in the upper lobes.
with frequent hospital admission. Aspirin-sensitive asthma is a well- Airways become blocked with mucoid plugs rich in eosinophils, and
defined phenotype of asthma that is usually preceded by perennial patients may cough up brown plugs and have hemoptysis. BPA may
rhinitis and nasal polyps in nonatopic patients with a late onset of the result in bronchiectasis, particularly affecting central airways, if not
disease. Aspirin, even in small doses, characteristically provokes rhin- suppressed by corticosteroids. Asthma is controlled in the usual way
orrhea, conjunctival injection, facial flushing, and wheezing. There is a by ICS, but it is necessary to give a course of OCS if any sign of wors-
genetic predisposition to increased production of cysteinyl-leukotrienes ening or pulmonary shadowing is found. Treatment with the oral anti-
with functional polymorphism of cys-leukotriene C4 synthase. Asthma fungal itraconazole is beneficial in preventing exacerbations. Anti-IgE
is triggered by COX inhibitors, but is persistent even in their absence. therapy may also be useful to reduce the need for OCS.
All nonselective COX inhibitors should be avoided, but selective
COX2 inhibitors are safe to use when an anti-inflammatory analgesic ■■ASTHMA-COPD OVERLAP (ACO)
is needed. Aspirin-sensitive asthma responds to usual therapy with Although asthma and COPD are distinct syndromes with different
ICS. Although antileukotrienes should be effective in these patients, clinical presentations and underlying inflammatory mechanisms, some
they are no more effective than in allergic asthma. Occasionally, aspirin patients with asthma have features of COPD (for example, asthmatics
desensitization is necessary, but this should only be undertaken in who smoke and severe asthmatics with irreversible airflow limitation)
specialized centers. and some patients with COPD have features of asthma with more
reversibility and increased airway and blood eosinophils. This may
Asthma in the Elderly Asthma may start at any age, including in represent the coincidence of two common diseases, or these may be
elderly patients. The principles of management are the same as in other distinct phenotypes. ACO patients tend to have more symptoms and
asthmatics, but side effects of therapy may be a problem, including exacerbations. They may benefit from triple therapy with ICS, LABA,
muscle tremor with β2-agonists and more systemic side effects with ICS. and LAMA.
Comorbidities are more frequent in this age group, and interactions with
drugs such as β2-blockers, COX inhibitors, and agents that may affect ■■FURTHER READING
theophylline metabolism need to be considered. COPD is more likely Barnes PJ: Therapeutic approaches to asthma-chronic obstructive pul-
in elderly patients and may coexist with asthma. A trial of OCS may be monary disease overlap syndromes. J Allergy Clin Immunol 136:531,
very useful in documenting the steroid responsiveness of asthma. 2015.
Barnes PJ: Asthma mechanisms. Medicine 44:265, 2016.
Pregnancy Approximately one-third of asthmatic patients who are Bel EH: Clinical Practice. Mild asthma. N Engl J Med 369:549, 2013.
pregnant improve during the course of a pregnancy, one-third deteri- Gina Report 2016: http://ginasthma.org/2016-gina-report-global-strategy-
orate, and one-third are unchanged. It is important to maintain good for-asthma-management-and-prevention/.
control of asthma as poor control may have adverse effects on fetal Gross NJ, Barnes PJ: New therapies for asthma and COPD. Am J
development. Adherence may be a problem as there is often concern Respir Crit Care Med 195:159, 2017.
about the effects of antiasthma medications on fetal development. The Lambrecht B, Hammid H: The immunology of asthma. Nature Immu-
drugs that have been used for many years in asthma therapy have nol 16:45–56, 2016.
now been shown to be safe and without teratogenic potential. These Postma DS, Rabe K: The Asthma-COPD overlap syndrome. N Engl J
drugs include SABA, ICS, and theophylline; there is less safety infor- Med 373:1241, 2015.
mation about newer classes of drugs such as LABA, antileukotrienes, Ray A et al: Current concepts of severe asthma. J Clin Invest 126:2394,
and anti-IgE. If an OCS is needed, it is better to use prednisone rather 2016.
than prednisolone as it cannot be converted to the active prednisolone Tarlo SM, Lemire C: Occupational asthma. N Engl J Med 370:640,
by the fetal liver, thus protecting the fetus from systemic effects of 2014.

1970
282
TABLE 282-1 Examples of Hypersensitivity Pneumonitis
Hypersensitivity DISEASE ANTIGEN SOURCE
Pneumonitis and Farming/Food Processing
Pulmonary Infiltrates
Farmer’s lung Thermophilic Grain, moldy hay, silage
actinomycetes (e.g.,
with Eosinophilia Saccharopolyspora

rectivirgula); fungus
Bagassosis Thermophilic Sugarcane
Praveen Akuthota, Michael E. Wechsler actinomycetes
Cheese washer’s lung Penicillium casei; Cheese
Aspergillus clavatus
HYPERSENSITIVITY PNEUMONITIS
PART 7
Coffee worker’s lung Coffee bean dust Coffee beans

Malt worker’s lung Aspergillus species Barley
■■INTRODUCTION AND DEFINITION
Hypersensitivity pneumonitis (HP), also referred to as extrinsic aller- Miller’s lung Sitophilus granarius Wheat flour
(wheat weevil)
gic alveolitis, is a pulmonary disease that occurs due to inhalational
Mushroom worker’s lung Thermophilic Mushrooms
exposure to a variety of antigens leading to an inflammatory response

actinomycetes;
of the alveoli and small airways. Systemic manifestations such as fever mushroom spores
and fatigue can accompany respiratory symptoms. Although sensiti-
Potato riddler’s lung Thermophilic Moldy hay around
zation to an inhaled antigen as manifested by specific circulating IgG actinomycetes; potatoes
antibodies is necessary for the development of HP, sensitization alone Aspergillus species
is not sufficient as a defining characteristic, because many sensitized Tobacco grower’s lung Aspergillus species Tobacco
individuals do not develop HP. The incidence and prevalence of HP are Wine maker’s lung Botrytis cinerea Grapes
variable, depending on geography, occupation, avocation, and environ-
Birds and Other Animals
ment of the cohort being studied. As yet unexplained is the decreased
risk of developing HP in smokers. Bird fancier’s lung (alsoProteins derived by Bird feathers, droppings,
named by specific bird parakeets, pigeons, serum proteins
exposures) budgerigars
■■OFFENDING ANTIGENS
Duck fever Duck feathers, serum Ducks
HP can be caused by any of a large list of potential offending inhaled proteins
antigens (Table 282-1). The various antigens and environmental condi-
Fish meal worker’s lung Fish meal dust Fish meal
tions described to be associated with HP give rise to an expansive list of
Furrier’s lung Dust from animal furs Animal furs
monikers given to specific forms of HP. Antigens derived from fungal,
Laboratory worker’s lung Rat urine, serum, fur Laboratory rats
bacterial, mycobacterial, bird-derived, and chemical sources have all
been implicated in causing HP. Pituitary snuff taker’s Animal proteins Pituitary snuff from
lung bovine and porcine
Categories of individuals at particular risk in the United States sources
include farmers, bird owners, industrial workers, and hot tub users.
Poultry worker’s lung Chicken serum proteins Chickens
Farmer’s lung occurs as a result of exposure to one of several possible
Turkey handling disease Turkey serum proteins Turkeys
sources of bacterial or fungal antigens such as grain, moldy hay, or
silage. Potential offending antigens include thermophilic actinomy- Other Occupational and Environmental Exposures
cetes or Aspergillus species. Bird fancier’s lung (also referred to by Chemical worker’s lung Isocyanates Polyurethane foam,
names corresponding to specific birds) must be considered in patients varnish, lacquer
who give a history of keeping birds in their home and is precipitated Detergent worker’s lung Bacillus subtilis enzymes Detergent
by exposure to antigens derived from feathers, droppings, and serum Hot tub lung Cladosporium species; Contaminated water,
proteins. Occupational exposure to birds may also cause HP, as is seen Mycobacterium avium mold on ceiling
in poultry worker’s lung. Chemical worker’s lung is provoked by complex
exposure to occupational chemical antigens such as diphenylmethane Humidifier fever (and air Several microorganisms Humidifiers and
diisocyanate and toluene diisocyanate. Mycobacteria may cause HP conditioner lung) including: Aureobasidium air conditioners
pullulans; Candida (contaminated water)
rather than frank infection, a phenomenon observed in hot tub lung albicans; thermophilic
and in HP due to metalworking fluid. actinomycetes;
Mycobacterium species;
■■PATHOPHYSIOLOGY Klebsiella oxytoca;
While much remains to be learned regarding the pathophysiology of Naegleria gruberi
HP, it has been established that HP is an immune-mediated condition Machine operator’s lung Pseudomonas species; Metal working fluid
that occurs in response to inhaled antigens that are small enough to Mycobacteria species
deposit in distal airways and alveoli. From a lymphocyte perspective, Sauna taker’s lung Aureobasidium species; Sauna water
HP has been categorized as a condition with a TH1 inflammatory other antigens
pattern. However, emerging evidence suggests that TH17 lymphocyte Suberosis Penicillium glabrum; Cork dust
subsets may be involved in the pathogenesis of the disease as well. Chrysonilia sitophila
Although the presence of precipitating IgG antibodies against specific Summer-type Trichosporon cutaneum House dust mites, bird
pneumonitis droppings
antigens in HP suggests a prominent role for adaptive immunity in the
pathophysiology of HP, innate immune mechanisms likely also make Woodworker’s lung Alternaria species; Oak, cedar, pine,
Bacillus subtilis mahogany dusts
an important contribution. This is highlighted by the observation that
Toll-like receptors and downstream signaling proteins such as MyD88
are activated in HP, leading to neutrophil recruitment. Although no
clear genetic basis for HP has been established, in specific cohorts, ■■CLINICAL PRESENTATION
polymorphisms in genes involved in antigen processing and presen- Given the heterogeneity among patients, variability in offending
tation, including TAP1 and major histocompatibility complex type II, antigens, and differences in the intensity and duration of exposure to
have been observed. In chronic HP, bone marrow-derived fibrocytes antigen, the presentation of HP is accordingly variable. Although these
may contribute to lung inflammation and fibrosis. categories are not fully satisfactory in capturing this variability, HP has

been traditionally categorized as having acute, subacute, and chronic 1971
forms. Acute HP usually manifests itself 4–8 h following exposure
to the inciting antigen, often intense in nature. Systemic symptoms,
including fevers, chills, and malaise, are prominent and are accompa-
nied by dyspnea. Symptoms resolve within hours to days if no further
exposure to the offending antigen occurs. In subacute HP resulting
from ongoing antigen exposure, the onset of respiratory and systemic
symptoms is typically more gradual over the course of weeks. A sim-
ilar presentation may occur as a culmination of intermittent episodes
of acute HP. Although respiratory impairment may be quite severe,
antigen avoidance generally results in resolution of the symptoms, but
CHAPTER 282 Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia

with a slower time course, on the order of weeks to months, than that
seen with acute HP. Chronic HP can present with an even more grad-
ual onset of symptoms than subacute HP, with progressive dyspnea,
cough, fatigue, weight loss, and clubbing of the digits. The insidious
onset of symptoms and frequent lack of an anteceding episode of acute
HP make diagnosing chronic HP a challenge. Unlike with the other
forms of HP, there can be an irreversible component to the respiratory
impairment that is not responsive to removal of the responsible antigen
from the patient’s environment. The disease progression of chronic HP
to lung fibrosis and hypoxemic respiratory failure can mirror that seen
FIGURE 282-1 Chest computed tomography scan of a patient with subacute
in idiopathic pulmonary fibrosis (IPF). Diagnostic uncertainty between hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates
these two entities is not uncommon. Fibrotic lung disease is a potential in a mosaic pattern consistent with air trapping are seen bilaterally. This patient
feature of chronic HP due to exposure to bird antigens, whereas an had bird fancier’s lung. (Courtesy of TJ Gross; with permission.)
emphysematous phenotype may be seen in farmer’s lung.
The categories of acute, subacute, and chronic HP are not completely
sufficient in classifying HP. The HP Study Group found on cluster anal- likely caused by involvement of the small airways (Fig. 282-1). Reticular
ysis that a cohort of HP patients is best described in bipartite fashion, changes and traction bronchiectasis can be observed in chronic HP.
with one group featuring recurrent systemic signs and symptoms and Subpleural honeycombing similar to that seen in IPF may be present in
the other featuring more severe respiratory findings. advanced cases, although unlike in IPF, the lung bases are frequently
Concordant with the variability in the presentation of HP is the spared.
observed variability in outcome. HP that has not progressed to chronic Pulmonary Function Testing Either restrictive or obstructive
lung disease has a more favorable outcome with likely resolution if PFTs can be present in HP, so the pattern of PFT change is not useful in
antigen avoidance can be achieved. However, chronic HP resulting in establishing the diagnosis of HP. However, obtaining PFTs is of use in
lung fibrosis has a poorer prognosis, with patients with chronic pigeon characterizing the physiologic impairment of an individual patient and
breeder’s lung having demonstrated a similar mortality as seen in IPF. in gauging the response to antigen avoidance and/or corticosteroid
therapy. Diffusion capacity for carbon monoxide may be significantly
■■DIAGNOSIS impaired, particularly in cases of chronic HP with fibrotic pulmonary
Although there is no set of universally accepted criteria for arriving at parenchymal changes.
a diagnosis of HP, diagnosis depends foremost on establishing a history
of exposure to an offending antigen that correlates with respiratory and Serum Precipitins Assaying for precipitating IgG antibodies
systemic symptoms. A careful occupational and home exposure history against specific antigens can be a useful adjunct in the diagnosis of
should be taken and may be supplemented if necessary by a clinician HP. However, the presence of an immunologic response alone is not
visit to the work or home environment. Specific inquiries will be influ- sufficient for establishing the diagnosis, because many asymptomatic
enced by geography and the occupation of the patient. When HP is individuals with high levels of exposure to antigen may display serum
suspected by history, the additional workup is aimed at establishing an precipitins, as has been observed in farmers and in pigeon breeders.
immunologic and physiologic response to inhalational antigen expo- It should also be noted that panels that test for several specific serum
sure with chest imaging, pulmonary function testing (PFT), serologic precipitins often provide false-negative results, because they represent
studies, bronchoscopy, and, on occasion, lung biopsy. Re-exposure to an extremely limited proportion of the universe of potential offending
the offending environment may be performed to aid in confirming the environmental antigens.
diagnosis of HP. Bronchoscopy Bronchoscopy with bronchoalveolar lavage (BAL)
may be used in the evaluation of HP. Although not a specific finding,
Chest Imaging Chest x-ray findings in HP are nonspecific and can
BAL lymphocytosis is characteristic of HP. However, in active smok-
even lack any discernible abnormalities. In cases of acute and subacute
ers, a lower threshold should be used to establish BAL lymphocytosis,
HP, findings may be transient and can include ill-defined micronod-
because smoking will result in lower lymphocyte percentages. Most
ular opacities or hazy ground-glass airspace opacities. Findings on
cases of HP have a CD4+/CD8+ lymphocyte ratio of <1, but again, this
chest x-ray will often resolve with removal from the offending antigen,
is not a specific finding and has limited utility in the diagnosis of HP.
although the time course of resolution may vary. With chronic HP, the
abnormalities seen on the chest radiograph are frequently more fibrotic Lung Biopsy Tissue samples may be obtained by a broncho-
in nature and may be difficult to distinguish from IPF. scopic approach using transbronchial biopsy, or more architecturally
With the wide availability of high-resolution computed tomog- preserved specimens may be obtained by a surgical approach (video-
raphy (HRCT), this modality has become a common component in assisted thoracoscopy or open approach). As is the case with BAL,
the diagnostic workup for HP. Although the HRCT may be normal histologic specimens are not absolutely necessary to establish the
in acute forms of HP, this may be due to lack of temporal correlation diagnosis of HP, but they can be useful in the correct clinical context.
between exposure to the offending antigen and obtaining the imaging. A common histologic feature in HP is the presence of noncaseating
Additionally, because of the transient nature of acute HP, HRCT is granulomas in the vicinity of small airways (Fig. 282-2). As opposed
not always performed. In subacute forms of the disease, ground-glass to pulmonary sarcoidosis, in which noncaseating granulomas are well
airspace opacities are characteristic, as is the presence of centrilobular defined, the granulomas seen in HP are loose and poorly defined in
nodules. Expiratory images may show areas of air trapping that are nature. Within the alveolar spaces and in the interstitium, a mixed

1972 minimize patient exposure. This may be accomplished with mea-
sures such as removal of birds, removal of molds, and improved
ventilation. Personal protective equipment including respirators
and ventilated helmets can be used but may not provide adequate
protection for sensitized individuals. In some cases, fully avoiding
specific environments may be necessary, although such a recom-
mendation must be balanced against the effects to an individual’s
lifestyle or occupation. It is not uncommon for patients with HP
due to exposure to household birds to be unwilling to remove them
from the home.
Because acute HP is generally a self-limited disease after a dis-
crete exposure to an offending antigen, pharmacologic therapy is
PART 7
generally not necessary. However, in so-called subacute and chronic

forms of the disease, there is a role for glucocorticoid therapy. In
patients with particularly severe symptoms as a result of subacute
HP, antigen avoidance may be insufficient after establishing the
diagnosis. Although glucocorticoids do not change the long-term

outcome in these patients, they can accelerate the resolution of
symptoms. While there is significant variability in the approach to
FIGURE 282-2 Open-lung biopsy from a patient with subacute hypersensitivity glucocorticoid therapy by individual clinicians, prednisone ther-
pneumonitis demonstrating a loose, nonnecrotizing granuloma made up of
histiocytes and multinucleated giant cells. Peribronchial inflammatory infiltrate apy can be initiated at 0.5–1 mg/kg of ideal body weight per day
made up of lymphocytes and plasma cells is also seen. (Courtesy of TJ Gross; (not to exceed 60 mg/d or alternative glucocorticoid equivalent)
with permission.) over a duration of 1–2 weeks, followed by a taper over the next
2–6 weeks. In chronic HP, a similar trial of corticosteroids may be
used, although a variable component of fibrotic disease may be
cellular infiltrate with a lymphocytic predominance is observed that irreversible. In advanced cases of chronic HP with extensive lung
is frequently patchy in distribution. Bronchiolitis with the presence of fibrosis, lung transplantation may be necessary.
organizing exudate is also often observed. Fibrosis may be present as
well, particularly in chronic HP. Fibrotic changes may be focal but can ■■GLOBAL CONSIDERATIONS
be diffuse and severe with honeycombing in advanced cases, similar As the ever-expanding list of antigens and exposures associ-
to findings in IPF. ated with the development of HP suggests, populations at risk
Clinical Prediction Rule Although not meant as a set of vali- for HP will vary globally based on specifics of local occupa-
dated diagnostic criteria, a clinical prediction rule for predicting the tional, avocational, and environmental factors. Specific examples of
presence of HP has been published by the HP Study Group. They geographically limited HP include summer-type pneumonitis seen in
identified six statistically significant predictors for HP, the strongest of Japan and suberosis seen in cork workers in Portugal and Spain.
which was exposure to an antigen known to cause HP. Other predictive
criteria were the presence of serum precipitins, recurrent symptoms, PULMONARY INFILTRATES WITH
symptoms occurring 4–8 h after antigen exposure, crackles on inspira- EOSINOPHILIA
tion, and weight loss. Although eosinophils are normal constituents of the lungs, there are
several pulmonary eosinophilic syndromes that are characterized by
■■DIFFERENTIAL DIAGNOSIS pulmonary infiltrates on imaging along with an increased number of
Differentiating HP from other conditions that cause a similar constella- eosinophils in lung tissue, in sputum, and/or in BAL fluid, with resul-
tion of respiratory and systemic symptoms requires an increased index tant increased respiratory symptoms and the potential for systemic
of suspicion based on obtaining a history of possible exposure to an manifestations. Because the eosinophil plays such an important role
offending antigen. Presentations of acute or subacute HP can be misin each of these syndromes, it is often difficult to distinguish between
taken for respiratory infection. In cases of chronic disease, HP must be them, but there are important clinical and pathologic differences as
differentiated from interstitial lung disease, such as IPF or nonspecific well as differences in prognosis and treatment paradigms.
interstitial pneumonitis (NSIP); this can be a difficult task even with
lung biopsy. Given the presence of pulmonary infiltrates and nonca- ■■CLASSIFYING PULMONARY INFILTRATES WITH
seating granulomas on biopsy, sarcoidosis is also a consideration in the EOSINOPHILIA AND GENERAL APPROACH
differential diagnosis of HP. Unlike in HP, however, hilar adenopathy Because there are so many different diagnoses associated with pulmo-
may be prominent on chest x-ray, organs other than the lung may be nary infiltrates with eosinophilia, the first step in classifying pulmonary
involved, and noncaseating granulomas in pathologic specimens tend eosinophilic syndromes is distinguishing between primary pulmonary
to be well formed. Other inhalational syndromes, such as organic toxic eosinophilic lung disorders and those with eosinophilia that are sec-
dust syndrome (OTDS), can be misdiagnosed as HP. OTDS occurs with ondary to a specific cause such as a drug reaction, an infection, a malig-
exposure to organic dusts, including those produced by grains or mold nancy, or another pulmonary condition such as asthma. Table 282-2 lists
silage, but neither requires prior antigen sensitization nor is character- primary and secondary pulmonary eosinophilic disorders.
ized by positive serum precipitins. For each patient, a detailed history is of utmost importance and
can help elucidate what the underlying disease is. Details regarding
onset, timing, and precipitants of specific symptoms can help discern
TREATMENT one diagnosis from another. History regarding pharmacologic, occu-
Hypersensitivity Pneumonitis pational, and environmental exposures is instructive, and family and
travel history are crucial. In addition to details about the sinuses and
The mainstay of treatment for HP is antigen avoidance, if possible. lungs, it is important to inquire about systemic manifestations and
A careful exposure history must be obtained to attempt to identify assess for physical findings of cardiac, gastrointestinal (GI), neurologic,
the potential offending antigen and to identify the location where dermatologic, and genitourinary involvement, all of which may give
a patient is exposed. Once a potential antigen and location are clues to specific diagnoses. Once the details from history and physical
identified, efforts should be made to modify the environment to are teased out, laboratory testing (including measurements of blood

TABLE 282-2 Pulmonary Infiltrates with Eosinophilia TABLE 282-3 Diagnostic Criteria of Acute Eosinophilic Pneumonia 1973
Primary Pulmonary Eosinophilic Disorders Acute febrile illness with respiratory manifestations of <1 month in duration
Acute eosinophilic pneumonia Hypoxemic respiratory failure
Chronic eosinophilic pneumonia Diffuse pulmonary infiltrates on chest x-ray
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) Bronchoalveolar lavage eosinophilia >25%
Hypereosinophilic syndrome Absence of parasitic, fungal, or other infection
Pulmonary Disorders of Known Cause Associated with Eosinophilia Absence of drugs known to cause pulmonary eosinophilia
Asthma and eosinophilic bronchitis Quick clinical response to corticosteroids
Allergic bronchopulmonary aspergillosis Failure to relapse after discontinuation of corticosteroids

Bronchocentric granulomatosis
Drug/toxin reaction
Clinical Features and Etiology At presentation, acute eos-
Infection (Table 282-4) inophilic pneumonia is often mistaken for acute lung injury or acute
Parasitic/helminthic disease respiratory distress syndrome (ARDS), until a BAL is performed and
Nonparasitic infection reveals >25% eosinophils. Although the predominant symptoms of
Lung Diseases Associated with Eosinophilia acute eosinophilic pneumonia are cough, dyspnea, malaise, myalgias,
Cryptogenic organizing pneumonia night sweats, and pleuritic chest pain, physical examination findings
Hypersensitivity pneumonitis include high fevers, basilar rales, and rhonchi on forced expiration.
Idiopathic pulmonary fibrosis
Acute eosinophilic pneumonia most often affects males between age
20 and 40 with no history of asthma. Although no clear etiology has
Pulmonary Langerhans cell granulomatosis
been identified, several case reports have linked acute eosinophilic
Malignant Neoplasms Associated with Eosinophilia pneumonia to recent initiation of tobacco smoking or exposure to other
Leukemia environmental stimuli including dust from indoor renovations.
Lymphoma In addition to a suggestive history, the key to establishing a
Lung cancer diagnosis of acute eosinophilic pneumonia is the presence of >25%
Adenocarcinoma of various organs eosinophilia on BAL fluid. While lung biopsies show eosinophilic
Squamous cell carcinoma of various organs infiltration with acute and organizing diffuse alveolar damage, it is
Systemic Disease Associated with Eosinophilia
generally not necessary to proceed to biopsy to establish a diagnosis.
Although patients present with an elevated white blood cell count, in
Postradiation pneumonitis
contrast to other pulmonary eosinophilic syndromes, acute eosino-
Rheumatoid arthritis philic pneumonia is often not associated with peripheral eosinophilia
Sarcoidosis upon presentation. However, between 7 and 30 days of disease onset,
Sjögren’s syndrome peripheral eosinophilia often occurs with mean eosinophil counts of
1700. Erythrocyte sedimentation rate (ESR), C-reactive protein, and
eosinophils, cultures, and markers of inflammation), spirometry and IgE levels are high but nonspecific, whereas HRCT is always abnormal
radiographic imaging can help distinguish between different dis- with bilateral random patchy ground-glass or reticular opacities, and
eases. Often, however, BAL, transbronchial, or open lung biopsies are small pleural effusions in as many as two-thirds of patients. Pleural
required. In many cases, biopsies or noninvasive diagnostic studies of fluid is characterized by a high pH with marked eosinophilia.
other organs (e.g., echocardiogram, electromyogram, or bone marrow Clinical Course and Response to Therapy Although some
biopsy) can be helpful. patients improve spontaneously, most patients require admission to
■■PATHOPHYSIOLOGY an intensive care unit and respiratory support with either invasive
Pathologically, the pulmonary eosinophilic syndromes are character- (intubation) or noninvasive mechanical ventilation. However, what
ized by tissue infiltration by eosinophils (Fig. 282-2). In eosinophilic distinguishes acute eosinophilic pneumonia from both other cases of
granulomatosis with polyangiitis (EGPA), extravascular granulomas acute lung injury as well as some of the other pulmonary eosinophilic
and necrotizing vasculitis may occur in the lungs, as well as in the syndromes is the absence of organ dysfunction or multisystem organ
heart, skin, muscle, liver, spleen, and kidneys, and may be associated failure other than respiratory failure. One of the characteristic features
with fibrinoid necrosis and thrombosis. of acute eosinophilic pneumonia is the high degree of corticosteroid
The exact etiology of the various pulmonary eosinophilic syndromes responsiveness and the excellent prognosis. Another distinguishing
is unknown; however, it is felt that these syndromes result from dys- feature of acute eosinophilic pneumonia is that complete clinical and
regulated eosinophilopoiesis or an autoimmune process because of radiographic recovery without recurrence or residual sequelae occurs
the prominence of allergic features and the presence of immune com- in almost all patients within several weeks of initiation of therapy.
plexes, heightened T cell immunity, and altered humoral immunity as
evidenced by elevated IgE and rheumatoid factor. Because of its inte- ■■CHRONIC EOSINOPHILIC PNEUMONIA
gral involvement in eosinophilopoiesis, interleukin 5 (IL-5) has been In contrast to acute eosinophilic pneumonia, chronic eosinophilic
hypothesized to play an etiologic role. Monoclonal antibodies against pneumonia is a more indolent syndrome that is characterized by pul-
IL-5 are now in clinical use for the treatment of eosinophilic asthma monary infiltrates and eosinophilia in both the tissue and blood. Most
and are under investigation for conditions characterized by pulmonary patients are female nonsmokers with a mean age of 45, and patients do
infiltrates with eosinophilia. Antineutrophil cytoplasmic antibodies not usually develop the acute respiratory failure and significant hypox-
(ANCAs) are present in about half of patients with EGPA; binding of emia appreciated in acute eosinophilic pneumonia. Similar to EGPA, a
ANCAs to vascular walls likely contributes to vascular inflammation majority have asthma, with many having a history of allergies.
and injury as well as chemotaxis of inflammatory cells. Patients present with a subacute illness over weeks to months, with
cough, low-grade fevers, progressive dyspnea, weight loss, wheezing,
■■ACUTE EOSINOPHILIC PNEUMONIA malaise, and night sweats, and a chest x-ray with migratory bilateral
Acute eosinophilic pneumonia is a syndrome characterized by fevers, peripheral or pleural-based opacities. Although this “photographic
acute respiratory failure that often requires mechanical ventilation, dif- negative pulmonary edema” appearance on chest x-ray and chest
fuse pulmonary infiltrates, and pulmonary eosinophilia in a previously CT is pathognomonic of chronic eosinophilic pneumonia, <25%
healthy individual (Table 282-3). of patients present with this finding. Other radiographic findings

1974 include atelectasis, pleural effusions, lymphadenopathy, and septal may also occur and are important causes of death. Despite treatment,
line thickening. neurologic sequelae often do not completely resolve.
Almost 90% of patients have peripheral eosinophilia, with mean DERMATOLOGIC Approximately half of EGPA patients develop derma-
eosinophil counts of over 30% of total white blood cell count. BAL tologic manifestations. These include palpable purpura, skin nodules,
eosinophilia is also an important distinguishing feature with mean urticarial rashes, and livedo.
BAL eosinophil counts of ~60%. Both peripheral and BAL eosinophilia
are very responsive to treatment with corticosteroids. Other laboratory CARDIOVASCULAR Granulomas, vasculitis, and widespread myocardial
features of chronic eosinophilic pneumonia include increased ESR, damage may be found on biopsy or at autopsy, and cardiomyopathy
C-reactive protein, platelets, and IgE. Lung biopsy is also often not and heart failure may be seen in up to half of all patients but are often
required to establish a diagnosis, but may show accumulation of eosin- at least partially reversible. Acute pericarditis, constrictive pericardi-
ophils and histiocytes in the lung parenchyma and interstitium, as well tis, myocardial infarction, and other electrocardiographic changes all
as cryptogenic organizing pneumonia, but with minimal fibrosis. Non- may occur. The heart is a primary target organ in EGPA, and cardiac
PART 7
respiratory manifestations are uncommon, but arthralgias, neuropathy, involvement often portends a worse prognosis.
and skin and GI symptoms have all been reported; their presence may GI GI symptoms are common in EGPA and likely represent an eosin-
suggest EGPA or a hypereosinophilic syndrome. Another similarity is ophilic gastroenteritis characterized by abdominal pain, diarrhea, GI
the rapid response to corticosteroids with quick resolution of periph- bleeding, and colitis. Ischemic bowel, pancreatitis, and cholecystitis
eral and BAL eosinophilia and improvement in symptoms. In contrast have also been reported in association with EGPA and usually portend
to acute eosinophilic pneumonia, though, >50% of patients relapse, and a worse prognosis.
many require prolonged courses of corticosteroids for months to years.
RENAL Renal involvement is more common than once thought, and
■■EOSINOPHILIC GRANULOMATOSIS ~25% of patients have some degree of renal involvement. This may
WITH POLYANGIITIS (EGPA) include proteinuria, glomerulonephritis, renal insufficiency, and rarely,
Previously known as allergic angiitis granulomatosis or Churg-Strauss renal infarct.
syndrome, this complex syndrome is characterized by eosinophilic Lab Abnormalities Systemic eosinophilia is the hallmark labora-
vasculitis that may involve multiple organ systems including the lungs, tory finding in patients with EGPA and reflects the likely pathogenic
heart, skin, GI tract, and nervous system. Although EGPA is charac- role that the eosinophil plays in this disease. Eosinophilia >10% is one
terized by peripheral and pulmonary eosinophilia with infiltrates on of the defining features of this illness and may be as high as 75% of the
chest x-ray, the primary features that distinguish EGPA from other peripheral white blood cell count. It is present at the time of diagnosis
pulmonary eosinophilic syndromes are the presence of eosinophilic in >80% of patients, but may respond quickly (often within 24 h) to
vasculitis in the setting of asthma and involvement of multiple end initiation of systemic corticosteroid therapy. Even in the absence of
organs (a feature it shares with hypereosinophilic syndrome). Although systemic eosinophilia, tissue eosinophilia may be present.
perceived to be quite rare, in the last few years, there has appeared to Although not specific to EGPA, ANCAs are present in up to
be an increased incidence of this disease, particularly in association two-thirds of patients, mostly with a perinuclear staining pattern.
with various asthma therapies, including leukotriene modifiers and Nonspecific lab abnormalities that may be present in patients with
anti-IGE therapy with omalizumab, possibly due to concurrent sys- EGPA include a marked elevation in ESR, a normochromic normocytic
temic corticosteroid withdrawal (forme fruste EGPA). anemia, an elevated IgE, hypergammaglobulinemia, and positive rheu-
The primary features of EGPA include asthma, peripheral eosino- matoid factor and antinuclear antibodies (ANA). Although BAL often
philia, neuropathy, pulmonary infiltrates, paranasal sinus abnormality, reveals significant eosinophilia, this may be seen in other eosinophilic
and presence of eosinophilic vasculitis. The mean age at diagnosis is lung diseases. Similarly, PFT often reveals an obstructive defect similar
48 years, with a range of 14–74 years; the average length of time to asthma.
between diagnosis of asthma and vasculitis is 9 years. EGPA typically
occurs in several phases. The prodromal phase is characterized by Radiographic Features Chest x-ray abnormalities are extremely
asthma and allergic rhinitis, and usually begins when the individual common in EGPA and consist of bilateral, nonsegmental, patchy infil-
is in his or her twenties or thirties, typically persisting for many years. trates that often migrate and may be interstitial or alveolar in appear-
The eosinophilic infiltrative phase is characterized by peripheral eosin- ance. Reticulonodular and nodular disease without cavitation can be
ophilia and eosinophilic tissue infiltration of various organs including seen, as can pleural effusions and hilar adenopathy. The most com-
the lungs and GI tract. The third phase is the vasculitic phase and may mon CT findings include bilateral ground-glass opacity and airspace
be associated with constitutional signs and symptoms including fever, consolidation that is predominantly subpleural. Other CT findings
weight loss, malaise, and fatigue. This phasic progression supports the include bronchial wall thickening, hyperinflation, interlobular septal
hypothesis that there is a pathophysiologic continuum between eosin- thickening, lymph node enlargement, and pericardial and pleural effu-
ophilic asthma, chronic eosinophilic asthma, and EGPA. sions. Angiography may be used diagnostically and may show signs
Similar to other pulmonary eosinophilic syndromes, constitutional of vasculitis in the coronary, central nervous system, and peripheral
symptoms are very common in EGPA and include weight loss of vasculature.
10–20 lb, fevers, and diffuse myalgias and migratory polyarthralgias.
Myositis may be present with evidence of vasculitis on muscle biopsies. Treatment and Prognosis of EGPA Most patients diagnosed
In contrast to the eosinophilic pneumonias, EGPA involves many organ with EGPA have previously been diagnosed with asthma, rhinitis, and
systems including the lungs, skin, nerves, heart, GI tract, and kidneys. sinusitis, and have received treatment with inhaled or systemic corti-
costeroids. Because these agents are also the initial treatment of choice
Symptoms and Clinical Manifestations • RESPIRATORY
for EGPA patients, institution of these therapies in patients with EGPA
Most EGPA patients have asthma that arises later in life and in indi- who are perceived to have severe asthma may delay the diagnosis
viduals who have no family history of atopy. The asthma can often be of EGPA because signs of vasculitis may be masked. Corticosteroids
severe, and oral corticosteroids are often required to control symptoms dramatically alter the course of EGPA: up to 50% of those who are
but may lead to suppression of vasculitic symptoms. In addition to untreated die within 3 months of diagnosis, whereas treated patients
the more common symptoms of cough, dyspnea, sinusitis, and allergic have a 6-year survival of >70%. Common causes of death include heart
rhinitis, alveolar hemorrhage and hemoptysis may also occur. failure, cerebral hemorrhage, renal failure, and GI bleeding. Recent data
NEUROLOGIC Over three-fourths of EGPA patients have neurologic suggest that clinical remission may be obtained in >90% of patients
manifestations. Mononeuritis multiplex most commonly involves the treated; ~25% of those patients may relapse, often due to corticosteroid
peroneal nerve, but also involves the ulnar, radial, internal popliteal, tapering, with a rising eosinophil count heralding the relapse. Myocar-
and occasionally, cranial nerves. Cerebral hemorrhage and infarction dial, GI, and renal involvement most often portend a poor prognosis.

In such cases, treatment with higher doses of corticosteroids or the presentation of ABPA is an asthmatic phenotype, often accompanied by 1975
addition of cytotoxic agents such as cyclophosphamide is often war- cough with production of brownish plugs of mucus. ABPA has also been
ranted. Although survival does not differ between those treated or well described as a complication of cystic fibrosis. A workup for ABPA
untreated with cyclophosphamide, cyclophosphamide is associated may be beneficial in patients who carry a diagnosis of asthma but have
with a reduced incidence of relapse and an improved clinical response proven refractory to usual therapy. ABPA is a distinct diagnosis from
to treatment. Other therapies that have been used successfully in the simple asthma, characterized by prominent peripheral eosinophilia and
management of EGPA include azathioprine, methotrexate, rituximab, elevated circulating levels of IgE (>417 IU/mL). Establishing a diagno-
omalizumab, intravenous gamma globulin, and interferon α. Plasma sis of ABPA also requires establishing sensitivity to Aspergillus antigens
exchange has not been shown to provide any additional benefit. Recent by skin test reactivity, positive serum precipitins for Aspergillus, and/or
studies examining the efficacy of anti-IL-5 therapy compared with pla- direct measurement of circulating specific IgG and IgE to Aspergillus.
cebo have shown promise as safe and effective corticosteroid sparing

Central bronchiectasis is described as a classic finding on chest imaging
agents that can reduce exacerbations. in ABPA but is not necessary for making a diagnosis. Other possible
findings on chest imaging include patchy infiltrates and evidence of
■■HYPEREOSINOPHILIC SYNDROMES mucus impaction.
Hypereosinophilic syndromes (HES) constitute a heterogeneous group Systemic glucocorticoids may be used in the treatment of ABPA that
of disease entities manifest by persistent eosinophilia >1500 eosinophils/ is persistently symptomatic despite the use of inhaled therapies for
μL in association with end organ damage or dysfunction, in the asthma. Courses of glucocorticoids should be tapered over 3–6 months,
absence of secondary causes of eosinophilia. In addition to familial, and their use must be balanced against the risks of prolonged steroid
undefined, and overlap syndromes with incomplete criteria, the pre- therapy. Antifungal agents such as fluconazole and voriconazole given
dominant HES subtypes are the myeloproliferative and lymphocytic over a 4-month course reduce the antigenic stimulus in ABPA and
variants. The myeloproliferative variants may have acquired genetic may therefore modulate disease activity in selected patients. The use
abnormalities, including to platelet-derived growth factor receptor of monoclonal antibody against IgE (omalizumab) has been described
α (PDGFRα), attributed to a constitutively activated tyrosine kinase in treating severe ABPA, particularly in individuals with ABPA as a
fusion protein (Fip1L1-PDGFRα) due to a chromosomal deletion on complication of cystic fibrosis.
4q12; this variant is often responsive to imatinib. Myeloproliferative ABPA-like syndromes have been reported as a result to sensitization
HES may also be associated with mutations involving platelet- to several non-Aspergillus species fungi. However, these conditions are
derived growth factor β (PDGFRβ), Janus kinase 2 (JAK2), and substantially rarer than ABPA, which may be present in a significant
fibroblast growth factor receptor 1 (FGFR1). Chronic eosinophilic proportion of patients with refractory asthma.
leukemia with demonstrable cytogenetic abnormalities and/or blasts
on peripheral smear is often categorized with the myeloproliferative ■■INFECTIOUS PROCESSES
HES. Clinical and laboratory findings in myeloproliferative HES may Infectious etiologies of pulmonary eosinophilia are largely due to hel-
include dysplastic peripheral eosinophils, increased serum vitamin B12, minths and are of particular importance in the evaluation of pulmonary
increased tryptase, anemia, thrombocytopenia, splenomegaly, bone eosinophilia in tropical environments and in the developing world
marrow cellularity >80%, spindle-shaped mast cells, and myelofibrosis. (Table 282-4). These infectious conditions may also be considered in
The evaluation for lymphocytic HES includes searching for abnormal T recent travelers to endemic regions. Loffler syndrome refers to tran-
cell clonal populations. sient pulmonary infiltrates with eosinophilia that occurs in response to
Extrapulmonary Manifestations of HES More common in passage of helminthic larvae through the lungs, most commonly larvae
men than in women, HES occurs between the ages of 20 and 50 and is of Ascaris species (roundworm). Symptoms are generally self-limited
characterized by significant extrapulmonary involvement, including and may include dyspnea, cough, wheeze, and hemoptysis. Loffler
infiltration of the heart, GI tract, kidney, liver, joints, and skin. Cardiac syndrome may also occur in response to hookworm infection with
involvement includes myocarditis and/or endomyocardial fibrosis, as Ancylostoma duodenale or Necator americanus. Chronic Strongyloides
well as a restrictive cardiomyopathy. stercoralis infection can lead to recurrent respiratory symptoms with
Pulmonary Manifestations of HES Similar to the other pulmo-

nary eosinophilic syndromes, these HES are manifested by high levels TABLE 282-4 Infectious Causes of Pulmonary Eosinophilia
of blood, BAL, and tissue eosinophilia. Lung involvement occurs in Löffler Syndrome
40% of these patients and is characterized by cough and dyspnea, as Ascaris
well as pulmonary infiltrates. Although it is often difficult to discern Hookworm
the pulmonary infiltrates and effusions seen on chest x-ray from pul- Schistosomiasis
monary edema resulting from cardiac involvement, CT scan findings
Heavy Parasite Burden
include interstitial infiltrates, ground-glass opacities, and small nod-
ules. HES are typically not associated with ANCA. IgE may be elevated Strongyloidiasis
in lymphocytic HES variants. Direct Pulmonary Penetration
Paragonimiasis
Course and Response to Therapy Unlike the other pulmonary
Visceral larval migrans
eosinophilic syndromes, less than half of patients with these HES
respond to corticosteroids as first-line therapy. Although other treat- Immunologic Response to Organisms in Lungs
ment options include hydroxyurea, cyclosporine, and interferon, the Filariasis
tyrosine kinase inhibitor imatinib has emerged as an important ther- Dirofilariasis
apeutic option for patients with the myeloproliferative variant, partic- Cystic Disease
ularly in individuals with the Fip1L1-PDGFRA gene fusion. Anti-IL-5 Echinococcus
therapy with mepolizumab also holds promise for these patients and is
Cysticercosis
currently being investigated.
Other Nonparasitic
ALLERGIC BRONCHOPULMONARY Coccidioidomycosis
Basidiobolomycosis
ASPERGILLOSIS
Allergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic Paracoccidioidomycosis
pulmonary disorder that occurs in response to allergic sensitization Tuberculosis
to antigens from Aspergillus species fungi. The predominant clinical Source: Adapted from P Akuthota, PF Weller: Clin Microbiol Rev 25:649, 2012.

1976 peripheral eosinophilia between flares. In immunocompromised hosts, exposed people may be identified as having the disease or prevented
including patients on glucocorticoids, a severe, potentially fatal, hyper- from getting it. In addition, new associations between exposure and
infection syndrome can result from Strongyloides infection. Paragonim- disease may be identified (e.g., nylon flock worker’s lung disease and
iasis, filariasis, and visceral larval migrans can all cause pulmonary diacetyl-induced bronchiolitis obliterans).
eosinophilia as well. Although the exact proportion of lung disease due to occupational
and environmental factors is unknown, a large number of individuals
■■DRUGS AND TOXINS are at risk. For example, 15–20% of the burden of adult asthma and
A host of medications are associated with the development of pulmo- chronic obstructive pulmonary disease (COPD) has been estimated to
nary infiltrates with peripheral eosinophilia. Therefore, drug reaction be due to occupational factors.
must always be included in the differential diagnosis of pulmonary
eosinophilia. Although the list of medications associated with pulmo- ■■HISTORY AND EXPOSURE ASSESSMENT
nary eosinophilia is ever expanding, common culprits include nonste- The patient’s history is of paramount importance in assessing any
PART 7
roidal anti-inflammatory medications and systemic antibiotics, most potential occupational or environmental exposure. Inquiry into specific
specifically nitrofurantoin. Additionally, various and diverse envi- work practices should include questions about the specific contaminants
ronmental exposures such as particulate metals, scorpion stings, and involved, the presence of visible dusts, chemical odors, the size and
inhalational drugs of abuse may also cause pulmonary eosinophilia. ventilation of workspaces, the use of respiratory protective equipment,
Radiation therapy for breast cancer has been linked with eosinophilic
and whether co-workers have similar complaints. The temporal associ-

pulmonary infiltration as well. The mainstay of treatment is removal of ation of exposure at work and symptoms may provide clues to occupa-
the offending exposure, although glucocorticoids may be necessary if tion-related disease. In addition, the patient must be questioned about
respiratory symptoms are severe. alternative sources of exposure to potentially toxic agents, including
hobbies, home characteristics, exposure to secondhand smoke, and
■■GLOBAL CONSIDERATIONS proximity to traffic or industrial facilities. Short-term and long-term
In the United States, drug-induced eosinophilic pneumonias
exposures to potential toxic agents in the distant past also must be
are the most common cause of eosinophilic pulmonary infil-
considered.
trates. A travel history or evidence of recent immigration
Workers in the United States have the right to know about potential
should prompt the consideration of parasite-associated disorders. Trop-
hazards in their workplaces under federal Occupational Safety and
ical eosinophilia is usually caused by filarial infection; however, eosin-
Health Administration (OSHA) regulations. Employers must provide
ophilic pneumonias also occur with other parasites such as Ascaris spp.,
specific information about potential hazardous agents in products
Ancylostoma spp., Toxocara spp., and Strongyloides stercoralis. Tropical
being used through Safety Data Sheets as well as training in personal
eosinophilia due to Wuchereria bancrofti or Wuchereria malayi occurs
protective equipment and environmental control procedures. However,
most commonly in southern Asia, Africa, and South America and is
the introduction of new processes and/or new chemical compounds
treated successfully with diethylcarbamazine. In the United States,
may change exposure significantly, and often only the employee on the
Strongyloides is endemic to the southeastern and Appalachian regions.
production line is aware of the change. For the physician caring for a
■■FURTHER READING patient with a suspected work-related illness, a visit to the work site
Akuthota P, Weller PF: Eosinophilic pneumonias. Clin Microbiol Rev can be very instructive. Alternatively, an affected worker can request an
25:649, 2012. inspection by OSHA. If reliable environmental sampling data are avail-
Cottin V: Eosinophilic Lung Diseases. Clin Chest Med 37:535, 2016. able, that information should be used in assessing a patient’s exposure.
Selman M et al: Hypersensitivity pneumonitis: Insights in diagnosis Because chronic diseases may result from exposure over many years,
and pathobiology. Am J Respir Crit Care Med 186:314, 2012. current environmental measurements should be combined with work
histories to arrive at estimates of past exposure.
■■LABORATORY TESTS
Exposures to inorganic and organic dusts can cause interstitial lung
disease that presents with a restrictive pattern and a decreased diffus-
ing capacity (Chap. 279). Similarly, exposures to a number of dusts or
283 Occupational and

Environmental Lung Disease
chemical agents may result in occupational asthma or COPD that is
characterized by airway obstruction. Measurement of change in forced
expiratory volume (FEV1) before and after a working shift can be used
to detect an acute bronchoconstrictive response.
John R. Balmes The chest radiograph is useful in detecting and monitoring the pul-
monary response to mineral dusts, certain metals, and organic dusts
capable of inducing hypersensitivity pneumonitis. The International
Occupational and environmental lung diseases are difficult to dis- Labour Organisation (ILO) International Classification of Radiographs
tinguish from those of nonenvironmental origin. Virtually all major of Pneumoconioses classifies chest radiographs by the nature and size
categories of pulmonary disease can be caused by environmental of opacities seen and the extent of involvement of the parenchyma. In
agents, and environmentally related disease usually presents clinically general, small rounded opacities are seen in silicosis or coal worker’s
in a manner indistinguishable from that of disease not caused by such pneumoconiosis, and small linear opacities are seen in asbestosis.
agents. In addition, the etiology of many diseases may be multifacto- Although useful for epidemiologic studies and screening large num-
rial; occupational and environmental factors may interact with other bers of workers, the ILO system can be problematic when applied to
factors (such as smoking and genetic risk). It is often only after a careful an individual worker’s chest radiograph. With dusts causing rounded
exposure history is taken that the underlying workplace or general opacities, the degree of involvement on the chest radiograph may
environmental exposure is uncovered. be extensive, whereas pulmonary function may be only minimally
Why is knowledge of occupational or environmental etiology so impaired. In contrast, in pneumoconiosis causing linear, irregular
important? Patient management and prognosis are affected signifi- opacities like those seen in asbestosis, the radiograph may lead to
cantly by such knowledge. For example, patients with occupational underestimation of the severity of the impairment until relatively late
asthma or hypersensitivity pneumonitis often cannot be managed in the disease. For patients with a history of asbestos exposure, conven-
adequately without cessation of exposure to the offending agent. Estab- tional computed tomography (CT) is more sensitive for the detection
lishment of cause may have significant legal and financial implications of pleural thickening, and high-resolution CT (HRCT) improves the
for a patient who no longer can work in his or her usual job. Other detection of asbestosis.

Other procedures that may be of use in identifying the role of toxic agents can deposit and be carried to the lower airways, is dom- 1977
environmental exposures in causing lung disease include skin prick inated by particles <2.5 μm (fine-mode fraction). These fine particles
testing or specific IgE antibody titers for evidence of immediate hyper- are created primarily by the burning of fossil fuels or high-temper-
sensitivity to agents capable of inducing occupational asthma (flour ature industrial processes resulting in condensation products from
antigens in bakers), specific IgG precipitating antibody titers for agents gases, fumes, or vapors. The smallest particles, those <0.1 μm in size,
capable of causing hypersensitivity pneumonitis (pigeon antigen in represent the ultrafine fraction and make up the largest number of
bird handlers), and assays for specific cell-mediated immune responses particles; they tend to remain in the airstream and deposit in the lung
(beryllium lymphocyte proliferation testing in nuclear workers or only on a random basis as they come into contact with the alveolar
tuberculin skin testing in health care workers). Sometimes a bronchos- walls. If they do deposit, however, particles of this size range may
copy to obtain transbronchial biopsies of lung tissue may be required penetrate into the circulation and be carried to extrapulmonary sites.
for histologic diagnosis (chronic beryllium disease [CBD]). Rarely, New technologies create particles of this size (“nanoparticles”) for use
CHAPTER 283 Occupational and Environmental Lung Disease

video-assisted thoracoscopic surgery to obtain a larger sample of lung in many commercial applications. Besides the size characteristics of
tissue may be required to determine the specific diagnosis of environ- particles and the solubility of gases, the actual chemical composition,
mentally induced lung disease (hypersensitivity pneumonitis or giant mechanical properties, and immunogenicity or infectivity of inhaled
cell interstitial pneumonitis due to cobalt exposure). material determine in large part the nature of the diseases found
among exposed persons.
■■DETERMINANTS OF INHALATIONAL EXPOSURE
The chemical and physical characteristics of inhaled agents affect both
the dose and the site of deposition in the respiratory tract. Water- OCCUPATIONAL EXPOSURES AND
soluble gases such as ammonia and sulfur dioxide are absorbed in PULMONARY DISEASE
the lining fluid of the upper and proximal airways and thus tend to Table 283-1 provides broad categories of exposure in the workplace
produce irritative and bronchoconstrictive responses. In contrast, and diseases associated with chronic exposure in those industries.
nitrogen dioxide and phosgene, which are less soluble, may penetrate
to the bronchioles and alveoli in sufficient quantities to produce acute
chemical pneumonitis. ■■ASBESTOS-RELATED DISEASES
Particle size of air contaminants must also be considered. Because Asbestos is a generic term for several different mineral silicates, includ-
of their settling velocities in air, particles >10–15 μm in diameter do ing chrysolite, amosite, anthophyllite, and crocidolite. In addition to
not penetrate beyond the nose and throat. Particles <10 μm in size are workers involved in the production of asbestos products (mining,
deposited below the larynx. These particles are divided into three size milling, and manufacturing), many workers in the shipbuilding and
fractions on the basis of their size characteristics and sources. Particles construction trades, including pipe fitters and boilermakers, were
~2.5–10 μm (coarse-mode fraction) contain crustal elements such as occupationally exposed because asbestos was widely used during the
silica, aluminum, and iron. These particles mostly deposit relatively twentieth century for its thermal and electrical insulation properties.
high in the tracheobronchial tree. Although the total mass of an Asbestos also was used in the manufacture of fire-resistant textiles,
ambient sample is dominated by these larger respirable particles, the in cement and floor tiles, and in friction materials such as brake and
number of particles, and therefore the surface area on which potential clutch linings.
TABLE 283-1 Categories of Occupational Exposure and Associated Respiratory Conditions

OCCUPATIONAL EXPOSURES NATURE OF RESPIRATORY RESPONSES COMMENT
Inorganic Dusts
Asbestos: mining, processing, construction, ship Fibrosis (asbestosis), pleural disease, cancer, Virtually all new mining and construction with asbestos
repair mesothelioma done in developing countries
Silica: mining, stone cutting, sandblasting, Fibrosis (silicosis), progressive massive fibrosis Improved protection in United States; persistent risk in
quarrying (PMF), cancer, tuberculosis, chronic obstructive developing countries
pulmonary disease (COPD)
Coal dust: mining Fibrosis (coal worker’s pneumoconiosis), PMF, Risk persists in certain areas of United States, increasing
COPD in countries where new mines open
Beryllium: processing alloys for high-tech Acute pneumonitis (rare), chronic granulomatous Risk in high-tech industries persists
industries disease, lung cancer (highly suspect)
Other metals: aluminum, chromium, cobalt, Wide variety of conditions from acute New diseases appear with new process development
nickel, titanium, tungsten carbide, or “hard pneumonitis to lung cancer and asthma
metal” (contains cobalt)
Organic Dusts
Cotton dust: milling, processing Byssinosis (an asthma-like syndrome), chronic Increasing risk in developing countries with drop in
bronchitis, COPD United States as jobs shift overseas
Grain dust: elevator agents, dock workers, Asthma, chronic bronchitis, COPD Risk shifting more to migrant labor pool
milling, bakers
Other agricultural dusts: fungal spores, vegetable Hypersensitivity pneumonitis (farmer’s lung), Important in migrant labor pool but also resulting from
products, insect fragments, animal dander, bird asthma, chronic bronchitis in-home exposures
and rodent feces, endotoxins, microorganisms,
pollens
Toxic chemicals: wide variety of industries; see Asthma, chronic bronchitis, COPD, Reduced risk with recognized hazards; increasing risk for
Table 283-2 hypersensitivity pneumonitis, pneumoconiosis, developing countries where controlled labor practices are
and cancer less stringent
Other Environmental Agents
Uranium and radon daughters, secondhand Occupational exposures estimated to contribute In-home exposures important; in developing countries,
tobacco smoke, polycyclic aromatic hydrocarbons to up to 10% of all lung cancers; chronic biomass smoke is a major risk factor for COPD among
(PAHs), biomass smoke, diesel exhaust, welding bronchitis, COPD, and fibrosis women in these countries
fumes, wood finishing

1978 Exposure to asbestos is not limited to persons who directly handle
the material. Cases of asbestos-related diseases have been encountered
in individuals with only bystander exposure, such as painters and elec-
tricians who worked alongside insulation workers in a shipyard. Com-
munity exposure resulted from the use of asbestos-containing mine
and mill tailings as landfill, road surface, and playground material
(e.g., Libby, MT, the site of a vermiculite mine in which the ore was
contaminated with asbestos). Finally, exposure can occur from the dis-
turbance of naturally occurring asbestos (e.g., from increasing residen-
tial development in the foothills of the Sierra Mountains in California).
Asbestos has largely been replaced in the developed world with
synthetic mineral fibers such as fiberglass and refractory ceramic
PART 7
fibers, but it continues to be used in the developing world. The major

health effects from exposure to asbestos are pleural and pulmonary
fibrosis, cancers of the respiratory tract, and pleural and peritoneal
mesothelioma.
Asbestosis is a diffuse interstitial fibrosing disease of the lung that is

directly related to the intensity and duration of exposure. The disease
resembles other forms of diffuse interstitial fibrosis (Chap. 287). Usu-
ally, exposure has taken place for at least 10 years before the disease
becomes manifest. The mechanisms by which asbestos fibers induce
lung fibrosis are not completely understood but are known to involve
oxidative injury due to the generation of reactive oxygen species by
the transition metals on the surface of the fibers as well as from cells
engaged in phagocytosis.
Past exposure to asbestos is specifically indicated by pleural plaques
on chest radiographs, which are characterized by either thickening or
calcification along the parietal pleura, particularly along the lower
lung fields, the diaphragm, and the cardiac border. Without additional
manifestations, pleural plaques imply only exposure, not pulmonary
impairment. Benign pleural effusions also may occur. The fluid is
typically a serous or bloody exudate. The effusion may be slowly pro-
gressive or may resolve spontaneously.
Irregular or linear opacities that usually are first noted in the lower
lung fields are the chest radiographic hallmark of asbestosis. An indis-
tinct heart border or a “ground-glass” appearance in the lung fields
may be seen. HRCT may show distinct changes of subpleural curvi-
linear lines 5–10 mm in length that appear to be parallel to the pleural
surface (Fig. 283-1).
Pulmonary function testing in asbestosis reveals a restrictive pattern
with a decrease in both lung volumes and diffusing capacity. There
may also be evidence of mild airflow obstruction (due to peribronchi-
olar fibrosis).
Because no specific therapy is available for asbestosis, supportive
care is the same as that given to any patient with diffuse interstitial
fibrosis of any cause. In general, newly diagnosed cases will have FIGURE 283-1 Asbestosis. A. Frontal chest radiograph shows bilateral calcified
resulted from exposures that occurred many years before. pleural plaques consistent with asbestos-related pleural disease. Poorly defined
Lung cancer (Chap. 74) is the most common cancer associated with linear and reticular abnormalities are seen in the lower lobes bilaterally. B. Axial
asbestos exposure. The excess frequency of lung cancer (all histologic high-resolution computed tomography of the thorax obtained through the lung
bases shows bilateral, subpleural reticulation (black arrows), representing fibrotic
types) in asbestos workers is associated with a minimum latency of lung disease due to asbestosis. Subpleural lines are also present (arrowheads),
15–19 years between first exposure and development of the disease. characteristic of, though not specific for, asbestosis. Calcified pleural plaques
Persons with more exposure are at greater risk of disease. In addition, representing asbestos-related pleural disease (white arrows) are also evident.
there is a significant interactive effect of smoking and asbestos expo-
sure that results in greater risk than what would be expected from the
additive effect of each factor.
Mesotheliomas (Chap. 288), both pleural and peritoneal, are also ■■SILICOSIS
associated with asbestos exposure. In contrast to lung cancers, these Despite being one of the oldest known occupational pulmonary haz-
tumors do not appear to be associated with smoking. Relatively short- ards, free silica (SiO2), or crystalline quartz, is still a major cause of
term asbestos exposures of ≤1–2 years, occurring up to 40 years in the disease. The major occupational exposures include mining; stonecut-
past, have been associated with the development of mesotheliomas (an ting; sand blasting; glass and cement manufacturing; foundry work;
observation that emphasizes the importance of obtaining a complete packing of silica flour; and quarrying, particularly of granite. Most
environmental exposure history). Although the risk of mesothelioma is often, pulmonary fibrosis due to silica exposure (silicosis) occurs in a
much less than that of lung cancer among asbestos-exposed workers, dose-response fashion after many years of exposure.
>2000 cases were reported in the United States per year at the start of Workers heavily exposed through sandblasting in confined spaces,
the twenty-first century. tunneling through rock with a high quartz content (15–25%), or the
Because epidemiologic studies have shown that >80% of mesothe- manufacture of abrasive soaps may develop acute silicosis with as
liomas may be associated with asbestos exposure, documented meso- little as 10 months of exposure. The clinical and pathologic features of
thelioma in a patient with occupational or environmental exposure to acute silicosis are similar to those of pulmonary alveolar proteinosis
asbestos may be compensable. (Chap. 287). The chest radiograph may show profuse miliary infiltration

1979

FIGURE 283-2 Acute silicosis. This high-resolution computed tomography scan
shows multiple small nodules consistent with silicosis but also diffuse ground-
glass densities with thickened intralobular and interlobular septa producing
polygonal shapes. This has been referred to as “crazy paving.”
or consolidation, and there is a characteristic HRCT pattern known as

“crazy paving” (Fig. 283-2). The disease may be quite severe and pro-
gressive despite the discontinuation of exposure. Whole-lung lavage FIGURE 283-3 Chronic silicosis. A. Frontal chest radiograph in a patient with
may provide symptomatic relief and slow the progression. silicosis shows variably sized, poorly defined nodules (arrows) predominating in
With long-term, less intense exposure, small rounded opacities in the upper lobes. B. Axial thoracic computed tomography image through the lung
the upper lobes may appear on the chest radiograph after 15–20 years apices shows numerous small nodules, more pronounced in the right upper lobe.
A number of the nodules are subpleural in location (arrows).
of exposure, usually without associated impairment of lung function
(simple silicosis). Calcification of hilar nodes may occur in as many as
20% of cases and produces a characteristic “eggshell” pattern. Silicotic ■■COAL WORKER’S PNEUMOCONIOSIS (CWP)
nodules may be identified more readily by HRCT (Fig. 283-3). The Occupational exposure to coal dust can lead to CWP, which has enor-
nodular fibrosis may be progressive in the absence of further exposure, mous social, economic, and medical significance in every nation in
with coalescence and formation of nonsegmental conglomerates of which coal mining is an important industry. Simple radiographically
irregular masses >1 cm in diameter (complicated silicosis). These masses identified CWP is seen in ~10% of all coal miners and in as many as
can become quite large, and when this occurs, the term progressive 50% of anthracite miners with >20 years of work on the coal face. The
massive fibrosis (PMF) is applied. Significant functional impairment prevalence of disease is lower in workers in bituminous coal mines.
with both restrictive and obstructive components may be associated With prolonged exposure to coal dust (i.e., 15–20 years), small,
with PMF. rounded opacities similar to those of silicosis may develop. As in silico-
Because silica causes alveolar macrophage dysfunction, patients sis, the presence of these nodules (simple CWP) usually is not associated
with silicosis are at greater risk of acquiring lung infections that with pulmonary impairment. In addition to CWP, coal dust can cause
involve these cells as a primary defense (Mycobacterium tuberculosis, chronic bronchitis and COPD (Chap. 286). The effects of coal dust are
atypical mycobacteria and fungi). Because of the increased risk of additive to those of cigarette smoking.
active tuberculosis, the recommended treatment of latent tuberculosis Complicated CWP is manifested by the appearance on the chest
in these patients is longer. Silica has immunoadjuvant properties and radiograph of nodules ≥1 cm in diameter generally confined to the
another potential clinical complication of silicosis is autoimmune con- upper half of the lungs. As in silicosis, this condition can progress to
nective tissue disorders such as rheumatoid arthritis and scleroderma. PMF that is accompanied by severe lung function deficits and associ-
In addition, there are sufficient epidemiologic data that the Interna- ated with premature mortality. Despite improvements in technology to
tional Agency for Research on Cancer lists silica as a probable lung protect coal miners, cases of PMF still occur in the United States at a
carcinogen. disturbing rate.
Other, less hazardous silicates include fuller’s earth, kaolin, mica, Caplan syndrome (Chap. 351), first described in coal miners but
diatomaceous earths, silica gel, soapstone, carbonate dusts, and cement subsequently in patients with silicosis, is the combination of pneumo-
dusts. The production of fibrosis in workers exposed to these agents is coniotic nodules and seropositive rheumatoid arthritis. Silica is often
believed to be related either to the free silica content of these dusts or, present in anthracitic coal dust and its presence may contribute to risk
for substances that contain no free silica, to the potentially large dust of PMF.
loads to which these workers may be exposed. Some silicates, includ-
ing talc and vermiculite, may be contaminated with asbestos. Fibrosis of ■■CHRONIC BERYLLIUM DISEASE
lung or pleura, lung cancer, and mesothelioma have been associated Beryllium is a lightweight metal with tensile strength, good electrical
with chronic exposure to talc and vermiculite dusts. conductivity, and value in the control of nuclear reactions through

1980 its ability to quench neutrons. Although beryllium may produce an yarns for textiles and rope making are at risk for an asthma-like syn-
acute pneumonitis, it is far more commonly associated with a chronic drome known as byssinosis. The risk of byssinosis is associated with
granulomatous inflammatory disease that is similar to sarcoidosis both cotton dust and endotoxin levels in the workplace environment.
(Chap. 360). Unless one inquires specifically about occupational Byssinosis is characterized clinically as occasional (early-stage) and
exposures to beryllium in the manufacture of alloys, ceramics, or high- then regular (late-stage) chest tightness toward the end of the first day
technology electronics in a patient with sarcoidosis, one may miss of the workweek (“Monday chest tightness”). Exposed workers may
entirely the etiologic relationship to the occupational exposure. What show a significant drop in FEV1 over the course of a Monday work-
distinguishes CBD from sarcoidosis is evidence of a specific cell- shift. Initially the symptoms do not recur on subsequent days of the
mediated immune response (i.e., delayed hypersensitivity) to beryllium. week, but in a subset of workers, chest tightness may recur or persist
The test that usually provides this evidence is the beryllium lympho- throughout the workweek. After >10 years of exposure, workers with
cyte proliferation test (BeLPT). The BeLPT compares the in vitro pro- recurrent symptoms are more likely to have an obstructive pattern on
liferation of lymphocytes from blood or bronchoalveolar lavage in the pulmonary function testing.
PART 7
presence of beryllium salts with that of unstimulated cells. Proliferation Dust exposure can be reduced by the use of exhaust hoods, general
is usually measured by lymphocyte uptake of radiolabeled thymidine. increases in ventilation, and wetting procedures, but respiratory pro-
Chest imaging findings are similar to those of sarcoidosis (nodules tective equipment may be required during certain operations. Regular
along septal lines) except that hilar adenopathy is somewhat less com- surveillance of pulmonary function in cotton dust–exposed workers
mon. As with sarcoidosis, pulmonary function test results may show using spirometry before and after the workshift is required by OSHA.
restrictive and/or obstructive ventilatory deficits and decreased dif- All workers with persistent symptoms or significantly reduced levels
fusing capacity. With early disease, both chest imaging studies and pul- of pulmonary function should be moved to areas of lower risk of
monary function tests may be normal. Fiberoptic bronchoscopy with exposure.
transbronchial lung biopsy usually is required to make the diagnosis of
CBD. In a beryllium-sensitized individual, the presence of noncaseat-
Grain Dust Worldwide, many farmers and workers in grain stor-
age facilities are exposed to grain dust. The presentation of obstructive
ing granulomas or monocytic infiltration in lung tissue establishes the
airway disease in grain dust–exposed workers is virtually identical to
diagnosis. Accumulation of beryllium-specific CD4+ T cells occurs in
the characteristic findings in cigarette smokers, i.e., persistent cough,
the granulomatous inflammation seen on lung biopsy. Susceptibility to
mucus hypersecretion, wheeze and dyspnea on exertion, and reduced
CBD is highly associated with human leukocyte antigen DP (HLA-DP)
FEV1 and FEV1/FVC (forced vital capacity) ratio (Chap. 279).
alleles that have a glutamic acid in position 69 of the β chain.
Dust concentrations in grain elevators vary greatly but can be
■■OTHER METALS >10,000 μg/m3 with many particles in the respirable size range. The
Aluminum and titanium dioxide have been rarely associated with effect of grain dust exposure is additive to that of cigarette smoking,
a sarcoid-like reaction in lung tissue. Exposure to dust containing with ~50% of workers who smoke having symptoms. Smoking grain
tungsten carbide, also known as “hard metal,” may produce giant cell dust–exposed workers are more likely to have obstructive ventilatory
interstitial pneumonitis. Cobalt is a constituent of tungsten carbide and deficits on pulmonary function testing. As in byssinosis, endotoxin
is the likely etiologic agent of both the interstitial pneumonitis and the may play a role in grain dust–induced chronic bronchitis and COPD.
occupational asthma that may occur. The most common exposures to Farmer’s Lung This condition results from exposure to moldy hay
tungsten carbide occur in tool and dye, saw blade, and drill bit manu- containing spores of thermophilic actinomycetes that produce a hyper-
facture. Diamond polishing may also involve exposure to cobalt dust. sensitivity pneumonitis (Chap. 282). A patient with acute farmer’s
In patients with interstitial lung disease, one should always inquire lung presents 4–8 h after exposure with fever, chills, malaise, cough,
about exposure to metal fumes and/or dusts. Especially when sarcoi- and dyspnea without wheezing. The history of exposure is obviously
dosis appears to be the diagnosis, one should always consider possible essential to distinguish this disease from influenza or pneumonia with
CBD. similar symptoms. In the chronic form of the disease, the history of
■■OTHER INORGANIC DUSTS repeated attacks after similar exposure is important in differentiating
Most of the inorganic dusts discussed thus far are associated with the this syndrome from other causes of patchy fibrosis (e.g., sarcoidosis).
production of either dust macules or interstitial fibrotic changes in the A wide variety of other organic dusts are associated with the occur-
lung. Other inorganic and organic dusts (see categories in Table 283-1), rence of hypersensitivity pneumonitis (Chap. 282). For patients who
along with some of the dusts previously discussed, are associated with present with hypersensitivity pneumonitis, specific and careful inquiry
chronic mucus hypersecretion (chronic bronchitis), with or without about occupations, hobbies, and other home environmental exposures
reduction of expiratory flow rates. Cigarette smoking is the major is necessary to uncover the source of the etiologic agent.
cause of these conditions, and any effort to attribute some component ■■TOXIC CHEMICALS
of the disease to occupational and environmental exposures must take Exposure to toxic chemicals affecting the lung generally involves gases
cigarette smoking into account. Most studies suggest an additive effect and vapors. A common accident is one in which the victim is trapped
of dust exposure and smoking. The pattern of the irritant dust effect in a confined space where the chemicals have accumulated to harmful
is similar to that of cigarette smoking, suggesting that small airway levels. In addition to the specific toxic effects of the chemical, the victim
inflammation may be the initial site of pathologic response in those often sustains considerable anoxia, which can play a dominant role in
cases and continued exposure may lead to chronic bronchitis and determining whether the individual survives.
COPD. Table 283-2 lists a variety of toxic agents that can produce acute
■■ORGANIC DUSTS and sometimes life-threatening reactions in the lung. All these agents
Some of the specific diseases associated with organic dusts are dis- in sufficient concentrations have been demonstrated, at least in animal
cussed in detail in the chapters on asthma (Chap. 281) and hypersensi- studies, to affect the lower airways and disrupt alveolar architecture,
tivity pneumonitis (Chap. 282). Many of these diseases are named for either acutely or as a result of chronic exposure. Some of these agents
the specific setting in which they are found, e.g., farmer’s lung, malt may be generated acutely in the environment (see below).
worker’s disease, and mushroom worker’s disease. Often the temporal Firefighters and fire victims are at risk of smoke inhalation, an
relation of symptoms to exposure furnishes the best evidence for the important cause of acute cardiorespiratory failure. Smoke inhalation
diagnosis. Three occupational exposures are singled out for discussion kills more fire victims than does thermal injury. Carbon monoxide
here because they affect the largest proportions of workers. poisoning with resulting significant hypoxemia can be life-threatening
(Chap. 450). Synthetic materials (plastic, polyurethanes), when burned,
Cotton Dust (Byssinosis) Workers occupationally exposed to may release a variety of other toxic agents (such as cyanide and
cotton dust (but also to flax, hemp, or jute dust) in the production of hydrochloric acid), and this must be considered in evaluating smoke

TABLE 283-2 Selected Common Toxic Chemical Agents That Affect the Lung 1981
ACUTE EFFECTS FROM HIGH OR CHRONIC EFFECTS FROM RELATIVELY

AGENT(s) SELECTED EXPOSURES ACCIDENTAL EXPOSURE LOW EXPOSURE
Acid anhydrides Manufacture of resin esters, polyester resins, Nasal irritation, cough Asthma, chronic bronchitis, hypersensitivity
thermoactivated adhesives pneumonitis
Acid fumes: H2SO4, Manufacture of fertilizers, chlorinated organic Mucous membrane irritation, followed Bronchitis and suggestion of mildly reduced
HNO3 compounds, dyes, explosives, rubber products, by chemical pneumonitis 2–3 days pulmonary function in children with lifelong
metal etching, plastics later residential exposure to high levels
Acrolein and other By-product of burning plastics, woods, tobacco Mucous membrane irritant, decrease Upper respiratory tract irritation
aldehydes smoke in lung function

Ammonia Refrigeration; petroleum refining; manufacture Same as for acid fumes, but Upper respiratory tract irritation, chronic
of fertilizers, explosives, plastics, and other bronchiectasis also has been reported bronchitis
chemicals
Cadmium fumes Smelting, soldering, battery production Mucous membrane irritant, acute Chronic obstructive pulmonary disease
respiratory distress syndrome (ARDS) (COPD)
Formaldehyde Manufacture of resins, leathers, rubber, Same as for acid fumes Nasopharyngeal cancer
metals, and woods; laboratory workers,
embalmers; emission from urethane foam
insulation
Halides and acid salts Bleaching in pulp, paper, textile industry; Mucous membrane irritation, Upper respiratory tract irritation, epistaxis,
(Cl, Br, F) manufacture of chemical compounds; pulmonary edema; possible reduced tracheobronchitis
synthetic rubber, plastics, disinfectant, rocket forced vital capacity (FVC) 1–2 years
fuel, gasoline after exposure
Hydrogen sulfide By-product of many industrial processes, oil, Increase in respiratory rate followed Conjunctival irritation, chronic bronchitis,
other petroleum processes and storage by respiratory arrest, lactic acidosis, recurrent pneumonitis
pulmonary edema, death
Isocyanates (TDI, HDI, Production of polyurethane foams, plastics, Mucous membrane irritation, dyspnea, Upper respiratory tract irritation, cough,
MDI) adhesives, surface coatings cough, wheeze, pulmonary edema asthma, hypersensitivity pneumonitis,
reduced lung function
Nitrogen dioxide Silage, metal etching, explosives, rocket fuels,Cough, dyspnea, pulmonary edema Emphysema in animals, chronic bronchitis,
welding, by-product of burning fossil fuels may be delayed 4–12 h; possible associated with reduced lung function growth
result from acute exposure: in children with lifelong residential exposure
bronchiolitis obliterans in 2–6 weeks
Ozone Arc welding, flour bleaching, deodorizing, Mucous membrane irritant, reduced Excess cardiopulmonary mortality rates,
emissions from copying equipment, pulmonary function transiently increased risk for new-onset asthma in
photochemical air pollutant in children and adults, asthma children
exacerbation
Phosgene Organic compound, metallurgy, volatilization of Delayed onset of bronchiolitis and Chronic bronchitis
chlorine-containing compounds pulmonary edema
Sulfur dioxide Manufacture of sulfuric acid, bleaches, Mucous membrane irritant, epistaxis, Chronic bronchitis
coating of nonferrous metals, food processing, bronchospasm (especially in people
refrigerant, burning of fossil fuels, wood pulp with asthma)
industry
Abbreviations: HDI, hexamethylene diisocyanate; MDI, methylene diphenyl diisocyanate; TDI, toluene diisocyanate.
inhalation victims. Exposed victims may have some degree of lower World Trade Center Disaster A consequence of the attack on
respiratory tract inflammation and/or pulmonary edema. the World Trade Center (WTC) on September 11, 2001, was relatively
Exposure to certain highly reactive, low-molecular-weight agents heavy exposure of a large number of firefighters and other rescue
used in the manufacture of synthetic polymers, paints, and coatings workers to the dust generated by the collapse of the buildings. Envi-
(diisocyanates in polyurethanes, aromatic amines and acid anhydrides ronmental monitoring and chemical characterization of WTC dust
in epoxies) is associated with a high risk of occupational asthma. has revealed a wide variety of potentially toxic constituents, although
Although this occupational asthma manifests clinically as if sensitiza- much of the dust was pulverized cement. Possibly because of the high
tion has occurred, an IgE antibody–mediated mechanism is not neces- alkalinity of WTC dust, significant cough, wheeze, and phlegm pro-
sarily involved. Hypersensitivity pneumonitis–like reactions also have duction occurred among firefighters and cleanup crews. New cough
been described in diisocyanate and acid anhydride–exposed workers. and wheeze syndromes also occurred among local residents. Heavier
Fluoropolymers such as Teflon, which at normal temperatures pro- exposure to WTC dust among New York City firefighters was associ-
duce no reaction, become volatilized upon heating. The inhaled agents ated with accelerated decline of lung function over the first year after
cause a characteristic syndrome of fever, chills, malaise, and occasion- the disaster. More recently, concerns have been raised about risk of
ally mild wheezing, leading to the diagnosis of polymer fume fever. A interstitial lung disease, especially of a granulomatous nature.
similar self-limited, influenza-like syndrome—metal fume fever—results
from acute exposure to fumes containing zinc oxide, typically from ■■OCCUPATIONAL RESPIRATORY CARCINOGENS
welding of galvanized steel. These inhalational fever syndromes may Exposures at work have been estimated to contribute to 10% of all lung
begin several hours after work and resolve within 24 h, only to return cancer cases. In addition to asbestos, other agents either proven or sus-
on repeated exposure. pected to be respiratory carcinogens include acrylonitrile, arsenic com-
Two other agents have been associated with potentially severe pounds, beryllium, bis(chloromethyl) ether, chromium (hexavalent),
lung disease. Occupational exposure to nylon flock has been shown to formaldehyde (nasal), isopropanol (nasal sinuses), mustard gas, nickel
induce a lymphocytic bronchiolitis, and workers exposed to diacetyl, carbonyl (nickel smelting), polycyclic aromatic hydrocarbons (coke
which is used to provide “butter” flavor in the manufacture of micro- oven emissions and diesel exhaust), secondhand tobacco smoke, silica
wave popcorn and other foods, have developed bronchiolitis obliterans (both mining and processing), talc (possible asbestos contamination in
(Chap. 287). both mining and milling), vinyl chloride (sarcomas), wood (nasal), and

1982 uranium. Workers at risk of radiation-related lung cancer include not particles from combustion sources probably generates oxidative stress
only those involved in mining or processing uranium but also those followed by local injury and inflammation in the lungs that in turn lead
exposed in underground mining operations of other ores where radon to autonomic and systemic inflammatory responses that can induce
daughters may be emitted from rock formations. endothelial dysfunction and/or injury. Recent research findings on the
health effects of air pollutants has led to stricter U.S. ambient air quality
■■ASSESSMENT OF DISABILITY standards for ozone, oxides of nitrogen, and particulate matter as well
Disability is the term used to describe the decreased ability to work due as greater emphasis on publicizing pollution alerts to encourage indi-
to the effects of a medical condition. Physicians are generally able to viduals with significant cardiopulmonary impairment to stay indoors
assess physiologic dysfunction, or impairment, but the rating of disabil- during high-pollution episodes.
ity for compensation of loss of income also involves nonmedical factors
such as the education and employability of the individual. The disabil- ■■INDOOR EXPOSURES
ity rating scheme differs with the compensation-granting agency. For Secondhand tobacco smoke (Chap. 448), radon gas, wood smoke, and
PART 7
example, the U.S. Social Security Administration requires that an indi- other biologic agents generated indoors must be considered. Several
vidual be unable to do any work (i.e., total disability) before he or she studies have shown that the respirable particulate load in any household
will receive income replacement payments. Many state workers’ com- is directly proportional to the number of cigarette smokers living in that
pensation systems allow for payments for partial disability. In the Social home. Increases in prevalence of respiratory illnesses, especially asthma,
Security scheme, no determination of cause is done, whereas work- and reduced levels of pulmonary function measured with simple
relatedness must be established in workers’ compensation systems. spirometry have been found in the children of smoking parents in a num-
For respiratory impairment rating, resting pulmonary function tests ber of studies. Recent meta-analyses for lung cancer and cardiopulmo-
(spirometry and diffusing capacity) are used as the initial assessment nary diseases, combining data from multiple secondhand tobacco smoke
tool, with cardiopulmonary exercise testing (to assess maximal oxygen epidemiologic studies, suggest an ~25% increase in relative risk for each
consumption) used if the results of the resting tests do not correlate condition, even after adjustment for major potential confounders.
with the patient’s symptoms. Methacholine challenge (to assess air- Exposure to radon gas in homes is a risk factor for lung cancer. The
way reactivity) can also be useful in patients with asthma who have main radon product (radon-222) is a gas that results from the decay
normal spirometry when evaluated. Some compensation agencies series of uranium-238, with the immediate precursor being radium-226.
(e.g., Social Security) have proscribed disability classification schemes The amount of radium in earth materials determines how much radon
based on pulmonary function test results. When no specific scheme is gas will be emitted. Levels associated with excess lung cancer risk may
proscribed, the Guidelines of the American Medical Association should be be present in as many as 10% of the houses in the United States. When
used. smokers reside in the home, the problem is potentially greater, because
the molecular size of radon particles allows them to attach readily to
GENERAL ENVIRONMENTAL EXPOSURES smoke particles that are inhaled. Fortunately, technology is available
for assessing and reducing the level of exposure.
■■OUTDOOR AIR POLLUTION Other indoor exposures of concern are bioaerosols that contain
In 1971, the U.S. government established national air quality standards antigenic material (fungi, cockroaches, dust mites, and pet danders)
for several pollutants believed to be responsible for excess cardiore- associated with an increased risk of atopy and asthma. Indoor chemical
spiratory diseases. Primary standards regulated by the U.S. Environ- agents include strong cleaning agents (bleach, ammonia), formalde-
mental Protection Agency (EPA) designed to protect the public health hyde, perfumes, pesticides, and oxides of nitrogen from gas appliances.
with an adequate margin of safety exist for sulfur dioxide, particulate Nonspecific responses associated with “tight-building syndrome,”
matter, nitrogen dioxide, ozone, lead, and carbon monoxide. Standards perhaps better termed “building-associated illness,” in which no
for each of these pollutants are updated regularly through an extensive particular agent has been implicated, have included a wide variety of
review process conducted by the EPA. (For details on current stan- complaints, among them respiratory symptoms that are relieved only
dards, go to https://www.epa.gov/criteria-air-pollutants/naaqs-table%20. by avoiding exposure in the building in question. The degree to which
Pollutants are generated from both stationary sources (power plants “smells” and other sensory stimuli are involved in the triggering of
and industrial complexes) and mobile sources (motor vehicles), and potentially incapacitating psychological or physical responses has yet
none of the regulated pollutants occurs in isolation. Furthermore, to be determined, and the long-term consequences of such environ-
pollutants may be changed by chemical reactions after being emitted. mental exposures are unknown.
For example, sulfur dioxide and particulate matter emissions from a
coal-fired power plant may react in air to produce acid sulfates and ■■GLOBAL CONSIDERATIONS
aerosols, which can be transported long distances in the atmosphere. Indoor exposure to household air pollution from cooking or
Oxides of nitrogen and volatile organic compounds from automobile heating with solid fuels (wood, dung, crop residues, charcoal,
exhaust react with sunlight to produce ozone. Although originally coal) is estimated to be responsible for >4% of worldwide
thought to be confined to Los Angeles, photochemically derived pol- disability-adjusted life-years (DALYs) lost, due to acute lower respira-
lution (“smog”) is now known to be a problem throughout the United tory infections in children, COPD and lung cancer in women, and car-
States and in many other countries. Both acute and chronic effects of diovascular disease among men. This burden of disease places exposure
these exposures have been documented in large population studies. to household air pollution as the leading environmental hazard for
The symptoms and diseases associated with air pollution are the poor health on a global scale.
same as conditions commonly associated with cigarette smoking. In Forty percent of the world’s population uses solid fuel for cooking,
addition, decreased growth of lung function and asthma have been heating, or baking. Kerosene (similar to diesel fuel) is often used for
associated with chronic exposure to only modestly elevated levels of lighting and sometimes cooking. This occurs predominantly in the
traffic-related gases and respirable particles. Multiple population-based rural areas of developing countries. Because many families burn coal
time-series studies within cities have demonstrated excess health care or biomass fuels in open stoves, which are highly inefficient, and inside
utilization for asthma and other cardiopulmonary conditions as well homes with poor ventilation, women and young children are exposed
as increased mortality rates. Cohort studies comparing cities that on a daily basis to high levels of smoke. In these homes, 24-h mean lev-
have relatively high levels of particulate exposures with less polluted els of fine particulate matter have been reported to be 2–30 times higher
communities suggest excess morbidity and mortality rates from cardio- than the National Ambient Air Quality Standard set by the U.S. EPA.
pulmonary conditions in long-term residents of the former. The strong Epidemiologic studies have consistently shown associations between
epidemiologic evidence that fine particulate matter is a risk factor exposure to biomass smoke and both chronic bronchitis and COPD.
for cardiovascular morbidity and mortality has prompted toxicologic Because of increased migration to the United States from developing
investigations into the underlying mechanisms. The inhalation of fine countries, clinicians need to be aware of the chronic respiratory effects

1983
CHAPTER 284 Bronchiectasis

FIGURE 283-4 Histopathologic features of biomass smoke–induced interstitial lung disease. A. Anthracitic pigment is seen accumulating along alveolar septae
(arrowheads) and within a pigmented dust macule (single arrow). B. A high-power photomicrograph contains a mixture of fibroblasts and carbon-laden macrophages.
of exposure to biomass smoke, which can include interstitial lung dis- TABLE 284-1 Major Etiologies of Bronchiectasis and Proposed
ease (Fig. 283-4). Evidence is beginning to emerge that improved stoves Workup
that reduce biomass smoke exposure can reduce risk of respiratory
PATTERN
illness in both children and adults. OF LUNG ETIOLOGY BY CATEGORY
Household air pollution (HAP) from domestic use of solid fuels INVOLVEMENT (EXAMPLES) WORKUP
also contributes substantially to outdoor air pollution. Contributions Focal Obstruction (aspirated foreign Chest imaging (chest
from HAP, coal-fired power plants without emission scrubbers, and body, tumor mass) x-ray and/or chest CT);
increased traffic congestion involving motor vehicles without pollution bronchoscopy
controls can lead to high concentrations of outdoor air pollution, espe- Diffuse Infection (bacterial, Sputum Gram’s stain/
cially fine particulate matter, in mega-cities in developing countries nontuberculous mycobacterial) culture; stains/cultures
(e.g., Delhi). for acid-fast bacilli and
fungi. If no pathogen
is identified, consider
Acknowledgment
bronchoscopy with
The author acknowledges the contribution of Dr. Frank Speizer to the prior bronchoalveolar lavage.
version of this chapter. Immunodeficiency Complete blood count
(hypogammaglobulinemia, with differential;
■■FURTHER READING HIV infection, bronchiolitis immunoglobulin
Banks DE: Clinical aspects of asbestos-related diseases—What are the obliterans after lung measurement; HIV
unresolved topics? J Occup Environ Med 56 Suppl 10:S8, 2014. transplantation) testing
Blanc PD, Torén K: COPD and occupation: Resetting the agenda. Genetic causes (cystic fibrosis, Measurement of
Occup Environ Med 73:357, 2016. Kartagener’s syndrome, α1 chloride levels in sweat
Gauderman WJ et al: Association of improved air quality with lung antitrypsin deficiency) (for cystic fibrosis),
development in children. N Engl J Med 372:905, 2015. α1 antitrypsin levels;
nasal or respiratory
Gordon SB et al: Respiratory risks from household air pollution in low tract brush/biopsy (for
and middle income countries. Lancet Respir Med 2:823, 2014. dyskinetic/immotile
Petsonk EL et al: Coal mine dust lung disease. New lessons from old cilia syndrome); genetic
exposure. Am J Respir Crit Care Med 187:1178, 2013. testing
Autoimmune or rheumatologic Clinical examination
causes (rheumatoid arthritis, with careful joint exam,
Sjögren’s syndrome, serologic testing
284 Bronchiectasis
inflammatory bowel disease); (e.g., for rheumatoid
immune-mediated disease factor). Consider
(allergic bronchopulmonary workup for allergic
Rebecca M. Baron, Miriam Baron Barshak aspergillosis) bronchopulmonary
aspergillosis, especially
in patients with
refractory asthma.a
Bronchiectasis refers to an irreversible airway dilation that involves the
Recurrent aspiration Test of swallowing
lung in either a focal or a diffuse manner and that classically has been function and general
categorized as cylindrical or tubular (the most common form), varicose, neuromuscular strength
or cystic. Miscellaneous (yellow Guided by clinical
nail syndrome, traction condition
■■ETIOLOGY bronchiectasis from
Bronchiectasis can arise from infectious or noninfectious causes postradiation fibrosis or
(Table 284-1). Clues to the underlying etiology are often provided by idiopathic pulmonary fibrosis)
the pattern of lung involvement. Focal bronchiectasis refers to bronchiec- Idiopathic Exclusion of other
tatic changes in a localized area of the lung and can be a consequence of causes
obstruction of the airway—either extrinsic (e.g., due to compression by a
Skin testing for Aspergillus reactivity; measurement of serum precipitins for
adjacent lymphadenopathy or parenchymal tumor mass) or intrinsic Aspergillus, serum IgE levels, serum eosinophils, etc.

1984 (e.g., due to an airway tumor or aspirated foreign body, a scarred/ Classic studies of the pathology of bronchiectasis from the 1950s
stenotic airway, or bronchial atresia from congenital underdevelop- demonstrated significant small-airway wall inflammation and
ment of the airway). Diffuse bronchiectasis is characterized by wide- larger-airway wall destruction as well as dilation, with loss of elastin,
spread bronchiectatic changes throughout the lung and often arises smooth muscle, and cartilage. It has been proposed that inflammatory
from an underlying systemic or infectious disease process. cells in the small airways release proteases and other mediators, such
More pronounced involvement of the upper lung fields is most as reactive oxygen species and proinflammatory cytokines, that dam-
common in cystic fibrosis (CF) and is also observed in postradiation age the larger-airway walls. Furthermore, the ongoing inflammatory
fibrosis, corresponding to the lung region encompassed by the radia- process in the smaller airways results in airflow obstruction. It is
tion port. Bronchiectasis with predominant involvement of the lower thought that antiproteases, such as α1 antitrypsin, play an important
lung fields usually has its source in chronic recurrent aspiration (e.g., role in neutralizing the damaging effects of neutrophil elastase and in
due to esophageal motility disorders like those in scleroderma), end- enhancing bacterial killing. Bronchiectasis and emphysema have been
stage fibrotic lung disease (e.g., traction bronchiectasis from idiopathic observed in patients with α1 antitrypsin deficiency.
PART 7
pulmonary fibrosis), or recurrent immunodeficiency-associated infec- Proposed mechanisms for noninfectious bronchiectasis include
tions (e.g., hypogammaglobulinemia). Bronchiectasis resulting from immune-mediated reactions that damage the bronchial wall (e.g., those
infection by nontuberculous mycobacteria (NTM), most commonly associated with systemic autoimmune conditions such as Sjögren’s
the Mycobacterium avium-intracellulare complex (MAC), often prefer- syndrome and rheumatoid arthritis). Traction bronchiectasis refers to
entially affects the midlung fields. Congenital causes of bronchiectasis dilated airways arising from parenchymal distortion as a result of lung
with predominant midlung field involvement include the dyskinetic/ fibrosis (e.g., postradiation fibrosis or idiopathic pulmonary fibrosis).
immotile cilia syndrome. Finally, predominant involvement of the
central airways is reported in association with allergic bronchopulmo- ■■CLINICAL MANIFESTATIONS
nary aspergillosis (ABPA), in which an immune-mediated reaction to The most common clinical presentation is a persistent productive
Aspergillus damages the bronchial wall. Congenital causes of central cough with ongoing production of thick, tenacious sputum. Physical
airway–predominant bronchiectasis resulting from cartilage defi- findings often include crackles and wheezing on lung auscultation, and
ciency include tracheobronchomegaly (Mounier-Kuhn syndrome) and some patients with bronchiectasis exhibit clubbing of the digits. Mild to
Williams-Campbell syndrome. moderate airflow obstruction is often detected on pulmonary function
In many cases, the etiology of bronchiectasis is not determined. In tests, overlapping with that seen at presentation with other conditions,
case series, as many as 25–50% of patients referred for bronchiectasis such as chronic obstructive pulmonary disease (COPD). Acute exacer-
have idiopathic disease. bations of bronchiectasis are usually characterized by changes in the
nature of sputum production, with increased volume and purulence.
■■EPIDEMIOLOGY However, typical signs and symptoms of lung infection, such as fever
The overall reported prevalence of bronchiectasis in the United States and new infiltrates, may not be present.
has recently increased, but the epidemiology of bronchiectasis varies
greatly with the underlying etiology. For example, patients born with ■■DIAGNOSIS
CF often develop significant clinical bronchiectasis in late adolescence or The diagnosis is usually based on presentation with a persistent
early adulthood, although atypical presentations of CF in adults in their chronic cough and sputum production accompanied by consistent
thirties and forties are also possible. In contrast, bronchiectasis resulting radiographic features. Although chest radiographs lack sensitivity, the
from MAC infection classically affects nonsmoking women >50 years of presence of “tram tracks” indicating dilated airways is consistent with
age. In general, the incidence of bronchiectasis increases with age. Bron- bronchiectasis. Chest CT is more specific for bronchiectasis and is the
chiectasis is more common among women than among men. imaging modality of choice for confirming the diagnosis. CT findings
In areas where tuberculosis is prevalent, bronchiectasis more include airway dilation (detected as parallel “tram tracks” or as the
frequently occurs as a sequela of granulomatous infection. “signet-ring sign”—a cross-sectional area of the airway with a diameter
Focal bronchiectasis can arise from extrinsic compression of at least 1.5 times that of the adjacent vessel), lack of bronchial tapering
the airway by enlarged granulomatous lymph nodes and/or from (including the presence of tubular structures within 1 cm from the pleu-
development of intrinsic obstruction as a result of erosion of a calcified ral surface), bronchial wall thickening in dilated airways, inspissated
lymph node through the airway wall (e.g., broncholithiasis). Especially secretions (e.g., the “tree-in-bud” pattern), or cysts emanating from
in reactivated tuberculosis, parenchymal destruction from infection can the bronchial wall (especially pronounced in cystic bronchiectasis)
result in areas of more diffuse bronchiectasis. Apart from cases associ- (Fig. 284-1).
ated with tuberculosis, an increased incidence of non-CF bronchiectasis
with an unclear underlying mechanism has been reported as a signifi-
cant problem in developing nations. It has been suggested that the high
incidence of malnutrition in certain areas may predispose to immune
dysfunction and development of bronchiectasis.
■■PATHOGENESIS AND PATHOLOGY

The most widely cited mechanism of infectious bronchiectasis is the
“vicious cycle hypothesis,” in which susceptibility to infection and
poor mucociliary clearance result in microbial colonization of the bron-
chial tree. Some organisms, such as Pseudomonas aeruginosa, exhibit a
particular propensity for colonizing damaged airways and evading
host defense mechanisms. Impaired mucociliary clearance can result
from inherited conditions such as CF or dyskinetic cilia syndrome, and
it has been proposed that a single severe infection (e.g., pneumonia
caused by Bordetella pertussis or Mycoplasma pneumoniae) can result in
significant airway damage and poor secretion clearance. The presence
of the microbes incites continued chronic inflammation, with conse-
quent damage to the airway wall, continued impairment of secretions
and microbial clearance, and ongoing propagation of the infectious/ FIGURE 284-1 Representative chest CT image of severe bronchiectasis. This
inflammatory cycle. Moreover, it has been proposed that mediators patient’s CT demonstrates many severely dilated airways, seen both longitudinally
released directly from bacteria can interfere with mucociliary clearance. (arrowhead) and in cross-section (arrow).

glucocorticoids may be important in treatment of bronchiectasis 1985
APPROACH TO THE PATIENT
due to certain etiologies, such as ABPA, or of noninfectious bron-
Bronchiectasis chiectasis due to underlying conditions, especially that in which
an autoimmune condition is believed to be active (e.g., rheumatoid
The evaluation of a patient with bronchiectasis entails elicitation arthritis or Sjögren’s syndrome). Patients with ABPA may also ben-
of a clinical history, chest imaging, and a workup to determine efit from a prolonged course of treatment with the oral antifungal
the underlying etiology. Evaluation of focal bronchiectasis almost agent itraconazole.
always requires bronchoscopy to exclude airway obstruction by an
underlying mass or foreign body. A workup for diffuse bronchiec- REFRACTORY CASES
tasis includes analysis for the major etiologies (Table 284-1), with In select cases, surgery can be considered, with resection of a focal
an initial focus on excluding CF. Pulmonary function testing is an area of suppuration. In advanced cases, lung transplantation can be
CHAPTER 284 Bronchiectasis

important component of a functional assessment of the patient. considered.
■■COMPLICATIONS
TREATMENT In more severe cases of infectious bronchiectasis, recurrent infections
Bronchiectasis and repeated courses of antibiotics can lead to microbial resistance to
antibiotics. In certain cases, combinations of antibiotics that have inde-
Treatment of infectious bronchiectasis is directed at the control of pendent toxicity profiles may be necessary to treat resistant organisms.
active infection and improvements in secretion clearance and bron- Recurrent infections can result in injury to superficial mucosal ves-
chial hygiene so as to decrease the microbial load within the airways sels, with bleeding and, in severe cases, life-threatening hemoptysis.
and minimize the risk of repeated infections. Management of massive hemoptysis usually requires intubation to
ANTIBIOTIC TREATMENT stabilize the patient, identification of the source of bleeding, and pro-
tection of the nonbleeding lung. Control of bleeding often necessitates
Antibiotics targeting the causative or presumptive pathogen (with
bronchial artery embolization and, in severe cases, surgery.
Haemophilus influenzae and P. aeruginosa isolated commonly) should
be administered in acute exacerbations, usually for a minimum of
■■PROGNOSIS
7–10 days and perhaps for as long as 14 days. Decisions about treat-
Outcomes of bronchiectasis can vary widely with the underlying
ment of NTM infection can be difficult, given that these organisms
etiology and comorbid conditions and may also be influenced by the
can be colonizers as well as pathogens and the prolonged treatment
frequency of exacerbations and (in infectious cases) the specific patho-
course often is not well tolerated. Consensus guidelines have advised
gens involved (with worse outcomes associated with P. aeruginosa
that diagnostic criteria for true clinical infection with NTM should
colonization). Increasing attention is being given to defining clinical
be considered in patients with symptoms and radiographic findings
phenotypes of bronchiectasis in light of clinical, radiographic, and
of lung disease who have at least two sputum samples positive on
microbial features and to developing screening tools for the assessment
culture; at least one bronchoalveolar lavage (BAL) fluid sample pos-
of quality of life and disease severity. In one study, the decline of lung
itive on culture; a biopsy sample displaying histopathologic features
function in patients with non-CF bronchiectasis was similar to that in
of NTM infection (e.g., granuloma or a positive stain for acid-fast
patients with COPD, with the forced expiratory volume in 1 s (FEV1)
bacilli) along with one positive sputum culture; or a pleural fluid
declining by 50–55 mL per year as opposed to 20–30 mL per year for
sample (or a sample from another sterile extrapulmonary site) posi-
healthy controls.
tive on culture. MAC strains are the most common NTM pathogens,
and the recommended regimen for HIV-negative patients infected ■■PREVENTION
with macrolide-sensitive MAC includes a macrolide combined with Reversal of an underlying immunodeficient state (e.g., by administra-
rifampin and ethambutol. Consensus guidelines recommend mac- tion of gamma globulin for immunoglobulin-deficient patients) and
rolide susceptibility testing for clinically significant MAC isolates. vaccination of patients with chronic respiratory conditions (e.g., influ-
BRONCHIAL HYGIENE enza and pneumococcal vaccines) can decrease the risk of recurrent
The numerous approaches used to enhance secretion clearance infections. Patients who smoke should be counseled about smoking
in bronchiectasis include hydration and mucolytic administration, cessation.
aerosolization of bronchodilators and hyperosmolar agents (e.g., After resolution of an acute infection in patients with recurrences
hypertonic saline), and chest physiotherapy (e.g., postural drainage, (e.g., ≥3 episodes per year), the use of suppressive antibiotics to mini-
traditional mechanical chest percussion via hand clapping to the mize the microbial load and reduce the frequency of exacerbations has
chest, or use of devices such as an oscillatory positive expiratory been proposed. Although there is less consensus about this approach
pressure flutter valve or a high-frequency chest wall oscillation in non-CF-associated bronchiectasis than in CF-related bronchiectasis,
vest). Pulmonary rehabilitation and a regular exercise program small studies have supported benefits of selected therapies. Possible
may assist with secretion clearance as well as with other aspects of suppressive treatments include (1) administration of an oral antibiotic
bronchiectasis, including improved exercise capacity and quality of (e.g., ciprofloxacin) daily for 1–2 weeks per month; (2) use of a rotating
life. The mucolytic dornase (DNase) is recommended routinely in schedule of oral antibiotics (to minimize the risk of development of drug
CF-related bronchiectasis but not in non-CF bronchiectasis, given resistance); (3) administration of a macrolide antibiotic (see below) daily
concerns about lack of efficacy and potential harm in the non-CF or three times per week (with mechanisms of possible benefit related
population. to non-antimicrobial properties, such as anti-inflammatory effects
and reduction of gram-negative bacillary biofilms); (4) inhalation of
ANTI-INFLAMMATORY THERAPY aerosolized antibiotics (e.g., tobramycin inhalation solution) for select
It has been proposed that control of the inflammatory response patients on a rotating schedule (e.g., 30 days on, 30 days off), with the
may be of benefit in bronchiectasis, and relatively small-scale trials goal of decreasing the microbial load without eliciting the side effects
have yielded evidence of alleviated dyspnea, decreased need for of systemic drug administration; and (5) intermittent administration
inhaled β-agonists, and reduced sputum production with inhaled of IV antibiotics (e.g., “clean-outs”) for patients with more severe
glucocorticoids. However, no significant differences in lung func- bronchiectasis and/or resistant pathogens. In relation to macrolide
tion or bronchiectasis exacerbation rates have been observed. Risks therapy (point 3 above), a number of double-blind, placebo-controlled,
of immunosuppression and adrenal suppression must be care- randomized trials have been published in non-CF bronchiectasis and
fully considered with use of anti-inflammatory therapy in infec- support a benefit of long-term macrolides (6–12 months of azithromy-
tious bronchiectasis. Nevertheless, administration of oral/systemic cin or erythromycin) in decreasing rates of bronchiectasis exacerbation,

1986 mucus production, and decline in lung function. However, two of these to eradicate P. aeruginosa early in the course of disease have been suc-
studies also reported increased macrolide resistance in commensal cessful and are thought to improve prognosis significantly if sustained.
pathogens, dampening enthusiasm for universal use of macrolides in
this setting and raising the question of whether there might be select Pancreatic Findings The complete name of the disease, cystic
non-CF bronchiectasis patients with higher morbidity for whom bene- fibrosis of the pancreas, refers to profound tissue destruction of the exo-
fits of long-term macrolides might outweigh the risks of emergence of crine pancreas, with fibrotic scarring and/or fatty replacement, cyst
antibiotic resistance. In particular, development of macrolide-resistant proliferation, loss of acinar tissue, and ablation of normal pancreatic
NTM is a potential concern, making treatment of those pathogens much architecture. As in the lung, tenacious exocrine secretions (sometimes
more difficult. Furthermore, patients with different patterns of micro- termed concretions) obstruct pancreatic ducts and impair production
bial colonization may not all experience similar benefits with macrolide and flow of digestive enzymes to the duodenum. The sequelae of
therapy. Therefore, before chronic macrolide therapy is considered, exocrine pancreatic insufficiency include chronic malabsorption, poor
it is advisable to rule out NTM infection and carefully consider each growth, fat-soluble vitamin insufficiency, high levels of serum immu-
PART 7
patient’s scenario closely, obtaining an electrocardiogram to rule out a noreactive trypsinogen (a diagnostic test used in newborn screening),
prolonged QT interval that might place the patient at increased risk of and loss of pancreatic islet cell mass. CF-related diabetes mellitus is
arrhythmias. a manifestation in over 30% of adults with the disease and is likely
In addition, ongoing consistent attention to bronchial hygiene can multifactorial in nature (attributable to progressive destruction of the
endocrine pancreas, insulin resistance due to stress hormones, and
promote secretion clearance and decrease the microbial load in the

airways. additional factors).
■■FURTHER READING Other Organ System Damage As in CF lung and pancreas,

Aliberti S et al: Clinical phenotypes in adult patients with bronchiec- thick and tenacious secretions compromise numerous other exocrine
tasis. Eur Respir J 47:1113, 2016. tissues. Obstruction of intrahepatic bile ducts and parenchymal fibrosis
Khoo JK et al: Bronchiectasis in the last five years: New developments. are commonly observed in pathologic specimens, with multilobular
J Clin Med 5:115, 2016. cirrhosis in 4–15% of patients with CF and significant hepatic insuf-
McGrath EE et al: Guidelines on the diagnosis and treatment of ficiency as a resulting manifestation among adults. Contents of the
pulmonary non-tuberculous mycobacteria infection. In J Clin Pract intestinal lumen are often difficult to excrete, leading to meconium
62:1947, 2008. ileus (a presentation in 10–20% of newborns with CF) or distal intes-
Rogers GB et al: The effect of long-term macrolide treatment on respi- tinal obstructive syndrome in older individuals. Men typically exhibit
ratory microbiota composition in non–cystic fibrosis bronchiectasis: complete involution of the vas deferens and infertility (despite func-
An analysis from the randomized, double-blind, placebo-controlled tioning spermatogenesis), and ~99% of males with CF are infertile. The
Bless Trial. Lancet Respir Med 2:988, 2014. etiology of this dramatic anatomic defect in the male genitourinary
system is not understood but may represent a developmental abnor-
mality secondary to improper secretion by the vas or associated struc-
tures. Abnormalities of female reproductive tract secretions are likely
contributors to an increased incidence of infertility among women
285 Cystic Fibrosis

with the disease. Radiographic evidence of sinusitis occurs in most CF
patients and is associated with pathogens similar to those recovered
from lower airways, suggesting that the sinus may serve as a reservoir
Eric J. Sorscher for bacterial seeding.
■■PATHOGENESIS
■■CLINICAL FEATURES
Cystic fibrosis (CF) is an autosomal recessive exocrinopathy affecting Cystic Fibrosis Transmembrane Conductance Regulator
multiple epithelial tissues. The gene product responsible for CF (the (CFTR) CFTR is an integral membrane protein that functions as an
cystic fibrosis transmembrane conductance regulator [CFTR]) serves epithelial anion channel. The ~1480-amino-acid molecule encodes a
as an anion channel in the apical (luminal) plasma membranes of epi- passive conduit for chloride and bicarbonate transport across plasma
thelial cells and regulates volume and composition of exocrine secre- membranes of epithelial tissues, with direction of ion flow dependent
tion. An increasingly sophisticated understanding of CFTR molecular on the electrochemical driving force. Gating of CFTR involves con-
genetics and membrane protein biochemistry has facilitated CF drug formational cycling between an open and closed configuration and is
discovery, with a number of new agents recently approved or advanc- augmented by hydrolysis of adenosine triphosphate (ATP). Anion flux
ing through the clinical testing phase. mediated by CFTR does not involve active transport against a concen-
tration gradient but utilizes the energy provided from ATP hydrolysis
Respiratory Manifestations The major morbidity and mor- as a central feature of ion channel mechanochemistry and gating.
tality associated with CF is attributable to respiratory compromise, CFTR is situated in the apical plasma membranes of acinar and
characterized by copious hyperviscous and adherent pulmonary other epithelial cells where it regulates the amount and composition
secretions that obstruct small and medium-sized airways. CF airway of secretion by exocrine glands. In numerous epithelia, chloride and
secretions are exceedingly difficult to clear, and a complex bacterial bicarbonate release is followed passively by the flow of water, allowing
flora that includes Staphylococcus aureus, Haemophilus influenzae, and for mobilization and clearance of exocrine products. Along respiratory
Pseudomonas aeruginosa (among other pathogens) is routinely cultured mucosa, CFTR is necessary to provide sufficient depth of the periciliary
from CF sputum. Microbiome analysis has identified hundreds of other fluid layer (PCL), allowing normal ciliary extension and mucociliary
bacterial species in CF lungs, although their relationship to pulmonary transport. CFTR-deficient airway cells exhibit depleted PCL, causing
failure remains to be determined. Robust pulmonary inflammation in ciliary collapse and failure to clear overlying mucus (Video 285-1). In
the setting of inspissated mucus and chronic bacterial infection leads airway submucosal glands, CFTR is highly expressed in acini and may
to collateral tissue injury and further aggravates respiratory decline. participate both in the formation of mucus and extrusion of glandular
Organisms such as P. aeruginosa exhibit a stereotypic mode of patho- secretion onto the airway surface (Fig. 285-1). In other exocrine glands
genesis; a sentinel and early colonization event often engenders lifelong characterized by abrogated mucus transport (e.g., pancreatic acini and
pulmonary infection by the same genetic strain. Over a period of many ducts, as well as bile canaliculi, intestinal lumen), similar pathogenic
years, P. aeruginosa evolves in CF lungs to adopt a mucoid phenotype mechanisms have been implicated. In these tissues, a driving force for
(attributable to release of alginate exoproduct) that confers selective apical chloride and/or bicarbonate secretion is believed to promote
advantage for the pathogen and poor prognosis for the host. Strategies CFTR-mediated fluid and electrolyte release into the lumen, which

Pulmonary Inflammation and Remodeling The CF airway 1987
is characterized by an aggressive, unrelenting, neutrophilic inflamma-
tory response with release of proteases and oxidants leading to airway
remodeling and bronchiectasis. Intense pulmonary inflammation is
largely driven by chronic respiratory infection. Macrophages and other
cells resident in CF lungs augment elaboration of proinflammatory
cytokines, which contribute to innate and adaptive immune reactivity.
CFTR-dependent abnormalities of airway surface fluid composition
(e.g., pH) have been reported as contributors to impaired bacterial
killing in CF lungs. The role of CFTR as a direct mediator of inflam-
matory responsiveness and/or pulmonary remodeling represents an
CHAPTER 285 Cystic Fibrosis

important and topical area of investigation.
■■MOLECULAR GENETICS
DNA sequencing of CFTR from patients (and others) worldwide has
revealed almost 2000 allelic variants; several hundred of these have
been well-characterized as disease-causing mutations. Distinguishing
the single nucleotide transversions or other polymorphisms with
causal relevance can sometimes present a significant challenge. The
CFTR2 resource (www.cftr2.org/) delineates gene variants with a clear
etiologic role.
CFTR defects known to elicit disease are often categorized based
on molecular mechanism. For example, the common F508del mutation
(nomenclature denotes omission of a single phenylalanine residue
[F] at CFTR position 508) leads to a folding abnormality recognized
by cellular quality control pathways. CFTR encoding F508del retains
partial ion channel function, but protein maturation is arrested in the
endoplasmic reticulum, and CFTR fails to arrive at the plasma mem-
brane. Instead, F508del CFTR is misrouted and undergoes endoplasmic
reticulum–associated degradation via the proteasome. CFTR mutations
that disrupt protein maturation are termed class II defects and are by
far the most common genetic abnormalities. F508del alone accounts
for ~70% of defective CFTR alleles in the United States, where ~90% of
individuals with CF carry at least one F508del mutation.
Other gene defects include CFTR ion channels properly trafficked
to the apical cell surface but unable to open and/or gate. Such channel
proteins include G551D (a glycine to aspartic acid replacement at CFTR
position 551), which leads to an inability to transport Cl– or HCO3– in
the presence of ATP (a class III abnormality). Individuals with at least
one G551D allele represent 4–5% of CF patients in North America.
CFTR nonsense alleles such as G542X, R553X, and W1282X (premature
termination codon replaces glycine, arginine, or tryptophan at posi-
tions 542, 553, or 1282, respectively) are among the common class I
defects, in addition to large deletions or other major disruptions of the
gene. The W1282X mutation, for example, is prevalent among individ-
uals of Ashkenazi descent and is a predominant CF genotype in Israel.
Additional categories of CFTR mutation include defects in the ion
channel pore (class IV), RNA splicing (class V), and increased plasma
membrane turnover (class VI) (Fig. 285-2).
■■DIAGNOSIS
FIGURE 285-1 Extrusion of mucus secretion onto the epithelial surface of
During the past decade, newborn screening has led to most CF diag-
airways in cystic fibrosis (CF). A. Schematic of the surface epithelium and
supporting glandular structure of the human airway. B. The submucosal glands noses, with confirmation through CFTR mutation analysis and sweat
of a patient with CF are filled with mucus, and mucopurulent debris overlies the electrolyte measurements as cardinal diagnostic tests. DNA-based
airway surfaces, essentially burying the epithelium. C. A higher magnification view evaluation typically surveys numerous disease-associated mutations;
of a mucus plug tightly adhering to the airway surface, with arrows indicating the panels that identify on the order of 20–140 CFTR variants are avail-
interface between infected and inflamed secretions and the underlying epithelium able through a variety of public health laboratories and commercial
to which the secretions adhere. (Both B and C were stained with hematoxylin
sources. For difficult cases, complete CFTR exonic sequencing together
and eosin, with the colors modified to highlight structures.) Infected secretions
obstruct airways and, over time, dramatically disrupt the normal architecture of with analysis of splice junctions and key regulatory elements can be
the lung. D. CFTR is expressed in surface epithelium and serous cells at the base obtained.
of submucosal glands in a porcine lung sample, as shown by the dark staining, Sweat electrolytes following pilocarpine iontophoresis continue
signifying binding by CFTR antibodies to epithelial structures (aminoethylcarbazole to comprise an essential diagnostic element, with levels of chloride
detection of horseradish peroxidase with hematoxylin counterstain). (From SM markedly elevated in CF compared to non-CF individuals. The sweat
Rowe, S Miller, EJ Sorscher: N Engl J Med 352:1992, 2005.)
test result is highly specific and served as a mainstay of diagnosis
for many decades prior to availability of CFTR genotyping. Notably,
confers proper rheology of mucins and other exocrine products. Failure hyperviscosity of eccrine sweat is not a clinical feature of the disease.
of this mechanism disrupts normal hydration and transport of glandu- Sweat ducts function to reabsorb chloride from a primary sweat
lar secretion and is widely viewed as a proximate cause of obstruction, secretion produced by the glandular coil. Malfunction of CFTR leads
with concomitant tissue injury. to diminished chloride uptake from the ductular lumen, and sweat

1988 are strongly associated with CFTR mutations in at least one allele.
Although CF is a classic monogenic disease, the importance of non-
CFTR gene modifiers and proteins that regulate ion flux, inflammatory
pathways, and airway remodeling has been increasingly appreciated as
CFTR influencing clinical course. For example, the magnitude of transepithe-
lial sodium reabsorption in CF airways, which helps control periciliary
fluid depth and composition, is strongly influenced by CFTR and rep-
resents a molecular target for disease intervention.
■■THERAPEUTICS DIRECTED TOWARD CF SEQUELAE

Class III Class IV
Class VI Chronic Management Standard care for outpatients with CF is
PART 7
Accelerated intensive, with regimens that include exogenous pancreatic enzymes

turnover taken with meals, nutritional supplementation, anti-inflammatory
Cl–
Golgi medication, bronchodilators, and chronic or periodic administration of
complex oral or aerosolized antibiotics (e.g., as maintenance therapy for patients
with P. aeruginosa). Recombinant DNAse aerosols (degraded DNA

strands that contribute to mucus viscosity) and nebulized hypertonic
Proteosome saline (serves to augment PCL depth, activate mucociliary clearance,
and mobilize inspissated airway secretions) are administered routinely.
Chest physiotherapy several times each day is a standard means to
Class II promote clearance of airway mucus. Among adults with CF, malab-
sorption, chronic inflammation, and endocrine abnormalities can lead
Endoplasmic
to poor bone mineralization, requiring treatment with vitamin D, cal-
reticulum cium, and other measures. The time, complexity, and expense of home
care are considerable and take a significant toll on patients and their
families. Improved treatments directed toward nutritional deficits, pul-
monary inflammation, mucostasis, and other sequelae therefore remain
a high priority in the field.
Nucleus Class I Class V
Pulmonary Exacerbation Severe respiratory exacerbation is
commonly managed by hospital admission for frequent chest physio-
therapy and parenteral antibiotics directed against serious (and often
multiply resistant) bacterial pathogens. Aggressive intervention in this
setting can restore a large component of lung function, but ongoing
and cumulative loss of pulmonary reserve reflects the natural history
FIGURE 285-2 Categories of CFTR mutations. Classes of defects in the CFTR of the disease. Poor prognostic indicators such as sputum culture con-
gene include the absence of synthesis (class I); defective protein maturation taining Burkholderia cepacia complex, mucoid P. aeruginosa, or atypical
and premature degradation (class II); disordered gating/regulation, such as mycobacteria are rigorously monitored in the CF patient population.
diminished adenosine triphosphate (ATP) binding and hydrolysis (class III);
An increasing incidence of methicillin-resistant S. aureus has also been
defective conductance through the ion channel pore (class IV); a reduced number
of CFTR transcripts due to a promoter or splicing abnormality (class V); and observed, although the clinical significance of this finding has not been
accelerated turnover from the cell surface (class VI). (From SM Rowe, S Miller, EJ fully elucidated. Typical inpatient antibiotic coverage includes combi-
Sorscher: N Engl J Med 352:1992, 2005.) nation drug therapy with an aminoglycoside and β-lactam for at least
14 days. Maximal improvement in lung function is often achieved by
emerges on the skin with markedly elevated levels of chloride. For 8–10 days in this setting. Many families elect parenteral antibiotic treat-
the unusual situation in which both CFTR genotype and sweat elec- ment at home, and additional studies are needed to evaluate specific
trolytes are inconclusive, in vivo measurement of ion transport across drug combinations, duration of therapy, and home versus inpatient
the nasal airways can serve as a specific test for CF and is used by a management. Other CF respiratory sequelae that may require hospi-
number of referral centers. For example, elevated (sodium-dependent) talization include hemoptysis and pneumothorax. Hypersensitivity to
transepithelial charge separation across airway epithelial tissue and Aspergillus (allergic bronchopulmonary aspergillosis) occurs in ~5% of
persistent failure of isoproterenol-dependent chloride secretion (via individuals with the disease and should be suspected in the absence of
CFTR) represent bioelectric findings specific for the disease. Measure- a response to conventional treatment.
ments of CFTR activity in excised rectal mucosal biopsies can also be
obtained. Considerations Regarding Lung Transplantation In the
setting of end-stage CF pulmonary failure, lung transplantation is a
■■COMPLEXITY OF A CF PHENOTYPE viable therapeutic option with 5-year survival rates on the order of
CF classically presents in childhood with chronic productive cough, 60% and median survival >8 years. Determining the optimal timing for
malabsorption including steatorrhea, and failure to thrive. The disease surgery presents a substantial challenge, particularly because overall
is most common among whites (~1 in 3300 live births) and much less prognosis for individuals with severe lung disease is sometimes dif-
frequent among African-American (~1 in 10,000) or Asian populations ficult to predict, and mortality associated with transplantation can be
(~1 in 33,000). Several “severe” defects that impair CFTR activity significant. Forced expiratory volume in 1s (FEV1) measurements <30%
(including F508del, G551D, and truncation alleles) are predictive of pan- predicted, together with an assortment of other clinical parameters
creatic insufficiency, which is clinically evident in 80–90% of individuals (hospitalization frequency, need for supplemental oxygen, etc.), are
with CF. These few genotype-phenotype correlations notwithstanding, often used as thresholds for entry onto transplantation lists, although
genotype is, in general, a poor predictor of overall respiratory prognosis. waiting periods for healthy donor lungs can be quite protracted. Based
A spectrum of CFTR-related diseases with features resembling on clinical outcome and other features, CF patients and their families
classic CF has been well described. In addition to multiorgan involve- sometimes do not pursue this option. The decision is best approached
ment, forme frustes, such as isolated congenital bilateral absence of through consultation with health care providers specializing in both CF
the vas deferens or pancreatitis (without other organ system findings), clinical management and transplantation.

■■CFTR MODULATION (class III) and instability at the plasma membrane (class VI). Compre- 1989
hensive molecular analysis for hundreds of rare CFTR variants will
Potentiation of Mutant CFTR Gating A massive effort help guide therapeutics, and may be especially important given the
directed toward high-throughput drug analysis of large compound high cost of drugs such as ivacaftor and lumacaftor. Expense of these
libraries (containing millions of individual agents) has identified novel compounds has often restricted third-party reimbursement to include
and promising approaches to CF therapy. The approved compound only the specific genotypes for which FDA approval has been obtained.
ivacaftor, for example, robustly potentiates CFTR channel opening and As a consequence, patient access to potentially efficacious agents (and
stimulates ion transport. Ivacaftor overcomes the G551D CFTR gating off-label prescribing) is largely precluded. Moreover, clinical trials
defect, and individuals carrying this mutation exhibit pronounced intended to expand drug label are difficult based on the small numbers
improvement in lung function, weight gain, and other clinical benefit of patients carrying ultra-rare alleles. Similar challenges to drug access
after only a few weeks of oral therapy. Remarkably, sweat chloride val- have been noted in numerous other settings for which precision medi-
CHAPTER 285 Cystic Fibrosis

ues are significantly reduced. Prior to ivacaftor, no clinical intervention cine has become a therapeutic priority.
of any sort had been shown to normalize the CF sweat abnormality.
Partial function CFTR variants (in addition to G551D) for which iva- ■■CF QUALITY IMPROVEMENT
caftor has recently been approved include numerous other genotypes, As a direct result of advances in basic research, new therapies have
with the list of registered indications expected to increase. Chronic transformed CF from a disease typically leading to death in early
administration studies of the drug are ongoing, and indicate significant childhood to a condition with frequent survival well into the fourth
benefit in terms of respiratory function and other clinical parameters. decade of life. It has also become increasingly clear that carefully
Ivacaftor has been viewed as the harbinger of a new era for CF thera- specified approaches to patient management can have an impact on
peutics directed at treating the most fundamental causes of the disease. overall prognosis. For example, standardization of clinical intervention
throughout the United States has led to remarkable benefit among the
Correction of the F508del Processing Abnormality CF population. Well-defined measures for outpatient care are now
Advancement of new drugs that address specific CFTR defects in established, including thresholds for hospital admission, antibiotic reg-
protein folding and maturation has been bolstered by clinical studies imens, nutritional guidelines, periodicity of diagnostic tests, and other
of F508del rescue in combination with ivacaftor. Lumacaftor, the first clinical parameters. These recommendations have become standard
FDA approved “corrector” molecule (as distinct from a CFTR gating throughout specialized CF care centers and other accredited programs.
“potentiator” such as ivacaftor) partially overcomes defective F508del The initiative has improved endpoints such as weight gain, body mass
CFTR biogenesis, and was discovered through compound library index, and pulmonary function. Information regarding standardized
screening. The drug promotes cell surface localization of F508del protocols for CF therapy can be accessed at www.cff.org/treatments/
protein. A dual formulation with ivacaftor confers improvement in cfcareguidelines/ or through a number of excellent reviews.
pulmonary function among F508del homozygous individuals (~45% of
the U.S. CF population). The combination of lumacaftor with ivacaftor ■■GLOBAL CONSIDERATIONS
has been associated with several important pharmacologic interactions, Newborn screening for CF is universal throughout the United
including those mediated by CYP3A, and diminished activity of oral States, most of the Canadian provinces, Australia, New
contraceptives. A chest discomfort syndrome and dyspnea are also Zealand, and much of Europe, and will facilitate early CF
well-described. intervention. Based on data indicating that early nutritional and other
therapies can be beneficial, newborn diagnosis is expected to signifi-
Personalized Molecular Therapies The advent of CFTR mod- cantly promote health among those with the disease. Implementation
ulators with robust clinical impact has engendered new optimism of quality improvement measures and novel therapeutics worldwide
regarding care of patients with CF. It is clear that future interventions has become an increasing imperative. For example, median survival
will be tailored to specific genotypic abnormalities. Drug screening among individuals with CF is ~20 years in much of Latin America
campaigns and other research programs have identified agents capable (compared to >40 years in the United States). The less favorable prog-
of suppressing CFTR nonsense alleles, augmenting potentiator activity, nosis is attributable in part to lack of widespread diagnostic testing
and further promoting F508del correction. Efforts to apply emerging (newborn screening, sweat and genetic evaluation) and insufficient
compounds in a fashion that will benefit the ~90% of CF subjects carry- access to leading-edge, interdisciplinary CF care. Efforts to apply state-
ing at least one copy of F508del (i.e., with F508del or a different CFTR of-the-art management to underdiagnosed and underserved CF patient
mutation on the second allele) comprise an essential priority for the populations are expected to improve outcomes and mitigate CF health
future. Several new molecules in combination with ivacaftor or other disparities in the future.
CFTR modulators are under evaluation as part of multi-center efficacy
trials for this purpose. ■■FURTHER READING
Progress in CF drug discovery is emblematic of what might be Farrell PM et al: Diagnosis of cystic fibrosis. J Pediatr 181S:S4, 2017.
accomplished in numerous refractory inherited diseases using an Huang YJ, LiPuma JJ: The microbiome in cystic fibrosis. Clin Chest
approach grounded in molecular mechanism and unbiased compound Med 37:59, 2016.
library screening. Genetic manipulation (CFTR gene transfer, genome Morrell MR, Pilewski JM: Lung transplantation for cystic fibrosis.
editing, etc.) represents an alternative strategy less dependent on the Clin Chest Med 37:127, 2016.
specific defect, and potentially applicable to diverse CF variants. Such Sabusap C et al: Analysis of cystic fibrosis-associated P67L CFTR illus-
an approach in CF will require efficient and safe in vivo delivery strat- trates barriers to personalized therapeutics for orphan diseases. JCI
egies, particularly those addressing clinically prominent lung disease. Insight 1:e386581, 2016.
Sawicki GS et al: Sustained benefit from ivacaftor demonstrated by
Challenges to Precision CF Therapeutics Because hundreds combining clinical trial and cystic fibrosis patient registry data. Am J
of CF defects are very rare (or even “private,” e.g., reported in only Respir Crit Care Med 192:836, 2015.
one individual or family), detailed molecular profiling (ion transport Sosnay PR et al: Defining the disease liability of variants in the cys-
behavior, protein folding/biogenesis, response to emerging CFTR tic fibrosis transmembrane conductance regulator gene. Nat Genet
modulators, etc.) represents an essential scientific objective. In con- 45:1160, 2013.
trast to the classic and invaluable paradigm of tailored therapeutics Stevens DP, Marshall BC: A decade of healthcare improvement in
(Fig. 285-2, and above), a sizable majority of CF variants do not fall cystic fibrosis: Lessons for other chronic diseases. BMJ Qual Saf 23:i1,
into a single diagnostic category. F508del CFTR, for example, predom- 2014.
inately displays abnormalities of maturational processing (class II), Stoltz DA et al: Origins of cystic fibrosis lung disease. N Engl J Med
but also exhibits more subtle defects related to channel activity/gating 372:351, 2015.

1990 Veit G et al: From CFTR biology towards combinatorial pharmacother- bronchitis, a clinically defined condition with chronic cough and
apy: Expanded classification of cystic fibrosis mutations. Mol Biol phlegm; and small airway disease, a condition in which small bronchioles
Cell 27:424, 2016. are narrowed and reduced in number. The classic definition of COPD
Wainwright CE et al: Lumacaftor-ivacaftor in patients with cystic requires the presence of chronic airflow obstruction, determined by
fibrosis homozygous for Phe508del CFTR. N Engl J Med 373:220, spirometry, that usually occurs in the setting of noxious environmental
2015. exposures—most commonly cigarette smoking. Emphysema, chronic
bronchitis, and small airway disease are present in varying degrees in
different COPD patients. Patients with a history of cigarette smoking
VIDEO 285-1 Initial video sequences describe establishment of the normal
periciliary fluid layer bathing the surface airway epithelium, with spheres
without chronic airflow obstruction may have chronic bronchitis,
representing chloride and bicarbonate ions secreted through CFTR and across the emphysema, and dyspnea. Although these patients are not included
apical (mucosal) respiratory surface. Later video sequences depict failure of CFTR within the classic definition of COPD, they may have similar disease
anion transport and resulting depletion of the periciliary layer, “plastering” of processes. Respiratory symptoms and other features of COPD can
PART 7
cilia against the mucosal surface, and accumulation of mucus in the airway with occur in subjects who do not meet a definition of COPD based only on
resulting bacterial infection. (Video courtesy of the Cystic Fibrosis Foundation.) airflow obstruction determined by spirometric thresholds of normality.
COPD is the third leading cause of death and affects >10 million
persons in the United States. COPD is also a disease of increasing pub-
lic health importance around the world. Estimates suggest that COPD
286 Chronic Obstructive

Pulmonary Disease
will rise to the third most common cause of death worldwide by 2020.
PATHOGENESIS
Edwin K. Silverman, James D. Crapo, Airflow limitation, a major physiologic change in COPD, can result
Barry J. Make from small airway disease and/or emphysema. Small airways may
become narrowed by cells (hyperplasia and accumulation), mucus, and
fibrosis, and extensive small airway destruction has been demonstrated
Chronic obstructive pulmonary disease (COPD) is defined as a disease to be a hallmark of advanced COPD. Although the precise biological
state characterized by persistent respiratory symptoms and airflow mechanisms leading to COPD have not been determined, a number
limitation that is not fully reversible (http://www.goldcopd.com/). COPD of key cell types, molecules, and pathways have been identified from
includes emphysema, an anatomically defined condition characterized cell-based and animal model studies. The pathogenesis of emphysema
by destruction of the lung alveoli with air space enlargement; chronic (shown in Fig. 286-1) is more clearly defined than the pathogenesis of
Triggers Cigarette smoke Genetic susceptibility
Effector cells
Macrophages Neutrophils Epithelial cells Lymphocytes
Biological pathways Protease/Antiprotease Oxidant/Antioxidant Apoptosis Lung repair
Key molecules MMP12 Neutrophil NF KappaB SOD3 Rtp801 Ceramide TGFBeta Elastin
SERPINA1 Elastase NRF2 HDAC2
Pathobiological result Extracellular matrix Chronic Ineffective

destruction inflammation Cell death repair
FIGURE 286-1 Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke in genetically susceptible individuals, lung epithelial cells and T and B
lymphocytes recruit inflammatory cells to the lung. Biological pathways of protease-antiprotease imbalance, oxidant/antioxidant imbalance, apoptosis, and lung
repair lead to extracellular matrix destruction, cell death, chronic inflammation, and ineffective repair. Although most of these biological pathways influence multiple
pathobiological results, only a single relationship between pathways and results is shown. A subset of key molecules related to these biological pathways is listed.

small airway disease. Pulmonary vascular destruction occurs in concert Cell Death Cigarette smoke oxidant-mediated structural cell death 1991
with small airway disease and emphysema. occurs via a variety of mechanisms including excessive ceramide
The dominant current paradigm for the pathogenesis of emphysema production and Rtp801 inhibition of mammalian target of rapamycin
comprises a series of four interrelated events: (1) Chronic exposure to (mTOR), leading to cell death as well as inflammation and proteolysis.
cigarette smoke in genetically susceptible individuals triggers inflam- Involvement of mTOR and other senescence markers has led to the
matory and immune cell recruitment within large and small airways concept that emphysema resembles premature aging of the lung. Het-
and in the terminal air spaces of the lung. (2) Inflammatory cells release erozygous gene-targeting of one of the leading genetic determinants of
proteinases that damage the extracellular matrix supporting airways, COPD identified by genome-wide association studies (GWAS), hedge-
vasculature, and gas exchange surfaces of the lung. (3) Structural cell hog interacting protein (HHIP), in a murine model leads to aging-
death occurs through oxidant-induced damage, cellular senescence, related emphysema.
and proteolytic loss of cellular-matrix attachments leading to extensive
CHAPTER 286 Chronic Obstructive Pulmonary Disease

loss of smaller airways, vascular pruning, and alveolar destruction. Ineffective Repair The ability of the adult lung to replace lost
(4) Disordered repair of elastin and other extracellular matrix compo- smaller airways and microvasculature and to repair damaged alveoli
nents contributes to air space enlargement and emphysema. appears limited. Uptake of apoptotic cells by macrophages normally
results in production of growth factors and dampens inflammation,
■■INFLAMMATION AND EXTRACELLULAR MATRIX promoting lung repair. Cigarette smoke impairs macrophage uptake
PROTEOLYSIS of apoptotic cells, limiting repair. It is unlikely that the intricate and
Elastin, the principal component of elastic fibers, is a highly stable com- dynamic process of septation that is responsible for alveologenesis
ponent of the extracellular matrix that is critical to the integrity of the during lung development can be reinitiated in the adult human lung.
lung. The elastase:antielastase hypothesis, proposed in the mid-1960s,
postulated that the balance of elastin-degrading enzymes and their PATHOLOGY
inhibitors determines the susceptibility of the lung to destruction result- Cigarette smoke exposure may affect the large airways, small airways
ing in air space enlargement. This hypothesis was based on the clinical (≤2 mm diameter), and alveoli. Changes in large airways cause cough
observation that patients with genetic deficiency in α1 antitrypsin and sputum production, while changes in small airways and alveoli
(α1AT), the inhibitor of the serine proteinase neutrophil elastase, were are responsible for physiologic alterations. Airway inflammation,
at increased risk of emphysema, and that instillation of elastases, destruction, and the development of emphysema are present in most
including neutrophil elastase, into experimental animals, results in persons with COPD; however, they appear to be relatively indepen-
emphysema. The elastase:antielastase hypothesis remains a prevailing dent processes, and their relative contributions to obstruction vary
mechanism for the development of emphysema. However, a complex from one person to another. The early stages of COPD, based on the
network of immune and inflammatory cells and additional proteinases severity of airflow obstruction (Table 286-1), appear to be primarily
that contribute to emphysema has subsequently been identified. Upon associated with medium and small airway disease with the majority
exposure to oxidants from cigarette smoke, lung macrophages and epi- of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1
thelial cells become activated, producing proteinases and chemokines and GOLD 2 subjects demonstrating little or no emphysema. The early
that attract other inflammatory and immune cells. Oxidative stress development of chronic airflow obstruction is driven by small airway
is a key component of COPD pathobiology; the transcription factor disease. Advanced stages of COPD (GOLD 3 and 4) are typically char-
NRF2, a major regulator of oxidant-antioxidant balance, and SOD3, a acterized by extensive emphysema, although there are a small number
potent antioxidant, have been implicated in emphysema pathogenesis of subjects with very severe (GOLD 4) obstruction with virtually no
by animal models. Mitochondrial dysfunction in COPD may worsen emphysema. The subjects at greatest risk of progression in COPD are
oxidative stress. One mechanism of macrophage activation occurs those with both aggressive airway disease and emphysema. Thus, find-
via oxidant-induced inactivation of histone deacetylase-2 (HDAC2), ing emphysema (by chest CT) either early or late in the disease process
shifting the balance toward acetylated or loose chromatin, exposing suggests enhanced risk for disease progression.
nuclear factor-kappaB sites, and resulting in transcription of matrix
metalloproteinases and proinflammatory cytokines such as interleukin ■■LARGE AIRWAYS
8 (IL-8) and tumor necrosis factor α (TNF-α); this leads to neutrophil Cigarette smoking often results in mucus gland enlargement and
recruitment. CD8+ T cells are also recruited in response to cigarette goblet cell hyperplasia, leading to cough and mucus production that
smoke and release interferon-inducible protein-10 (IP-10, CXCL-7), define chronic bronchitis, but these abnormalities are not related to air-
which in turn leads to macrophage production of macrophage elastase flow limitation. In response to cigarette smoking, goblet cells not only
(matrix metalloproteinase-12 [MMP-12]). increase in number but in extent through the bronchial tree. Bronchi
Matrix metalloproteinases and serine proteinases, most notably neu- also undergo squamous metaplasia, predisposing to carcinogenesis
trophil elastase, work together by degrading the inhibitor of the other, and disrupting mucociliary clearance. Although not as prominent as
leading to lung destruction. Proteolytic cleavage products of elastin in asthma, patients may have smooth-muscle hypertrophy and bron-
serve as a macrophage chemokine, and proline-glycine-proline (gener- chial hyperreactivity leading to airflow limitation. Neutrophil influx
ated by proteolytic cleavage of collagen) is a neutrophil chemokine— has been associated with purulent sputum during respiratory tract
fueling this destructive positive feedback loop. Elastin degradation
and disordered repair are thought to be primary mechanisms in the
TABLE 286-1 GOLD Criteria for Severity of Airflow Obstruction in
development of emphysema. COPD
There is some evidence that autoimmune mechanisms may promote
GOLD STAGE SEVERITY SPIROMETRY
the progression of disease. Increased B cells and lymphoid follicles
are present around the airways of COPD patients, particularly those I Mild FEV1/FVC <0.7 and FEV1 ≥80% predicted
with advanced disease. Antibodies have been found against elastin II Moderate FEV1/FVC <0.7 and FEV1 ≥50% but <80%
predicted
fragments as well; IgG autoantibodies with avidity for pulmonary epi-
thelium and the potential to mediate cytotoxicity have been detected. III Severe FEV1/FVC <0.7 and FEV1 ≥30% but <50%
predicted
Concomitant cigarette smoke–induced loss of cilia in the airway
epithelium and impaired macrophage phagocytosis predispose to bac- IV Very severe FEV1/FVC <0.7 and FEV1 <30% predicted
terial infection with neutrophilia. In end-stage lung disease, long after Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global
smoking cessation, there remains an exuberant inflammatory response, Initiative for Chronic Obstructive Lung Disease.
suggesting that cigarette smoke–induced inflammation both initiates Source: Reproduced with permission from the Global Strategy for Diagnosis,
Management and Prevention of COPD 2014, © Global Initiative for Chronic
the disease and, in susceptible individuals, establishes a chronic process Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www
that can continue disease progression even after smoking cessation. .goldcopd.org.

1992 infections. Independent of its proteolytic activity, neutrophil elastase is ■■AIRFLOW OBSTRUCTION
among the most potent secretagogues identified. Airflow limitation, also known as airflow obstruction, is typically
determined for clinical purposes by spirometry, which involves forced
■■SMALL AIRWAYS expiratory maneuvers after the subject has inhaled to total lung capac-
The major site of increased resistance in most individuals with COPD ity. Key parameters obtained from spirometry include the volume of
is in airways ≤2 mm diameter. Characteristic cellular changes include air exhaled within the first second of the forced expiratory maneuver
goblet cell metaplasia, with these mucus-secreting cells replacing (FEV1) and the total volume of air exhaled during the entire spirometric
surfactant-secreting Club cells. Smooth-muscle hypertrophy may also maneuver (forced vital capacity [FVC]). Patients with airflow obstruc-
be present. Luminal narrowing can occur by fibrosis, excess mucus, tion related to COPD have a chronically reduced ratio of FEV1/FVC.
edema, and cellular infiltration. Reduced surfactant may increase In contrast to asthma, the reduced FEV1 in COPD seldom shows large
surface tension at the air-tissue interface, predisposing to airway nar- responses to inhaled bronchodilators, although improvements up to
rowing or collapse. Respiratory bronchiolitis with mononuclear inflam- 15% are common.
PART 7
matory cells collecting in distal airway tissues may cause proteolytic

destruction of elastic fibers in the respiratory bronchioles and alveolar ■■HYPERINFLATION
ducts where the fibers are concentrated as rings around alveolar Lung volumes are also routinely assessed in pulmonary function test-
entrances. Narrowing and drop-out of small airways precede the onset ing. In COPD there is often “air trapping” (increased residual volume
of emphysematous destruction. Advanced COPD has been shown to
and increased ratio of residual volume to total lung capacity) and

be associated with a loss of many of the smaller airways and a similar progressive hyperinflation (increased total lung capacity) late in the
significant loss of the lung microvasculature. disease. Hyperinflation of the thorax during tidal breathing preserves
maximum expiratory airflow, because as lung volume increases, elastic
■■LUNG PARENCHYMA recoil pressure increases, and airways enlarge so that airway resistance
Emphysema is characterized by destruction of gas-exchanging air decreases.
spaces, i.e., the respiratory bronchioles, alveolar ducts, and alveoli. Despite compensating for airway obstruction, hyperinflation can
Their walls become perforated and later obliterated with coalescence push the diaphragm into a flattened position with a number of adverse
of the delicate alveolar structure into large emphysematous air spaces. effects. First, by decreasing the zone of apposition between the dia-
Large numbers of macrophages accumulate in respiratory bronchioles phragm and the abdominal wall, positive abdominal pressure during
of essentially all smokers. Bronchoalveolar lavage fluid from such indi- inspiration is not applied as effectively to the chest wall, hindering rib
viduals contains roughly five times as many macrophages as lavage cage movement and impairing inspiration. Second, because the muscle
from nonsmokers. Neutrophils and T lymphocytes, particularly CD8+ fibers of the flattened diaphragm are shorter than those of a more nor-
cells, are also increased in the alveolar space of smokers. mally curved diaphragm, they are less capable of generating inspiratory
Emphysema is classified into distinct pathologic types, which include pressures than normal. Third, the flattened diaphragm must generate
centrilobular, panlobular, and paraseptal (Fig 286-2). Centrilobular greater tension to develop the transpulmonary pressure required to
emphysema, the type most frequently associated with cigarette smoking, produce tidal breathing. Fourth, the thoracic cage is distended beyond
is characterized by enlarged air spaces found (initially) in association its normal resting volume and during tidal breathing the inspiratory
with respiratory bronchioles. Centrilobular emphysema is usually most muscles must do work to overcome the resistance of the thoracic cage
prominent in the upper lobes and superior segments of lower lobes and to further inflation instead of gaining the normal assistance from the
is often quite focal. Panlobular emphysema refers to abnormally large air chest wall recoiling outward toward its resting volume.
spaces evenly distributed within and across acinar units. Panlobular
emphysema is commonly observed in patients with α1AT deficiency, ■■GAS EXCHANGE
which has a predilection for the lower lobes. Paraseptal emphysema Although there is considerable variability in the relationships between
occurs in 10–15% of cases and is distributed along the pleural margins the FEV1 and other physiologic abnormalities in COPD, certain gen-
with relative sparing of the lung core or central regions. It is commonly eralizations may be made. The partial pressure of oxygen in arterial
associated with significant airway inflammation and with centrilobular blood Pao2 usually remains near normal until the FEV1 is decreased to
emphysema. ~50% of predicted, and even much lower FEV1 values can be associated
with a normal Pao2, at least at rest. An elevation of arterial level of
PATHOPHYSIOLOGY carbon dioxide (Paco2) is not expected until the FEV1 is <25% of pre-
Persistent reduction in forced expiratory flow rates is the most typical dicted and even then may not occur. Pulmonary hypertension severe
finding in COPD. Increases in the residual volume and the residual enough to cause cor pulmonale and right ventricular failure due to
volume/total lung capacity ratio, non-uniform distribution of ventila- COPD typically occurs in individuals who have marked decreases in
tion, and ventilation-perfusion mismatching also occur. FEV1 (<25% of predicted) and chronic hypoxemia (Pao2 <55 mmHg);
however, recent evidence suggests that
some patients will develop significant
pulmonary hypertension independent of
COPD severity (Chap. 277).
Non-uniform ventilation and ven-
tilation-perfusion mismatching are
characteristic of COPD, reflecting the
heterogeneous nature of the disease
process within the airways and lung
parenchyma. Physiologic studies are
consistent with multiple parenchymal
compartments having different rates of
ventilation due to regional differences
A B C in compliance and airway resistance.
FIGURE 286-2 CT patterns of emphysema. A. Centrilobular emphysema with severe upper lobe involvement in a
Ventilation-perfusion mismatching
68-year-old man with a 70 pack-year smoking history but forced expiratory volume (FEV1) 81% predicted (GOLD accounts for essentially all of the reduc-
spirometry grade 1); B. Panlobular emphysema with diffuse loss of lung parenchymal detail predominantly in the tion in Pao2 that occurs in COPD; shunt-
lower lobes in a 64-year-old man with severe α1AT deficiency; and C. Paraseptal emphysema with marked airway ing is minimal. This finding explains
inflammation in a 52-year-old woman with a 37 pack-year smoking history and FEV1 40% predicted. the effectiveness of modest elevations of

inspired oxygen in treating hypoxemia due to COPD and therefore the FEV1/FVC, studies have shown that these subjects overall have a shift 1993
need to consider problems other than COPD when hypoxemia is diffi- toward lower FEV1 values, which is consistent with obstruction on an
cult to correct with modest levels of supplemental oxygen. individual level.
Although cigar and pipe smoking may also be associated with the
RISK FACTORS development of COPD, the evidence supporting such associations is
less compelling, likely related to the lower dose of inhaled tobacco
■■CIGARETTE SMOKING by-products during cigar and pipe smoking. The impact of electronic
By 1964, the Advisory Committee to the Surgeon General of the United cigarettes (e-cigarettes) on the development and progression of COPD
States had concluded that cigarette smoking was a major risk factor has not yet been determined.
for mortality from chronic bronchitis and emphysema. Subsequent
longitudinal studies have shown accelerated decline in FEV1 in a dose- ■■AIRWAY RESPONSIVENESS AND COPD

response relationship to the intensity of cigarette smoking, which is A tendency for increased bronchoconstriction in response to a variety
typically expressed as pack-years (average number of packs of ciga- of exogenous stimuli, including methacholine and histamine, is one of
rettes smoked per day multiplied by the total number of years of smok- the defining features of asthma (Chap. 281). However, many patients
ing). This dose-response relationship between reduced pulmonary with COPD also share this feature of airway hyperresponsiveness.
function and cigarette smoking intensity accounts, at least in part, for In older subjects, there is considerable overlap between persons with
the higher prevalence rates of COPD with increasing age. The histori- a history of chronic asthma and smokers with COPD in terms of air-
cally higher rate of smoking among males is the likely explanation for way responsiveness, airflow obstruction, and pulmonary symptoms.
the higher prevalence of COPD among males; however, the prevalence The origin of asthma is viewed as an allergic disease while COPD
of COPD among females is increasing as the gender gap in smoking is thought to primarily result from smoking-related inflammation
rates has diminished in the past 50 years. and damage; however, they likely share common environmental and
Although the causal relationship between cigarette smoking and genetic factors and the chronic form in older subjects can present sim-
the development of COPD has been absolutely proved, there is consid- ilarly. This is particularly true for childhood asthmatic subjects who
erable variability in the response to smoking. Pack-years of cigarette become chronic smokers.
smoking is the most highly significant predictor of FEV1 (Fig. 286-3), Longitudinal studies that compared airway responsiveness at the
but only 15% of the variability in FEV1 is explained by pack-years. This beginning of the study to subsequent decline in pulmonary function
finding suggests that additional environmental and/or genetic factors have demonstrated that increased airway responsiveness is clearly a
contribute to the impact of smoking on the development of chronic significant predictor of subsequent decline in pulmonary function. A
airflow obstruction. Nonetheless, many patients with a history of ciga- recent study from the Childhood Asthma Management Program iden-
rette smoking with normal spirometry have evidence for worse health- tified four lung function trajectories in children with persistent asthma.
related quality of life, reduced exercise capacity, and emphysema and/ Asthmatics with reduced lung function early in life were more likely
or airway disease on chest CT evaluation; thus, they have not escaped to meet spirometric criteria for COPD in early adulthood. Patients
the harmful effects of cigarette smoking. While they do not meet the with features of both asthma and COPD have been described as the
classic definition of COPD based on population normals for FEV1 and asthma-COPD overlap syndrome. Both asthma and airway hyperre-
sponsiveness are risk factors for COPD.
–1 S.D. Mean +1 S.D.
0 Pack years (945)
■■RESPIRATORY INFECTIONS
20 The impact of adult respiratory infections on decline in pulmonary func-
Median tion is controversial, but significant long-term reductions in pulmonary
10
function are not typically seen following an individual episode of acute
0
bronchitis or pneumonia. However, respiratory infections are important
0–20 Pack years (578) causes of COPD exacerbations, and recent results from the COPDGene
20 and ECLIPSE studies suggest that COPD exacerbations are associated
10 with increased loss of lung function longitudinally, particularly among
0 those individuals with better baseline lung function levels. The impact
of the effects of childhood respiratory illnesses on the subsequent devel-
21–40 Pack years (271)
% of Population
20
opment of COPD has been difficult to assess due to a lack of adequate
longitudinal data, but recent studies have suggested that childhood
10
pneumonia may lead to increased risk for COPD later in life.
0
41–60 Pack years (154) ■■OCCUPATIONAL EXPOSURES
20 Increased respiratory symptoms and airflow obstruction have been
10 suggested to result from exposure to dust and fumes at work. Several
0 specific occupational exposures, including coal mining, gold mining,
and cotton textile dust, have been implicated as risk factors for chronic
61+ Pack years (100) airflow obstruction. Although nonsmokers in these occupations can
20
develop some reductions in FEV1, the importance of dust exposure as a
10 risk factor for COPD, independent of cigarette smoking, is not certain
0 for most of these exposures. However, among coal miners, coal mine
dust exposure was a significant risk factor for emphysema in both
40 60 80 100 120 140 160 smokers and nonsmokers. In most cases, the magnitude of these occu-
% FEV1 pational exposures on COPD risk is likely substantially less important
than the effect of cigarette smoking.
FIGURE 286-3 Distributions of forced expiratory volume in 1 s (FEV1) values
in a general population sample, stratified by pack-years of smoking. Means, ■■AMBIENT AIR POLLUTION
medians, and ±1 standard deviation of percent predicted FEV1 are shown for each Some investigators have reported increased respiratory symptoms in
smoking group. Although a dose-response relationship between smoking intensity
and FEV1 was found, marked variability in pulmonary function was observed
those living in urban compared to rural areas, which may relate to
among subjects with similar smoking histories. (From B Burrows et al: Am Rev increased pollution in the urban settings. However, the relationship
Respir Dis 115:95, 1977; with permission.) of air pollution to chronic airflow obstruction remains unproved.

1994 Prolonged exposure to smoke produced by biomass combustion—a GWAS have identified >20 regions of the genome that contain COPD
common mode of cooking in some countries—also appears to be a susceptibility loci, including a region near the HHIP gene on chromo-
significant risk factor for COPD among women in those countries. some 4, a cluster of genes on chromosome 15 (including components of
However, in most populations, ambient air pollution is a much less the nicotinic acetylcholine receptor and another gene, IREB2, related to
important risk factor for COPD than cigarette smoking. mitochondrial iron regulation), and a region within a gene of unknown
function (FAM13A). As with most other complex diseases, the risk
■■PASSIVE, OR SECOND-HAND, SMOKING EXPOSURE associated with individual GWAS loci is modest, but these genetic
Exposure of children to maternal smoking results in significantly determinants may identify important biological pathways related to
reduced lung growth. In utero, tobacco smoke exposure also con- COPD. Gene-targeted murine models for HHIP, FAM13A, and IREB2
tributes to significant reductions in postnatal pulmonary function. exposed to chronic cigarette smoke had altered emphysema suscep-
Although passive smoke exposure has been associated with reductions tibility, suggesting that those genes are likely to be involved in COPD
in pulmonary function, the importance of this risk factor in the devel- pathogenesis. A regulatory single nucleotide polymorphisms (SNP)
PART 7
opment of the severe pulmonary function reductions often observed in upstream from the HHIP gene has been identified as one potential
COPD remains uncertain. functional variant; the specific genetic determinants in the other COPD
GWAS genomic regions have yet to be definitively identified.
■■GENETIC CONSIDERATIONS
Although cigarette smoking is the major environmental risk fac-

tor for the development of COPD, the development of airflow NATURAL HISTORY
obstruction in smokers is highly variable. Severe α1AT deficiency The effects of cigarette smoking on pulmonary function appear to
is a proven genetic risk factor for COPD; there is increasing evidence depend on the intensity of smoking exposure, the timing of smoking
that other genetic determinants also exist. exposure during growth, and the baseline lung function of the indi-
vidual; other environmental factors may have similar effects. Most
`1 Antitrypsin Deficiency Many variants of the protease inhibi- individuals follow a steady trajectory of increasing pulmonary function
tor (PI or SERPINA1) locus that encodes α1AT have been described. The with growth during childhood and adolescence, followed by a plateau
common M allele is associated with normal α1AT levels. The S allele, in early adulthood, and then gradual decline with aging. Individuals
associated with slightly reduced α1AT levels, and the Z allele, associ- appear to track in their quantile of pulmonary function based on envi-
ated with markedly reduced α1AT levels, also occur with frequencies ronmental and genetic factors that put them on different tracks. The risk
of >1% in most white populations. Rare individuals inherit null alleles, of eventual mortality from COPD is closely associated with reduced lev-
which lead to the absence of any α1AT production through a hetero- els of FEV1. A graphic depiction of the natural history of COPD is shown
geneous collection of mutations. Individuals with two Z alleles or one as a function of the influences on tracking curves of FEV1 in Fig. 286-4.
Z and one null allele are referred to as PiZ, which is the most common Death or disability from COPD can result from a normal rate of decline
form of severe α1AT deficiency. after a reduced growth phase (curve C), an early initiation of pulmo-
Although only ~1% of COPD patients are found to have severe α1AT nary function decline after normal growth (curve B), or an accelerated
deficiency as a contributing cause of COPD, these patients demonstrate decline after normal growth (curve D). Although accelerated rates of
that genetic factors can have a profound influence on the susceptibility lung function decline have classically been associated with COPD,
for developing COPD. PiZ individuals often develop early-onset COPD, recent analyses of several population-based cohorts demonstrated that
but the ascertainment bias in the published series of PiZ individuals— many subjects meeting the spirometric criteria for COPD had reduced
which have usually included many PiZ subjects who were tested for growth but normal rates of lung function decline. The rate of decline in
α1AT deficiency because they had COPD—means that the fraction of pulmonary function can be modified by changing environmental expo-
PiZ individuals who will develop COPD and the age-of-onset distri- sures (i.e., quitting smoking), with smoking cessation at an earlier age
bution for the development of COPD in PiZ subjects remain unknown. providing a more beneficial effect than smoking cessation after marked
Approximately 1 in 3000 individuals in the United States inherits reductions in pulmonary function have already developed. The abso-
severe α1AT deficiency, but only a small minority of these individuals lute annual loss in FEV1 tends to be highest in mild COPD and lowest
has been identified. The clinical laboratory test used most frequently to in very severe COPD. Multiple genetic factors influence the level of
screen for α1AT deficiency is measurement of the immunologic level of pulmonary function achieved during growth; genetic determinants
α1AT in serum (see “Laboratory Findings”).
A significant percentage of the variability in pulmonary function
among PiZ individuals is explained by cigarette smoking; cigarette Early decline
smokers with severe α1AT deficiency are more likely to develop COPD 100
FEV1, % normal level at age 20
at early ages. However, the development of COPD in PiZ subjects, even Normal
among current or ex-smokers, is not absolute. Among PiZ nonsmokers,
impressive variability has been noted in the development of airflow 75 C A
obstruction. Asthma and male gender also appear to increase the risk
of COPD in PiZ subjects. Other genetic and/or environmental factors Reduced growth
50 B
likely contribute to this variability.
Specific treatment in the form of α1AT augmentation therapy is
available for severe α1AT deficiency as a weekly IV infusion (see Rapid decline
“Treatment,” below). 25 Respiratory symptoms
D
The risk of lung disease in heterozygous PiMZ individuals, who have
intermediate serum levels of α1AT (~60% of PiMM levels), has been
controversial. Several recent large studies have demonstrated that PiMZ 0 10 20 30 40 50 60 70 80
subjects who smoke are likely at increased risk for the development Age, year
of COPD. However, alpha-1 antitrypsin augmentation therapy is not
recommended for use in PiMZ subjects. FIGURE 286-4 Hypothetical tracking curves of forced expiratory volume in 1 s
(FEV1) for individuals throughout their life spans. The normal pattern of growth
Other Genetic Risk Factors Studies of pulmonary function and decline with age is shown by curve A. Significantly reduced FEV1 (<65% of
measurements performed in general population samples have sug- predicted value at age 20) can develop from a normal rate of decline after a
reduced pulmonary function growth phase (curve C), early initiation of pulmonary
gested that genetic factors other than PI type influence variation in function decline after normal growth (curve B), or accelerated decline after normal
pulmonary function. Familial aggregation of airflow obstruction within growth (curve D). (From B Rijcken: Doctoral dissertation, p 133, University of
families of COPD patients has also been demonstrated. Groningen, 1991; with permission.)

likely also influence the rate of decline in response to smoking and lung volumes may increase, resulting in an increase in total lung capac- 1995
potentially to other environmental factors as well. ity, functional residual capacity, and residual volume. In patients with
emphysema, the diffusing capacity may be reduced, reflecting the lung
CLINICAL PRESENTATION parenchymal destruction characteristic of the disease. The degree of
airflow obstruction is an important prognostic factor in COPD and is
■■HISTORY the basis for the GOLD spirometric severity classification (Table 286-1).
The three most common symptoms in COPD are cough, sputum pro- Although the degree of airflow obstruction generally correlates with
duction, and exertional dyspnea. Many patients have such symptoms the presence and severity of respiratory symptoms, exacerbations,
for months or years before seeking medical attention. Although the emphysema, and hypoxemia, the correlations are far from perfect.
development of airflow obstruction is a gradual process, many patients Thus, clinical features should be carefully assessed in each individual
date the onset of their disease to an acute illness or exacerbation. A patient with COPD to determine the most appropriate therapies. It has

careful history, however, usually reveals the presence of symptoms been shown that a multifactorial index (BODE) incorporating airflow
prior to the acute exacerbation. The development of exertional dysp- obstruction, exercise performance, dyspnea, and body mass index is
nea, often described as increased effort to breathe, heaviness, air hun- a better predictor of mortality rate than pulmonary function alone.
ger, or gasping, can be insidious. It is best elicited by a careful history Recently, the GOLD added additional elements to their classification
focused on typical physical activities and how the patient’s ability to system incorporating respiratory symptoms and exacerbation history;
perform them has changed. Activities involving significant arm work, these metrics are used to guide COPD treatment (see below).
particularly at or above shoulder level, are particularly difficult for Arterial blood gases and oximetry may demonstrate resting or exer-
many patients with COPD. Conversely, activities that allow the patient tional hypoxemia. Arterial blood gases provide additional information
to brace the arms and use accessory muscles of respiration are better about alveolar ventilation and acid-base status by measuring arterial
tolerated. Examples of such activities include pushing a shopping cart Pco2 and pH. The change in pH with Pco2 is 0.08 units/10 mmHg
or walking on a treadmill. As COPD advances, the principal feature is acutely and 0.03 units/10 mmHg in the chronic state. Knowledge of
worsening dyspnea on exertion with increasing intrusion on the ability the arterial pH therefore allows the classification of ventilatory failure,
to perform vocational or avocational activities. In the most advanced defined as Pco2 >45 mmHg, into acute or chronic conditions with acute
stages, patients are breathless doing simple activities of daily living. respiratory failure being associated with acidemia. The arterial blood
Accompanying worsening airflow obstruction is an increased fre- gas is an important component of the evaluation of patients presenting
quency of exacerbations (described below). Patients may also develop with symptoms of an exacerbation. An elevated hematocrit suggests
resting hypoxemia and require institution of supplemental oxygen. the presence of chronic hypoxemia, as does the presence of signs of
right ventricular hypertrophy.
■■PHYSICAL FINDINGS Radiographic studies may assist in the classification of the type of
In the early stages of COPD, patients usually have an entirely normal COPD. Obvious bullae, paucity of parenchymal markings, or hyperlu-
physical examination. Current smokers may have signs of active smok- cency on chest x-ray suggests the presence of emphysema. Increased
ing, including an odor of smoke or nicotine staining of fingernails. In lung volumes and flattening of the diaphragm suggest hyperinflation
patients with more severe disease, the physical examination of the but do not provide information about chronicity of the changes. Chest
lungs is notable for a prolonged expiratory phase and may include computed tomography (CT) scan is the current definitive test for estab-
expiratory wheezing. In addition, signs of hyperinflation include a lishing the presence or absence of emphysema, the pattern of emphy-
barrel chest and enlarged lung volumes with poor diaphragmatic sema, and the presence of significant disease involving medium and
excursion as assessed by percussion. Patients with severe airflow large airways (Fig. 286-2). It also enables the discovery of coexisting
obstruction may also exhibit use of accessory muscles of respiration, interstitial lung disease and bronchiectasis, which are common compli-
sitting in the characteristic “tripod” position to facilitate the actions of cations in COPD. Smokers with COPD are at high risk for development
the sternocleidomastoid, scalene, and intercostal muscles. Patients may of lung cancer, which can be identified on a chest CT scan. In advanced
develop cyanosis, visible in the lips and nail beds. COPD, CT scans can help determine the possible value of surgical
Although traditional teaching is that patients with predominant therapy (described below).
emphysema, termed “pink puffers,” are thin and noncyanotic at rest Recent guidelines have suggested testing for α1AT deficiency in
and have prominent use of accessory muscles, and patients with all subjects with COPD or asthma with chronic airflow obstruction.
chronic bronchitis are more likely to be heavy and cyanotic (“blue Measurement of the serum α1AT level is a reasonable initial test. For
bloaters”), current evidence demonstrates that most patients have ele- subjects with low α1AT levels, the definitive diagnosis of α1AT defi-
ments of both chronic bronchitis and emphysema and that the physical ciency requires PI type determination. This is typically performed by
examination does not reliably differentiate the two entities. isoelectric focusing of serum or plasma, which reflects the genotype at
Advanced disease may be accompanied by cachexia, with significant the PI locus for the common alleles and many of the rare PI alleles as
weight loss, bitemporal wasting, and diffuse loss of subcutaneous adi- well. Molecular genotyping of DNA can be performed for the common
pose tissue. This syndrome has been associated with both inadequate PI alleles (M, S, and Z).
oral intake and elevated levels of inflammatory cytokines (TNF-α).
Such wasting is an independent poor prognostic factor in COPD. Some
patients with advanced disease have paradoxical inward movement TREATMENT
of the rib cage with inspiration (Hoover’s sign), the result of alteration
of the vector of diaphragmatic contraction on the rib cage as a result of Chronic Obstructive Pulmonary Disease
chronic hyperinflation.
Signs of overt right heart failure, termed cor pulmonale, are relatively STABLE PHASE COPD
infrequent since the advent of supplemental oxygen therapy. The two main goals of therapy are to provide symptomatic relief
Clubbing of the digits is not a sign of COPD, and its presence should (reduce respiratory symptoms, improve exercise tolerance, improve
alert the clinician to initiate an investigation for causes of clubbing. health status) and reduce future risk (prevent disease progression,
In this population, the development of lung cancer is the most likely prevent and treat exacerbations, and reduce mortality). The institu-
explanation for newly developed clubbing. tion of therapies should be based on symptom assessment, benefits
of therapy, potential risks, and costs. Figure 286-5 provides the
■■LABORATORY FINDINGS currently suggested categories of COPD patients based on respi-
The hallmark of COPD is airflow obstruction (discussed above). Pul- ratory symptoms and risk for exacerbations. Response to therapy
monary function testing shows airflow obstruction with a reduction should be assessed, and decisions should be made whether or not to
in FEV1 and FEV1/FVC (Chap. 279). With worsening disease severity, continue or alter treatment.

1996 COPD Severity Group survival. Thus, all patients with COPD should be strongly urged
Exacerbation History to quit smoking and educated about the benefits of quitting. An
C D emerging body of evidence demonstrates that combining phar-
≥2 Low High
or macotherapy with traditional supportive approaches considerably
symptoms, symptoms,
≥1 with hospital admission enhances the chances of successful smoking cessation. There are
High risk High risk
three principal pharmacologic approaches to the problem: nicotine
A B replacement therapy available as gum, transdermal patch, lozenge,
0 or 1 Low High inhaler, and nasal spray; bupropion; and varenicline, a nicotinic
(without hospital admission) symptoms, symptoms, acid receptor agonist/antagonist. Current recommendations from
Low risk Low risk the U.S. Surgeon General are that all adult, nonpregnant smokers
considering quitting be offered pharmacotherapy, in the absence of
mMRC 0–1 mMRC ≥2 any contraindication to treatment. Smoking cessation counseling is
PART 7
or or also recommended and free counseling is available through state

CAT <10 CAT ≥10
Smoking QuitLines.
Symptoms Bronchodilators In general, bronchodilators are the primary
FIGURE 286-5 COPD severity assessment. COPD severity categories are based treatment for almost all patients with COPD and are used for
on respiratory symptoms (based on the mMRC or CAT scales) and annual symptomatic benefit and to reduce exacerbations. The inhaled
frequency of COPD exacerbations. mMRC—Modified Medical Research Council route is preferred for medication delivery, because side effects
Dyspnea Scale. Provides a single number for degree of breathlessness: 0—only
are less than with systemic medication delivery. In symptomatic
with strenuous activity; 1—hurrying on level ground or walking up a slight hill; 2—
walk slower than peers or stop walking at their own pace; 3—walking about 100 patients, both regularly scheduled use of long-acting agents and
yards or after a few minutes on level ground; 4—too breathless to leave the house as-needed short-acting medications are indicated. Figure 286-6
or when dressing. CAT—COPD Assessment Test. An 8-item COPD health status provides suggestions for prescribing inhaled medication therapy
measure with Likert scale responses for questions about cough, phlegm, chest based on grouping patients by severity of symptoms and risk of
tightness, dyspnea on one flight of stairs, limitation in home activities, confidence exacerbations.
in leaving the home, sleep and energy. Range of total score is 0–40. Both mMRC
and CAT are available from Global Strategy for the Diagnosis, Management and Anticholinergic Muscarinic Antagonists Short-acting ipratropium
Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) bromide improves symptoms with acute improvement in FEV1.
2017. With permission from http://goldcopd.org. Long-acting muscarinic antagonists (LAMA, including aclidinium,
glycopyrrolate, tiotropium, and umeclidinium) improve symptoms
Only three interventions—smoking cessation, oxygen therapy and reduce exacerbations. In a large randomized clinical trial, there
in chronically hypoxemic patients, and lung volume reduction was a trend toward reduced mortality rate in tiotropium-treated
surgery (LVRS) in selected patients with emphysema—have been patients that approached statistical significance. Side effects are
demonstrated to improve survival of patients with COPD. There minor; dry mouth is the most frequent side effect.
is suggestive, but not definitive, evidence that the use of inhaled
Beta Agonists Short-acting beta agonists ease symptoms with
corticosteroids (ICS) and muscarinic antagonists may reduce the
acute improvements in lung function. Long-acting agents (LABA)
mortality rate.
provide symptomatic benefit and reduce exacerbations, though to a
PHARMACOTHERAPY lesser extent than a LAMA. Currently available long-acting inhaled
Smoking Cessation (See also Chap. 448) It has been shown that β agonists are arformoterol, formoterol, indacaterol, olodaterol,
middle-aged smokers who were able to successfully stop smoking salmeterol, and vilanterol. The main side effects are tremor and
experienced a significant improvement in the rate of decline in pul- tachycardia.
monary function, often returning to annual changes similar to that Combinations of Beta Agonist — Muscarinic Antagonist The com-
of nonsmoking patients. In addition, smoking cessation improves bination inhaled β agonist and muscarinic antagonist therapy has
Group C Group D
Consider roflumilast if
Consider macrolide
FEV1 <50% pred. and
(in former smokers)
chronic bronchitis
LAMA + LABA LABA + ICS Persistent
Further
LAMA symptoms/further
exacerbation(s) exacerbation(s)
Further + LABA
exacerbation(s) Further + ICS
exacerbation(s)
LAMA
LAMA LAMA + LABA LABA +ICS
Group A Continue, stop or try Group B

LAMA + LABA
alternative class of
bronchodilator
Persistent
symptoms
Evaluate
effect
A long-acting bronchodilator
(LABA or LAMA)
A bronchodilator
FIGURE 286-6 Medication therapy for stable COPD. Recommended pharmacologic treatment of stable COPD is based on respiratory symptoms and exacerbation
frequency. Preferred treatment Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD)
2017. Reproduced with permission from http://goldcopd.org.

been demonstrated to provide improvement in lung function that is in patients receiving α1AT augmentation therapy. Eligibility for 1997
greater than either agent alone and reduces exacerbations. α1AT augmentation therapy requires a serum α1AT level <11 μM
(~50 mg/dL). Typically, PiZ individuals will qualify, although other
Inhaled Corticosteroids The main role of ICS is to reduce exacer-
rare types associated with severe deficiency (e.g., null-null) are also
bations. Although one large trial and a meta-analysis demonstrated
eligible. Because only a fraction of individuals with severe α1AT
an apparent benefit from the regular use of inhaled glucocorticoids
deficiency will develop COPD, α1AT augmentation therapy is not
on the rate of decline of lung function, a number of other well-
recommended for severely α1AT-deficient persons with normal
designed randomized trials have not. A meta-analysis and retro-
pulmonary function and a normal chest CT scan.
spective studies suggest a mortality benefit, but in a large random-
ized trial, differences in mortality rate approached, but did not NONPHARMACOLOGIC THERAPIES
reach, conventional criteria for statistical significance. Their use has Patients with COPD should receive the influenza vaccine annually.

been associated with increased rates of oropharyngeal candidiasis Pneumococcal vaccines and vaccination for Bordetella pertussis are
and pneumonia and in some studies an increased rate of loss of recommended.
bone density. A trial of ICS should be considered in patients with
frequent exacerbations, defined as two or more per year, and in Pulmonary Rehabilitation This refers to a comprehensive treat-
patients with features of asthma, such as eosinophilia. In stable ment program that incorporates exercise, education, and psychoso-
patients, ICS withdrawal may be considered. Although ICS with- cial and nutritional counseling. In COPD, pulmonary rehabilitation
drawal does not lead to an increase in exacerbations, there may be has been demonstrated to improve health-related quality of life,
a small decline in lung function. dyspnea, and exercise capacity. It has also been shown to reduce
rates of hospitalization over a 6- to 12-month period.
Oral Glucocorticoids The chronic use of oral glucocorticoids for
Lung Volume Reduction Surgery In carefully selected patients with
treatment of COPD is not recommended because of an unfavorable
emphysema, surgery to remove the most emphysematous portions
benefit/risk ratio. The chronic use of oral glucocorticoids is asso-
of lung improves exercise, lung function, and survival. The ana-
ciated with significant side effects, including osteoporosis, weight
tomic distribution of emphysema and post-rehabilitation exercise
gain, cataracts, glucose intolerance, and increased risk of infection.
capacity are important prognostic characteristics. Patients with
A recent study demonstrated that patients tapered off chronic low-
upper lobe–predominant emphysema and a low post-rehabilitation
dose prednisone (~10 mg/d) did not experience any adverse effect
exercise capacity are most likely to benefit from LVRS.
on the frequency of exacerbations, health-related quality of life, or
Patients with an FEV1 <20% of predicted and either diffusely
lung function.
distributed emphysema on CT scan or diffusing capacity of lung for
Theophylline Theophylline produces modest improvements in carbon monoxide (DLCO) <20% of predicted have increased mortal-
airflow and vital capacity, but is not first-line therapy due to side ity after the procedure, and thus are not candidates for LVRS.
effects and drug interactions. Nausea is a common side effect; Methods of achieving lung volume reduction by using broncho-
tachycardia and tremor have also been reported. Monitoring of scopic techniques are under investigation.
blood theophylline levels is required to minimize toxicity.
Lung Transplantation (See also Chap. 292) COPD is currently the
PDE4 Inhibitors The selective phosphodiesterase 4 (PDE4) inhib- second leading indication for lung transplantation. Current recom-
itor roflumilast has been demonstrated to reduce exacerbation mendations are that candidates for lung transplantation should
frequency in patients with severe COPD, chronic bronchitis, and a have very severe airflow limitation, severe disability despite maxi-
prior history of exacerbations; its effects on airflow obstruction and mal medical therapy, and be free of significant comorbid conditions
symptoms are modest. such as liver, renal, or cardiac disease.
Antibiotics There are strong data implicating bacterial infection EXACERBATIONS OF COPD
as a precipitant of a substantial portion of exacerbations. A ran- Exacerbations are a prominent feature of the natural history of
domized clinical trial of azithromycin, chosen for both its anti- COPD. Exacerbations are episodic acute worsening of respiratory
inflammatory and antimicrobial properties, administered daily to symptoms, including increased dyspnea, cough, wheezing, and/
subjects with a history of exacerbation in the past 6 months demon- or change in the amount and character of sputum. They may or
strated a reduced exacerbation frequency and longer time to first may not be accompanied by other signs of illness, including fever,
exacerbation in the macrolide-treated cohort (hazard ratio, 0.73). myalgias, and sore throat. The strongest single predictor of exac-
Oxygen Supplemental O2 is the only pharmacologic therapy erbations is a history of a previous exacerbation. The frequency of
demonstrated to unequivocally decrease mortality rates in patients exacerbations increases as airflow obstruction worsens; patients
with COPD. For patients with resting hypoxemia (resting O2 satura- with severe (FEV1 <50% predicted) or very severe airflow obstruc-
tion ≤88% in any patient or ≤89% with signs of pulmonary hyperten- tion (FEV1 <30% predicted) on average have 1–3 episodes per year.
sion or right heart failure), the use of O2 has been demonstrated to However, some individuals with very severe airflow obstruction do
have a significant impact on mortality. Patients meeting these criteria not have frequent exacerbations. Other factors, such as an elevated
should be on continuous oxygen supplementation because the mor- ratio of the diameter of the pulmonary artery to aorta on chest CT,
tality benefit is proportional to the number of hours per day oxygen and gastroesophageal reflux, are also associated with increased risk
is used. Various delivery systems are available, including portable of COPD exacerbations. Economic analyses have shown that >70%
systems that patients may carry to allow mobility outside the home. of COPD-related health care expenditures are due to emergency
A recent study failed to demonstrate significant benefits to COPD department visits and hospital care for COPD exacerbations; this
patients with moderate hypoxemia at rest or with hypoxemia only translates to over $10 billion annually in the United States.
with activity. Precipitating Causes and Strategies to Reduce Frequency of
`1AT Augmentation Therapy Specific treatment in the form of IV Exacerbations A variety of stimuli may result in the final common
α1AT augmentation therapy is available for individuals with severe pathway of airway inflammation and increased respiratory symp-
α1AT deficiency. Despite sterilization procedures for these blood- toms that are characteristic of COPD exacerbations. Studies suggest
derived products and the absence of reported cases of viral infection that acquiring a new strain of bacteria is associated with increased
from therapy, some physicians recommend hepatitis B vaccination near-term risk of exacerbation and that bacterial infection/super-
prior to starting augmentation therapy. Although biochemical effi- infection is involved in >50% of exacerbations. Viral respiratory
cacy of α1AT augmentation therapy has been shown, the benefits infections are present in approximately one-third of COPD exacer-
of α1AT augmentation therapy are controversial. A recent ran- bations. In a significant minority of instances (20–35%), no specific
domized study suggested a reduction in emphysema progression precipitant can be identified.

1998 Patient Assessment An attempt should be made to establish the usually treated with antibiotics, even in the absence of data impli-
severity of the exacerbation as well as the severity of preexisting cating a specific pathogen.
COPD. The more severe either of these two components, the more In patients admitted to the hospital, the use of systemic glucocor-
likely that the patient will require hospital admission. The history ticoids reduces the length of stay, hastens recovery, and reduces the
should include quantification of the degree and change in dyspnea chance of subsequent exacerbation or relapse. One study demon-
by asking about breathlessness during activities of daily living and strated that 2 weeks of glucocorticoid therapy produced benefit
typical activities for the patient. The patient should be asked about indistinguishable from 8 weeks of therapy. Current recommenda-
fever; change in character of sputum; and associated symptoms tions suggest 30–40 mg of oral prednisolone or its equivalent typ-
such as wheezing, nausea, vomiting, diarrhea, myalgias, and chills. ically for a period of 5–10 days in outpatients. Hyperglycemia,
Inquiring about the frequency and severity of prior exacerbations particularly in patients with preexisting diagnosis of diabetes, is
can provide important information; the single greatest risk factor the most frequently reported acute complication of glucocorticoid
for hospitalization with an exacerbation is a history of previous treatment.
PART 7
hospitalization. Oxygen Supplemental O2 should be supplied to maintain oxy-

The physical examination should incorporate an assessment of gen saturation ≥90%. Studies have demonstrated that in patients
the degree of distress of the patient. Specific attention should be with both acute and chronic hypercarbia, the administration of
focused on tachycardia, tachypnea, use of accessory muscles, signs of supplemental O2 does not reduce minute ventilation. It does, in
perioral or peripheral cyanosis, the ability to speak in complete sen- some patients, result in modest increases in arterial Pco2, chiefly
tences, and the patient’s mental status. The chest examination should by altering ventilation-perfusion relationships within the lung. This
establish the presence or absence of focal findings, degree of air should not deter practitioners from providing the oxygen needed
movement, presence or absence of wheezing, asymmetry in the chest to correct hypoxemia.
examination (suggesting large airway obstruction or pneumothorax
mimicking an exacerbation), and the presence or absence of para- Mechanical Ventilatory Support The initiation of noninvasive
doxical motion of the abdominal wall. positive-pressure ventilation (NIPPV) in patients with respira-
Patients with severe underlying COPD, who are in moderate tory failure, defined as Paco2 >45 mmHg, results in a significant
or severe distress, or those with focal findings should have a chest reduction in mortality rate, need for intubation, complications of
x-ray or chest CT scan. Approximately 25% of x-rays in this clinical therapy, and hospital length of stay. Contraindications to NIPPV
situation will be abnormal, with the most frequent findings being include cardiovascular instability, impaired mental status, inability
pneumonia and congestive heart failure. Patients with advanced to cooperate, copious secretions or the inability to clear secretions,
COPD, a history of hypercarbia, mental status changes (confusion, craniofacial abnormalities or trauma precluding effective fitting of
sleepiness), or those in significant distress should have an arte- mask, extreme obesity, or significant burns.
rial blood-gas measurement. The presence of hypercarbia, defined Invasive (conventional) mechanical ventilation via an endotra-
as a Pco2 >45 mmHg, has important implications for treatment cheal tube is indicated for patients with severe respiratory distress
(discussed below). In contrast to its utility in the management of despite initial therapy, life-threatening hypoxemia, severe hypercar-
exacerbations of asthma, measurement of pulmonary function has bia and/or acidosis, markedly impaired mental status, respiratory
not been demonstrated to be helpful in the diagnosis or manage- arrest, hemodynamic instability, or other complications. The goal of
ment of exacerbations of COPD. Pulmonary embolus (PE) should mechanical ventilation is to correct the aforementioned conditions.
also be considered, as the incidence of PE is increased in COPD Factors to consider during mechanical ventilatory support include
exacerbations. the need to provide sufficient expiratory time in patients with
The need for inpatient treatment of exacerbations is suggested by severe airflow obstruction and the presence of auto-PEEP (positive
the presence of respiratory acidosis and hypercarbia, new or wors- end-expiratory pressure), which can result in patients having to
ening hypoxemia, severe underlying disease and those whose living generate significant respiratory effort to trigger a breath during a
situation is not conducive to careful observation and the delivery of demand mode of ventilation. The mortality rate of patients requiring
prescribed treatment. mechanical ventilatory support is 17–30% for that particular hospi-
talization. For patients aged >65 admitted to the intensive care unit
TREATMENT OF ACUTE EXACERBATIONS for treatment, the mortality rate doubles over the next year to 60%,
regardless of whether mechanical ventilation was required.
Bronchodilators Typically, patients are treated with inhaled β ago-
Following a hospitalization for COPD, about 20% of patients are
nists and muscarinic antagonists. These may be administered sepa-
re-hospitalized in the subsequent 30 days and 45% are hospitalized
rately or together, and the frequency of administration depends on
in the next year. Mortality following hospital discharge is about 20%
the severity of the exacerbation. Patients are often treated initially
in the following year.
with nebulized therapy, as such treatment is often easier to adminis-
ter in those in respiratory distress. It has been shown, however, that
conversion to metered-dose inhalers is effective when accompanied ■■FURTHER READING
by education and training of patients and staff. This approach has Global Strategy for the Diagnosis, Management and Prevention
significant economic benefits and also allows an easier transition of COPD, Global Initiative for Chronic Obstructive Lung Disease
to outpatient care. The addition of methylxanthines (theophylline) (GOLD) 2017. Available from: http://goldcopd.org.
to this regimen can be considered, although convincing proof of its Hobbs B et al: Genetic loci associated with chronic obstructive pul-
efficacy is lacking. If added, serum levels should be monitored in an monary disease overlap with loci for lung function and pulmonary
attempt to minimize toxicity. fibrosis. Nat Genet 49:426, 2017.
Lange P et al: Lung-function trajectories leading to chronic obstructive
Antibiotics Patients with COPD are frequently colonized with pulmonary disease. N Engl J Med 373:111, 2015.
potential respiratory pathogens, and it is often difficult to iden- The Long-Term Oxygen Treatment Trial Research Group: A
tify conclusively a specific species of bacteria responsible for a randomized trial of long-term oxygen for COPD with moderate
particular clinical event. Bacteria frequently implicated in COPD desaturation. N Engl J Med 375:1617, 2016.
exacerbations include Streptococcus pneumoniae, Haemophilus influ- Lynch D et al: CT definable subtypes of COPD: A statement of the
enzae, and Moraxella catarrhalis. In addition, Mycoplasma pneumoniae Fleischner Society. Radiology 277:192, 2015.
or Chlamydia pneumoniae are found in 5–10% of exacerbations. The Martinez FD: Early-life origins of chronic obstructive pulmonary
choice of antibiotic should be based on local patterns of antibiotic disease. N Engl J Med 375:871, 2016.
susceptibility of the above pathogens as well as the patient’s clin- McDonough JE et al: Small-airway obstruction and emphysema in
ical condition. Patients with moderate or severe exacerbations are chronic obstructive pulmonary disease. N Engl J Med 365:1567, 2011.

Regan E et al: Clinical and radiologic disease in smokers with normal because some ILDs are part of multisystem disorders, some patients 1999
spirometry. JAMA Intern Med 175:1539, 2015. will be identified based on non-respiratory symptomatology (e.g., skin
Sandhaus RA et al: The diagnosis and management of alpha-1 thickening in the setting of systemic sclerosis, Chap. 353) or physical
antitrypsin deficiency in the adult. The diagnosis and manage- examination findings (e.g., ulnar deviation of the fingers in the setting
ment of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr of rheumatoid arthritis [RA], Chap. 351). Additionally, ILDs can also
Pulm Dis (Miami). 3:668, 2016. doi: http://doi.org/10.15326/ be identified incidentally based on the results of abnormal pulmonary
jcopdf.3.3.2015.0182 function tests, chest x-rays (CXRs), computed tomography (CT) studies
Spruit MA et al: An official American Thoracic Society/European of both the chest and abdomen (which can both visualize, at least a
Respiratory Society statement: Key concept and advances in pulmo- portion, of the lung parenchyma), and positron emission tomography
nary rehabilitation. Am J Resp Crit Care Med 188:e13, 2013. (PET) scans. It is important to remember that ILDs can be associated
with high rates of morbidity and mortality, and although prognosis
CHAPTER 287 Interstitial Lung Disease

depends on both disease extent and specificity, this fact makes these
important disorders to recognize in a timely manner.
Owing to a variety of clinical presentations, as well as overlapping
imaging and histopathologic findings (Table 287-1), ILDs can be
287 Interstitial Lung Disease

difficult to diagnose. A generally accepted central tenet of ILD diag-
nosis is that the combined weight of clinical data, laboratory studies,
pulmonary function testing, imaging findings, and histopathology (if
Gary M. Hunninghake, Ivan O. Rosas obtained) are jointly required to make a confident diagnosis. No single
piece of data confers a diagnosis alone. For example, a lung biopsy
demonstrating a usual interstitial pneumonia (UIP) pattern is helpful
Diffuse parenchymal lung diseases include a large number (>200) of in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but
heterogeneous conditions that affect the lung parenchyma with vary- can also be present in some connective tissue diseases (CTDs) (e.g.,
ing degrees of inflammation and fibrosis. While remodeling of the RA-associated ILD, Chap. 351). In light of this challenge, most ILD cen-
interstitial space, the region between the epithelium and endothelium, ters recommend a multidisciplinary approach to the diagnosis (and in
tends to be the dominant site of involvement for most of the interstitial some cases the management) of ILDs. An example of a multidisciplin-
lung diseases (ILDs), it is important to recognize the prominent role of ary approach might include a conference attended by pulmonologists,
the alveolar epithelium and endothelial cells (including both airways rheumatologists, radiologists, and pathologists where all of the data
and vessels) in the pathogenesis of these interstitial lung disorders. generated on a patient can be discussed and reviewed jointly by those
Despite the diverse array of conditions, most patients ultimately with unique sets of expertise in the care of patients with ILD.
diagnosed with an ILD will come to medical attention with reports of While there are numerous ways to categorize the ILDs, one classic
progressive exertional dyspnea or a persistent dry cough. However, approach is to divide the ILDs into those of known and unknown
Table 287-1 Common Interstitial Lung Disease Findings

NONSPECIFIC RESPIRATORY
INTERSTITIAL BRONCHIOLITIS SYSTEMIC SCLEROSIS
IPF PNEUMONIA ASSOCIATED ILD ASSOCIATED ILD SARCOIDOSIS
Clinical symptoms Gradual onset of SOB, Subacute onset of SOB, Can be asymptomatic, or Gradual onset of SOB, Can be asymptomatic,
dry cough. Unusual in dry cough. Frequently have SOB, and cough. dry cough. Fatigue, or have SOB, and cough.
younger adults. associated with other tightening of skin, Can also have fatigue,
conditions. exaggerated cold palpitations, eye, skin,
response, reflux, and and joint findings.
difficulty swallowing.
Physical examination Frequent rales at lung Frequent rales. Clubbing Rales common. Clubbing Can have rales in Can be normal, rales
findings bases, digital clubbing is is less common. is rare. isolation. Also skin may be present. Can
common. thickening, joint swelling,
have skin findings, joint
and telangiectasias. pain, and enlarged lymph
nodes.
Exposures Idiopathic but many Can be idiopathic Strong association with Mostly unknown, some Mostly unknown,
exposed to smoke. but should prompt smoking. debate about solvent and although silicate dusts
Genetic findings may consideration for silicate exposures. thought to play a role in
explain >1/3 of the risk associated conditions. some cases.
of the disease.
HRCT findings Bilateral subpleural Peripheral subpleural Diffuse patchy Can have UIP or Can have
reticular changes most ground glass and centrilobular ground NSIP patterns, also mediastinal and hilar
prominent in lower, reticular patterns. glass nodules. dilated esophagus, lymphadenopathy.
posterior lung zones. Traction bronchiectasis occasional mediastinal Peribronchovascular
Traction bronchiectasis is common but calcifications, and reticular-nodular findings.
and honeycombing honeycombing is rare. pulmonary vascular
common. Classic UIP HRCT not diagnostic. enlargement.
pattern is considered
diagnostic.
Histopathology UIP pattern including Cellular or fibrotic pattern Respiratory bronchiolitis Both UIP or NSIP Non-caseating
fibroblastic foci, temporal of NSIP. More uniform with adjacent patterns can occur. granulomas.
and spatial heterogeneity, than a UIP pattern. inflammatory and
honeycombing. fibrosing changes.
Pigment laden
macrophages.
Clinical course 50% 3–5 year mortality. 18% 5-year mortality. 25% 7-year mortality. 20–30% 10-year Generally low but varies
mortality. by state.
Abbreviations: HRCT, high resolution chest CT; ILD, interstitial lung disease; NSIP, non-specific interstitial pneumonia; SOB, shortness of breath; UIP, usual interstitial
pneumonia

2000
Classification of Interstitial Lung Disease (ILD)
ILD of known cause ILD of unknown cause
Systemic Idiopathic interstitial

Exposure Other
disease pneumonias
Occupational: Connective tissue Idiopathic Pulmonary

PART 7
Asbestosis disease: Fibrosis

Silicosis Rheumatoid
Arthritis
Nonspecific interstitial pneumonia
Scleroderma
Treatment related: Respiratory Bronchiolitis—associated
Polymyositis/
interstitial lung disease
Radiation Dermatomyositis
Methotrexate Desquamative Interstitial Pneumonia
Amiodarone Cryptogenic Organizing Pneumonia
Nitrofurantoin Acute Interstitial Pneumonia
Chemotherapeutics Lymphocytic Interstitial Pneumonia
Granulomatous disease with Lymangioleiomyomatosis

Granulomatous lung disease:
Vasculitis: Pulmonary Alveolar Proteinosis
Sarcoidosis
Granulomatosis with Polyangiitis Langerhan’s Cell Histiocytosis
Hypersensitivity Pneumonia
Churg-Strauss Pleural Parenchymal Fibroelastosis
FIGURE 287-1 Classification of interstitial lung disease. This algorithm represents a common approach to sub-classifying the interstitial lung diseases. It is typical
to divide the interstitial lung diseases into those of known and unknown causes (although it is important to note that genetic studies demonstrate that a significant
portion of familial and idiopathic pulmonary fibrosis [classically described as diseases of unknown cause] may be explained, in part, by genetic factors). The idiopathic
interstitial pneumonias were more precisely defined by a 2002 study as described in Am J Respir Crit Care Med 165:277, 2002, referenced in the Further Reading list.
causes (Fig. 287-1). Although even this approach has limitations (e.g., in a histopathologic diagnosis of UIP (a pathologic hallmark of IPF)
genetic studies demonstrate that a significant portion of familial than they are to result in an alternate IIP diagnosis. Other common
and IPF [classically described as a diseases of unknown cause] may ILDs such as sarcoidosis, CTD associated ILD, and less common ILDs
be explained, in part, by genetic factors), it is a useful place to start. such as LAM, pulmonary Langerhans cell histiocytosis (PLCH) tend to
Known causes of ILD include occupational exposures (e.g., asbestosis), present between the ages of 20 and 40.
medications (e.g., nitrofurantoin), and those related to an underlying
systemic disease (e.g., cryptogenic organizing pneumonia [COP] in Sex Although less influential than age, sex has some influence on
the setting of polymyositis). Unknown causes of ILD include groups likelihood of various ILDs. LAM (and related disorder tuberous sclero-
of rare disorders often with classic presentations (e.g., a spontaneous sis) (see Chap. 315 in HPIM 19e) is a disorder that is frequently diag-
pneumothorax in a young female with diffuse cystic changes on a chest nosed in young women. Many CTD-associated ILDs are more common
CT might suggest lymphangioleiomyomatosis [LAM]) and the most among women, with the exception of RA associated ILD which is more
common group of ILDs, the idiopathic interstitial pneumonias (IIPs). common among men. IPF and occupational/exposure-related ILDs
Granulomatous lung diseases straddle both known (e.g., hypersensi- (likely due to work related exposures that tend to differ between men
tivity pneumonitis (HP) due to chronic bird exposure, Chap. 282), and and women) are more common among men.
unknown (e.g., sarcoidosis, Chap. 360) causes and are often separated
Duration of Symptoms Acute presentations (days to weeks) of
due to their unique presentations, imaging findings, and diagnostic
ILD are unusual and are commonly misdiagnosed as more common
evaluation. Equally important to knowledge of disease classification is
diseases such as pneumonia, a COPD exacerbation, or heart failure.
knowledge of disease prevalence. Although there is variability within
ILDs that can present acutely include eosinophilic pneumonia, acute
different demographic groups, most studies demonstrate that IPF, sar-
interstitial pneumonia (AIP), HP, and granulomatosis with polyangi-
coidosis (Chap. 360), and ILDs related to CTDs (Chap. 406) as a group
itis (GPA). An acute exacerbation of IPF as the initial presentation of
are among the most common forms of ILD.
this disease should also be a consideration given its prevalence. ILDs
DIAGNOSTIC APPROACH most commonly have a chronic indolent presentation (months to years)
The initial diagnostic approach to diffuse parenchymal lung disease typified by IPF. However subacute presentations (weeks to months) can
is often broader than a focus on ILD and should include an evalua- occur in most of the ILDs, but in the right context could suggest sarcoi-
tion for alternate causes including cardiovascular disease (e.g., heart dosis, CTD associated ILD, drug-induced ILD, or COP.
failure, Chap. 253), diffuse infections (e.g., pneumocystis pneumonia, Respiratory Symptoms Progressive dyspnea, most frequently
Chap. 215), and malignancy (e.g., bronchoalveolar cell carcinoma, noted with exertion, is the most common complaint in patients pre-
Chap. 315 in HPIM 19e). This chapter will focus on the diagnostic senting with an ILD. Despite this fact, both research studies of general
evaluation that helps to distinguish among the various forms of ILD. population samples and clinical experiences of asymptomatic patient
■■HISTORY referrals with abnormal chest CT imaging patterns have also demon-
strated that some patients, even those with more extensive disease, may
Age Age at presentation has a strong influence on the pretest prob- not report dyspnea. Cough, particularly a dry cough, is also common,
ability that IPF, in particular, is present. For example, IPF occurs most and can be the most prominent symptom in patients with IPF. Cough
commonly in patients aged >60 and is quite rare among patients aged is often reported in other ILDs, particularly those that have prominent
<50. In fact, in patients aged >65 without strong evidence for an alter- airway involvement including sarcoidosis and HP. Cough with hemop-
nate diagnosis, atypical chest CT findings are still more likely to result tysis is rare and could suggest an ILD associated with diffuse alveolar

hemorrhage (DAH) (e.g., Goodpasture’s syndrome), GPA, or LAM. ■■PULMONARY FUNCTION TESTS 2001
Cough with hemoptysis could also suggest a secondary pulmonary Most forms of ILD will eventually result in a restrictive deficit on pul-
infection that can be seen in patients with traction bronchiectasis and in monary function testing. A restrictive deficit is typified by a reduced
those receiving immunosuppressive therapy. Chest pain is rare in most total lung capacity (TLC), and symmetrically reduced measures of
of the ILDs with the exception of sarcoidosis where chest discomfort is forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC).
not uncommon. Fatigue is common to all of the ILDs. A reduction in the diffusing capacity of the lung for carbon monoxide
(DLCO) is also common and may precede a reduction in lung volumes;
Past Medical History The most pertinent history includes a however, there is more measurement variability in DLCO measure-
personal history of a CTD or a history of symptoms commonly associ- ment and the test is less specific for ILD. A reduced FEV1 to FVC ratio,
ated with a CTD (e.g., Raynaud’s phenomena). It is also important to which is diagnostic of airway obstruction, is unusual in many forms of
remember that ILD associated with a CTD can be the initial presenting ILD but can be present as an isolated finding, or in conjunction with

symptom of the disease and can precede the development of additional an additional restrictive deficit, in ILDs involving the airways such
symptomatology by many years. A history of malignancy is important; as sarcoidosis, HP, and LAM. Although pulmonary function testing
as some malignancies can be associated with dermatomyositis associ- is rarely diagnostic, reductions in lung function help to characterize
ated COP and sarcoid-like reactions. A history of asthma and allergic the extent of disease, and evidence for decline in repeated measures of
rhinitis might suggest a diagnosis of eosinophilic GPA. pulmonary function (e.g., FVC) have been correlated with an elevated
rate of mortality.
Medications Many medications have been associated with ILD
and to complicate matters further, many medications commonly used ■■CHEST IMAGING STUDIES
to treat inflammatory and granulomatous lung disease are also asso-
ciated with ILD development (e.g., methotrexate, azathioprine, ritux- Chest X-Ray Findings on CXR can be the first clinical indication
imab, and the tumor-necrosis factor-alpha blocking agents). Specific that an ILD might be present. For example, enlarged hilar lymph nodes
medications in many classes are also known to cause ILD, including and a pattern of central nodular opacities in the mid to upper lung zones
antibiotics (e.g., nitrofurantoin), anti-arrhythmics (e.g., amiodarone) can suggest sarcoidosis. A basilar reticular pattern, with small cystic
and many of the anti-neoplastic agents (e.g., bleomycin). spaces, in the absence of clinical evidence for heart failure, might suggest
IPF. With a few exceptions, CXR alone rarely leads to a specific diagnosis.
Family History A family history of ILD (of almost any type) is
important to ascertain. The percentage of pulmonary fibrosis that is Chest CT High resolution chest CT (HRCT) imaging is now con-
familial, as opposed to idiopathic, varies by study, with estimates rang- sidered to be standard of care in the initial evaluation of a patient with
ing from <5% to as high as 20%. Despite this variability, most agree that a suspected ILD. HRCT can be diagnostic for some ILDs (e.g., IPF) in
the presence of a close relative with an IIP is among the strongest risk right clinical context and may preclude the need for, and spare the
factors for IPF. Family studies have consistently noted familial aggrega- patient the risk of, a lung biopsy. HRCT also helps to define the extent
tion of diverse forms of IIP (such as IPF, non-specific interstitial pneu- of the ILD, the presence of more concerning features suggestive of
monia [NSIP], and DIP running in the same family) and in some cases advanced disease (e.g., honeycombing), can provide information on
other forms of ILD. To date, the most well replicated genetic factors for coexisting diseases (e.g., emphysema and lung cancer), and when not
pulmonary fibrosis (a promoter variant of a mucin gene [MUC5B]) and diagnostic, can help to provide the most useful locations for obtaining
various genetic determinants known to influence telomere length (e.g., lung biopsy specimens.
variants in the telomerase reverse transcriptase gene [TERT]) appear
to be associated with both familial and idiopathic forms of pulmonary ■■LUNG BIOPSY
fibrosis similarly. Fiberoptic Bronchscopy Bronchoscopy can be helpful in estab-
Social History A history of smoking is nearly always present in lishing a specific ILD diagnosis, and can help to establish an alternate
some forms of ILD (e.g., respiratory bronchiolitis and desquamative diagnosis, in select cases. Examination of serial lavage fluid can be help-
interstitial pneumonia [DIP]—sometimes referred by pathologists ful in establishing DAH which can be present in ILDs with vasculitis
jointly as smoking related—ILD) where it is felt to be causative. A (e.g., GPA), and in some cases, cellular examination can suggest a spe-
history of smoking is also noted in approximately three-quarters of IPF cific diagnosis (eosinophilia >25% in chronic eosinophilic pneumonia
patients. Occupational and environmental exposure histories are also or fat globules in macrophages in lipoid pneumonia). Trans-bronchial
important to obtain as they might identify exposures known to cause lung biopsies and lymph node biopsies (in sarcoidosis in particular)
pulmonary fibrosis (e.g., significant asbestos exposure) or HP (pigeon can lead to a confident diagnosis in patients with likely granulomatous
breeder’s lung). lung disease (e.g., sarcoidosis and HP). However, in general, bron-
choscopically obtained tissue samples are often felt to be insufficient
■■PHYSICAL EXAMINATION to diagnose most of the IIPs. There is some preliminary evidence that
End-inspiratory fine crackles, or rales, noted at the lung bases are bronchoscopically obtained cryobiopsies, which can result in yields
found in most patients with IPF and may be one of the earliest signs of larger than those obtained by transbronchial forceps biopsies, could
the disease. However, rales are nonspecific and can be found in many improve the diagnostic yield of bronchoscopy; however, the precise role
forms of ILD and other disorders. Wheezing is uncommon in most cryobiopsies in the diagnostic workup of ILD has yet to be clarified.
forms of ILD but can be present in some disorders, such as sarcoidosis, Surgical Lung Biopsy A surgically obtained lung biopsy spec-
HP, and eosinophilic GPA. Signs of advanced disease include cyanosis, imen can help solidify the diagnosis of ILD. In many cases these are
digital clubbing, and cor pulmonale. now obtained through a video-assisted thoracoscopic (VATS) approach
(as compared to an open thoracotomy), which tends to reduce the
■■LABORATORY STUDIES length of operative times and hospital stays. The diagnostic yield of
Laboratory studies can be particularly helpful in the workup for an biopsies tends to be higher if obtained prior to treatment. The desire
underlying CTD-associated ILD. As noted previously, these tests can to obtain a surgical lung biopsy should be weighed against the risks
reveal the presence of an underlying CTD as the cause of an ILD (e.g., which can include a short-term mortality rate of as high as 5%. These
a positive anti-cyclic citrullinated peptide [anti-CCP] antibody for RA) risks are reported to be higher in biopsies of patients ultimately diag-
even when no other symptomatology or physical examination findings nosed with IPF, and in those presenting acutely.
suggestive of the disorder are present. However, the cost-effectiveness
and the extent of laboratory testing that should be ordered in various ■■INDIVIDUAL FORMS OF ILD
clinical contexts have yet to be determined (as there is a relatively long The ILDs include a diverse group of lung pathologies that can be sub-
list of auto-antibody tests that could be ordered). classified into those disorders of unknown cause (e.g., IIPs), and those

2002 of known cause (e.g., sometimes referred to as secondary interstitial with a history of smoking or other environmental exposures. IPF is
pneumonias [connective tissue disease-associated ILDs]) (see Fig. 287-1). a variably progressive disease that carries a poor prognosis with an
Although this remains a useful approach to classifying this diverse estimated 50% 3–5-year survival.
group of disorders it is important to recognize that genetic studies are
challenging this classic categorization. For example, numerous ILDs
HRCT Image Findings Chest CT findings include subpleural
reticulation with a posterior basal predominance usually including
commonly listed as having an “unknown cause” have been determined
more advanced fibrotic features, such as honeycombing and traction
to have significant genetic underpinnings (e.g., IPF and LAM), while
bronchiectasis. Collectively these imaging findings are referred to as
the pathophysiologic processes that result in ILDs of “known cause”
a UIP pattern. The presence of extensive ground glass opacities, bron-
(e.g., connective tissue disease) remain incompletely understood. Diag-
chovascular changes, micronodules, mosaic attenuation, or an upper
nosis is based on combined information obtained from a patient’s clin-
lung predominance should raise suspicion for an alternative diagnosis
ical presentation, measures of pulmonary function, imaging, immune
(Fig. 287-2).
serologies, and histopathology. It is important to remember that prog-
PART 7
nosis and treatment vary widely by disorder (and disease extent). In Histopathology Diagnostic VATS biopsy findings include sub-
some cases, medical therapy that is felt to be effective for some ILDs pleural reticulation associated with honeycomb changes and fibroblast
has been proven to be harmful for others. Medical treatments range foci (subepithelial collections of myofibroblasts and collagen). These
from immune modulators to anti-fibrotic medications while lung trans- fibrotic changes alternate with areas of preserved normal alveolar archi-
plantation remains the standard of care for those with advanced and tecture consistent with temporal and spatial heterogeneity (Fig. 287-3).
rapidly progressive ILDs. Collectively, these pathologic findings are referred to as UIP.
Treatment Historically, IPF was felt to be refractory to medical ther-
IDIOPATHIC INTERSTITIAL PNEUMONIAS apy with lung transplantation the only viable therapeutic option. This
■■IDIOPATHIC PULMONARY FIBROSIS dogma changed in 2014 with large clinical trials that demonstrated that
antifibrotic therapy (pirfenidone and nintedanib) can slow decline of
Clinical Manifestations IPF is the most common ILD of lung function in IPF patients. Further meta-analyses have suggested
unknown cause. Prevalence increases with age and is estimated at that anti-fibrotic therapy may also improve survival. In contrast, treat-
50–200:100,000. IPF is commonly diagnosed in the fifth or sixth decade ment with immunosuppression, which had been commonly prescribed
in life, affects men more than women, and is frequently associated to many IPF patients, has now been demonstrated (in some cases) to
A B
C D
FIGURE 287-2 Chest CT imaging and interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Classic findings of IPF (apparent on this image) include a posterior,
basilar predominance of subpleural reticular markings and more advanced features of pulmonary fibrosis including traction bronchiectasis and honeycombing. This
constellation of findings is often referred to as a usual interstitial pneumonia (UIP) pattern. B. Non-specific interstitial pneumonia (NSIP): Chest CT findings of NSIP can
overlap with those of a UIP pattern but tend to include a bilateral, symmetric pattern that presents with a greater percentage of ground-glass opacities than is apparent
in a UIP pattern. Additional unique findings include more diffuse imaging abnormalities with a predominance not limited to the lung bases, imaging abnormalities
that spare the subpleural regions, and thickening of the bronchovascular bundles (as is apparent in the right mid lung zone on this image). C. Cryptogenic organizing
pneumonia: Chest CT findings include patchy, sometimes migratory, subpleural consolidative opacities (as is apparent on this image) often with associated ground-
glass opacities. Peribronchiolar, or perilobar opacities can be present and sometimes a rim of subpleural sparing (often referred to as a reversed halo or atoll sign)
can be seen which can help to aid in the diagnosis. D. Sarcoidosis: Sarcoidosis can present with varied imaging abnormalities but a pattern of mediastinal and hilar
lymphadenopathy with a pattern of reticular-nodular opacities involving the bronchovascular bundles (apparent in this image) are common features. Additional findings
can include diffuse small nodules in a miliary pattern, larger nodular opacities, extensive ground glass infiltrates and, mosaic attenuation suggestive of small airways
involvement, and in more advanced cases, signs of pulmonary fibrosis.

2003
A B

C D
FIGURE 287-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Histopathologic findings include subpleural reticulation associated
with honeycomb changes alternating with areas of preserved normal lung architecture referred to as temporal and spatial heterogeneity (as is apparent in the low power
image above). Additional important diagnostic findings include fibroblast foci, which are subepithelial collections of myofibroblasts and collagen (as is apparent in the
higher powered inset of this image). Collectively these pathologic findings are referred to as usual interstitial pneumonia (UIP). B. Non-specific interstitial pneumonia
(NSIP): Histopathologic findings of NSIP include varying amounts of interstitial inflammation and fibrosis with a uniform appearance (as is apparent in this image).
Honeycomb changes are usually absent and fibroblast foci are rare. NSIP is often referred to histopathologically as being either predominantly cellular or fibrotic.
C. Cryptogenic organizing pneumonia (COP): Histopathologic findings of COP include patchy regions of organizing pneumonia with granulation tissue that commonly
involves the small airways, alveolar ducts, and alveoli with surrounding inflammation that can involve the alveolar walls (as is apparent in this image). D. Sarcoidosis:
The hallmark histopathologic feature of sarcoidosis is presence of granulomas (as are apparent numerously in the low powered image and more closely visualized in
the higher powered inset image). Typically these are referred to as non-caseating which suggests the absence of necrosis. Caseating granulomas are rare in sarcoid
and should prompt additional evaluation for an underlying infection. Because malignancy can result in a granulomatous reaction it is important to closely survey biopsy
specimens with granulomatous involvement for additional signs of malignancy.
be associated with increased morbidity and mortality. Physical therapy appearance. Honeycomb changes are usually absent and fibroblast foci
and supplemental oxygen, when indicated, can improve exercise tol- are rare. NSIP is often referred to histopathologically as being either
erance and reduce likelihood of developing pulmonary hypertension. predominantly cellular (and potentially more responsive to medical
Lung transplantation can extend survival and improve the quality of therapy) or fibrotic (and potentially less likely to resolve with medical
life in a subset of IPF patients who meet criteria to undergo transplant. therapy).
■■NON-SPECIFIC INTERSTITIAL PNEUMONIA Treatment Pulmonary fibrosis associated with connective tissue
disease is commonly treated with immunosuppression despite the
Clinical Manifestations Idiopathic NSIP is a distinct clinical paucity of randomized clinical trials to demonstrate efficacy. Idiopathic
entity with characteristic clinical, radiologic, and pathologic features; NSIP is often treated with oral steroids (prednisone), cytotoxic agents
however, NSIP is also commonly observed in patients with connective (mycophenolate, azathioprine, and cyclophosphamide), or biologics
tissue disease and less frequently with familial interstitial pneumonia, (rituximab). Oxygen therapy, pulmonary rehabilitation, and lung trans-
drug toxicity, and infection. Although the prevalence of NSIP is not plantation may be required in patients with progressive disease.
well established, it is commonly diagnosed in non-smoking females in
their fifth decade of life. Positive serologic tests for connective tissue ■■SMOKING-RELATED ILD
disease are frequently observed. Idiopathic NSIP has a relatively good Although smoking-related ILDs including respiratory bronchiolitis
prognosis, with a 5-year survival >80%; patients with a predominant with interstitial lung disease (RB-ILD), and DIP are frequently subclas-
cellular NSIP pattern have a more favorable prognosis than those with sified with the IIPs, these disorders (along with PLCH, an ILD with
a fibrosing NSIP pattern. unique clinical, imaging and histopathologic manifestations) are com-
HRCT Image Findings Diffuse subpleural, symmetric, ground monly felt to be the result of active or prior tobacco smoke exposure.
glass, and reticular opacities are common. Volume loss and traction DIP has also been known to occur in children with familial pulmonary
bronchiectasis involving the lower lung zones can also be found. fibrosis (FPF). Smokers, particularly elderly smokers, frequently have
Occasionally subpleural sparing is noted, while peribronchiolar thick- radiologic (centrilobular) interstitial abnormalities. These interstitial
ening and honeycombing are uncommon. abnormalities are often incidentally found on routine CXR or chest
CT studies in asymptomatic, or minimally symptomatic individuals.
Histopathology Diagnostic lung biopsy findings include vary- Respiratory bronchiolitis is felt to correlate histopathologically with
ing amounts of interstitial inflammation and fibrosis with a uniform these imaging findings. However, in some cases these imaging findings

2004 can progress to more advanced radiologic changes where more diffuse (e.g., rituximab) therapies can be helpful in both treating the disease
signs of interstitial pneumonia tend to be present. and reducing the need for steroids. In some patients with secondary
forms of the disease, long-term therapy may be needed.
Clinical Manifestations These disorders predominantly occur
in active, and in many cases heavy, smokers who are typically between ACUTE OR SUBACUTE IIPS
40 and 50 years of age. In those ultimately diagnosed with RB-ILD
or DIP, dyspnea and cough are relatively common and symptomatic ■■ACUTE INTERSTITIAL PNEUMONIA (HAMMAN-RICH
wheezing is not rare. The prevalence of smoking-related ILDs is not SYNDROME)
well understood, but they are generally felt to account for <10% of the
IIPs. While there is minimal data on the natural histories and prognoses
Clinical Manifestations AIP is a rare and often fatal lung dis-
order that is characterized by an acute onset of respiratory distress
of these conditions, prolonged survival can be expected in most patients
and hypoxemia. A prodromal period of symptoms consistent with an
with RB-ILD and death secondary to progressive ILD is felt to be rare.
PART 7
acute upper respiratory infection is common. The mortality rate within

HRCT Image Findings Prominent and common findings in 6 months of presentation can be quite high (>50%) and recurrences are
RB-ILD include central bronchial wall thickening, peripheral bronchial common. In those that recover, lung function improvement can be sub-
wall thickening, centrilobular nodules, and ground-glass opacities. stantial. AIP can be difficult to distinguish from acute respiratory dis-
Septal lines and a reticular pattern are also not uncommon. Honey- tress syndrome (ARDS) and an acute exacerbation of an unsuspected
combing is generally felt to be rare (and indicates a worse prognosis). underlying pulmonary fibrotic process.
Similar findings are noted in patients with DIP where diffuse (or
HRCT Image Findings The most common imaging findings are
patchy) bilateral symmetric ground-glass opacities tend to be even
patchy bilateral ground-glass opacities. Dependent regions of air-space
more prominent.
consolidation are also common.
Histopathology Common features of RB-ILD include the accu- Histopathology Similar to ARDS and acute exacerbations of
mulation of pigmented macrophages within the lumens of respiratory underlying pulmonary fibrosis, AIP presents histopathologically as dif-
bronchioles and alveolar ducts, accompanied by chronic inflammation fuse alveolar damage (DAD) demonstrated on a surgical lung biopsy.
of the respiratory bronchiolar walls and both bronchiolar and peri-
bronchiolar alveolar fibrosis causing architectural distortion. These Treatment Treatment is mostly supportive and often includes
features are patchy and confined to the peribronchiolar region. DIP mechanical ventilation. There is no proven drug therapy for AIP.
tends to include similar changes but they have a more diffuse pattern Glucocorticoids are often given but they are not clearly effective and
characterized by pigmented macrophage accumulation, pneumocyte have been demonstrated not to be beneficial in other forms of DAD
hyperplasia, and prominent interstitial thickening. (e.g., ARDS).
Treatment All patients with smoking-related ILD should be coun- ■■ACUTE EXACERBATIONS OF IIPS
seled to discontinue smoking and/or encouraged to enroll in a formal
Clinical Manifestations Acute exacerbations are not separate
smoking cessation program. Small studies have evaluated, and patients
disorders, but rather an accelerated phase of lung injury that can occur
are often treated with immunosuppressive (e.g., prednisone) and cyto-
in any ILD resulting in pulmonary fibrosis. Acute exacerbations are
toxic (e.g., azathioprine, and cyclophosphamide) agents and in some
most commonly described, and most severe in, patients with known
cases with bronchodilators. To date there is no strong evidence that
IPF. Acute exacerbations are characterized by an acute onset (<30 days)
these therapies result in significant improvements symptoms, mea-
of respiratory distress and hypoxemia occurring in a patient with
sures of pulmonary function, or if they prevent clinical deterioration.
underlying pulmonary fibrosis not explained by an alternate cause
■■CRYPTOGENIC ORGANIZING PNEUMONIA (e.g., pneumonia, left heart failure). Reported mortality rates are very
high (>85%) and mean survival periods range from as little as days to
Clinical Manifestations COP typically involves patients in months.
their 50–60s and often presents as a subacute flu-like illness, with
cough, dyspnea, fever, and fatigue. Inspiratory rales are often present
HRCT Image Findings The most common imaging findings
include patchy bilateral ground-glass opacities and dependent regions
on examination and most patients are noted to have restrictive lung
of air-space consolidation. Sometimes these new changes can be
deficits on pulmonary function testing with hypoxemia. It is commonly
appreciated on the background of the imaging findings typified by
mistaken for pneumonia. It is important to note that this syndrome
the underlying IIP, although sometimes they obscure the preceding
can occur in isolation or can be secondary to an underlying connective
imaging findings.
tissue disease (e.g., polymyositis), medications, or can result from an
underlying malignancy. Laboratory testing for various connective tis- Histopathology Acute exacerbations of underlying pulmonary
sue diseases is helpful as they can both be diagnostic and suggest the fibrosis present histopathologically as DAD, although sometimes orga-
need for prolonged medical therapy. nizing pneumonia can also be demonstrated on a surgical lung biopsy.
HRCT Image Findings The most common imaging findings Treatment Treatment is mostly supportive. Mechanical ventilation,
include patchy, sometimes migratory, subpleural consolidative opac- when not being used as a bridge to lung transplantation, is controver-
ities often with associated ground-glass opacities. Peribronchiolar, or sial as the survival rate in these patients tends to be poor. There is some
perilobar opacities can be present and sometimes a rim of subpleural evidence that drug therapy (e.g., Nintedanib) may reduce the rate of
sparing (often referred to as a reversed halo or atoll sign) can be seen acute exacerbations in patients with IPF. Drug therapy, in the context
which can aid in the diagnosis. of an acute exacerbation is also controversial. Immunosuppressive
(e.g., prednisone) and cytotoxic (e.g., cyclophosphamide) therapies are
Histopathology Surgical lung biopsy specimens tend to reveal
commonly used without proven benefit.
patchy regions of organizing pneumonia with granulation tissue that
commonly involves the small airways, alveolar ducts, and alveoli ILD ASSOCIATED WITH CONNECTIVE TISSUE
with surrounding inflammation that can involve the alveolar walls
(Fig. 287-2).
DISEASE
ILD is a common disease manifestation of many connective tissue dis-
Treatment Corticosteroids can result in substantial clinical eases. Disease progression, response to therapy and survival is variable
improvement in many patients but usually need to be continued for at and associated with specific radiologic and histopathologic patterns.
least 6 months as relapse rates are high. Evidence is growing that alter- ILD occurs most commonly in patients with scleroderma (systemic
nate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic sclerosis form, or SSc), RA, polymyositis/dermatomyositis, and less

frequently Sjögren syndrome and systemic lupus erythematosus (SLE). destruction and dysfunction of muscle, however this disorder can 2005
ILD may precede the development of extrapulmonary manifestations affect the skin, joints, cardiovascular system and lung. The prevalence
of a specific connective tissue disease or may present as part of a poorly of ILD associated with inflammatory myopathy varies by report,
defined connective tissue disease. In rare cases, lung manifestations however ILD is present in up to 45% of patients with positive anti-
may be the sole feature of the patient’s clinical presentation. synthetase antibodies. The anti-synthetase syndrome is characterized
by positive anti-synthetase antibodies, myositis, fever, Raynaud phe-
■■SYSTEMIC SCLEROSIS nomenon, mechanic’s hands, arthritis, and progressive ILD. There is
a subset of anti–Jo-1 antibody–positive individuals who can develop a
Clinical Manifestations (Chap. 353) ILD is the most com-
rapidly progressive form of ILD consistent with an acute exacerbation.
mon pulmonary manifestation of SSc. ILD occurs in about 50% of SSc
Some studies have suggested that ILD may be even more common
patients with diffuse disease and in about 30% of patients with limited
in those with other antibodies (e.g., anti-PL-12). Dermatomyositis/

disease. Pulmonary hypertension can occur separately or concomi-
polymyositis can occur as an isolated connective tissue disease or as a
tantly with ILD and is more frequent in patients with limited SSc.
process associated with an underlying malignancy.
HRCT Image Findings Similar imaging findings noted in both
patients with NSIP and IPF can be present, although findings consistent HRCT Image Findings Common imaging patterns of ILD in
with COP and DAD may also be present. Additional HRCT findings patients with dermatomyositis/polymyositis include those consistent
may include a dilated esophagus and pulmonary artery enlargement. with NSIP with or without evidence for COP. A UIP pattern can also
occur. Some studies have suggested that a UIP pattern may be more
Histopathology Comparable to the imaging overlap, histopatho- common among those with anti-PL-12 antibodies.
logic changes commonly noted in patients with NSIP and IPF are
frequently identified. Additionally, aspiration related to esophageal Histopathology The antisynthetase syndrome is associated with
dysmotility is common in SSc, in these patients histopathologic find- multiple histopathologic subtypes including NSIP, COP, and UIP. DAD,
ings consistent with COP and DAD may be observed. a histopathologic pattern observed in AIP and acute exacerbations, is
associated with rapidly progressive ILD in myositis patients.
Treatment Cyclophosphamide has a modest benefit in preser-
vation of lung function and is associated with significant toxicity. Treatment Immunosuppresive (e.g., prednisone) and cytotoxic
Mycophenolate has recently been shown to have similar efficacy and (e.g., mycophenolate, azathioprine, cyclophosphamide, and cal-
improved tolerability. Clinical trials testing antifibrotic therapies (pir- cineurin inhibitors) agents are often used in patients with progressive
fenidone and nintedanib) are presently being conducted. Minimizing ILD. Some patients (particularly those with less fibrosis) have been
the risk of reflux by using high-dose proton pump inhibitors or antire- noted to improve or resolve their ILD in response to medical therapy.
flux surgery should be considered in SSc with progressive ILD. Lung In small studies relapses have been more common in patients treated
transplantation can potentially be offered to select patients without with prednisone alone. Patients who fail immune suppressive therapy
significant aspiration or chest wall restriction. can benefit from lung transplantation.
■■RHEUMATOID ARTHRITIS ■■GRANULOMATOUS ILDS

The most common granulomatous ILD is sarcoidosis, a multisystem
Clinical Manifestations (Chap. 351) A common extraarticular disorder of unknown cause where lung involvement is often the most
complication of RA is ILD. Although RA is more common in females, dominant feature, will be discussed in Chap. 360. HP, a granulomatous
RA-ILD is more frequent in males and in patients with a history of reaction due to inhalation of organic (e.g., bird fancier’s lung secondary
tobacco exposure. In a small subset of patients, ILD is the first disease to exposure to bird feathers) and inorganic (e.g., coal worker’s pneumo-
manifestation of RA. Clinically evident disease RA-ILD occurs in coniosis secondary to exposure to coal dusts) dusts, is also an important
nearly 10% of the RA population; however, up to 40–50% of subjects and common cause of ILD and is discussed in Chap. 282.
have radiologic abnormalities on chest CT suggesting ILD in the con-
text of RA may be under-diagnosed. Granulomatous Vasculitides (See Chap. 60) These disor-
ders are characterized by blood vessels with inflammatory infiltrates
HRCT Image Findings The most common imaging pattern of
associated granulomatous lesions with or without the presence of
ILD in patients with RA is a UIP pattern, although NSIP patterns are
tissue necrosis. The lungs are commonly involved and a unique feature
not uncommon. There is evidence that survival in patients with RA
of these disorders is that hemoptysis can be a presenting symptom.
is decreased in those with a UIP pattern and among those with more
Although laboratory testing is often helpful and can provide specific
extensive fibrosis in general.
information, biopsies of involved tissue can be essential for making the
Histopathology Histopathologic findings of UIP and NSIP are diagnosis. Many of these disorders include additional systemic mani-
most common. Some studies suggest that UIP in the context of RA (as festations. GPA, also referred to as Wegener’s disease, is an example of
compared to IPF) may present with a reduced number of fibroblastic a granulomatous vasculitis that commonly affects the lung (including
foci and an increased amount of germinal centers. Comparable to the inflammatory infiltrates in small to medium sized vessels), the ears,
imaging findings, UIP (and DAD) patterns in patients with RA are nose, throat, and kidney (resulting in glomerulonephritis). Common
associated with reduced survival. imaging abnormalities of GPA include nodules, patchy ground glass,
and consolidative opacities that can be migratory, and hilar lymph-
Treatment In contrast with SSc, there are no randomized clinical adenopathy. Eosinophilic GPA (EG, also referred to as Churg-Strauss
trials testing the role of immune suppression in RA-ILD. Extrapolating syndrome) is another example of a granulomatous vasculitis that
from the scleroderma experience, immunosuppresive (e.g., prednisone) affects the lung (including eosinophilic infiltrates in small to medium
and cytotoxic (e.g., mycophenolate, azathioprine, cyclophosphamide, sized vessels) that can result in numerous clinical manifestations but
and calcineurin inhibitors) agents have been used with variable frequently includes chronic sinusitis, asthma, and peripheral blood
success. Clinical trials testing antifibrotic therapies (pirfenidone and eosinophilia. Common imaging abnormalities of EG include periph-
nintedanib) are presently being conducted. Lung transplantation is a eral consolidative opacities that can be migratory and small pleural
viable therapeutic approach for eligible patients with progressive dis- effusions.
ease that is not responsive to medical therapy.
■■GENETICS AND ILD
■■DERMATOMYOSITIS/POLYMYOSITIS
Studies of genetic epidemiology have led to important insights in
Clinical Manifestations (Chap. 358) The idiopathic inflam- our understanding of ILD. First, studies of families with FPF have
matory myopathies are disorders characterized by immune-mediated demonstrated that unique IIPs can cosegregate with specific genetic

2006 variants known to be associated with IPF. This suggests that many
genetic variants appear to predispose to interstitial lung injury patterns
more broadly than to unique diagnoses specifically. Second, most of
the genetic variants known to be associated with FPF are also asso-
288 Disorders of the Pleura
Richard W. Light
ciated with more sporadic forms of the disease. Third, at least one of
the genetic factors most strongly associated with FPF and IPF is both
common and confers a large increase in the risk of these diseases. At ■■PLEURAL EFFUSION
least one copy of a mucin 5B (MUC5B) promoter variant is present in The pleural space lies between the lung and the chest wall and nor-
~20% of Caucasian populations and 35–45% of patients with IPF and mally contains a very thin layer of fluid, which serves as a coupling
confers and approximate sixfold increase in the risk of this disease. system. A pleural effusion is present when there is an excess quantity
Fourth, studies of general population samples demonstrate that imag- of fluid in the pleural space.
ing abnormalities suggestive of an early stage of pulmonary fibrosis in
PART 7
research participants without known ILD are not uncommon (occur- Etiology Pleural fluid accumulates when pleural fluid formation
ring in ~7–9% of adults) and are also associated with the same genetic exceeds pleural fluid absorption. Normally, fluid enters the pleural
variants known to be associated with IPF (e.g., the MUC5B promoter space from the capillaries in the parietal pleura and is removed via
variant). This latter finding suggests a path forward towards an early the lymphatics in the parietal pleura. Fluid also can enter the pleural
detection of IPF. Additional genetic findings demonstrating replicable space from the interstitial spaces of the lung via the visceral pleura or
associations with pulmonary fibrosis include numerous genetic vari- from the peritoneal cavity via small holes in the diaphragm. The lym-
ants in, and adjacent to, genes known to be involved in the regulation phatics have the capacity to absorb 20 times more fluid than is formed
of telomere length (e.g., the TERT gene, the telomerase RNA compo- normally. Accordingly, a pleural effusion may develop when there is
nent [TERC] gene, and the regulator of telomere elongation helicase 1 excess pleural fluid formation (from the interstitial spaces of the lung,
[RTEL1] gene) and surfactant protein genes (e.g., surfactant protein A2 the parietal pleura, or the peritoneal cavity) or when there is decreased
[SFTPA2] gene). fluid removal by the lymphatics.
Genetic studies have also provided some insights into other forms Diagnostic Approach Patients suspected of having a pleural
of ILD. Genome-wide association studies of sarcoidosis have demon- effusion should undergo chest imaging to diagnose its extent. Chest
strated numerous variants in genes, and in genomic regions, that are ultrasound has replaced the lateral decubitus x-ray in the evaluation
associated with the disease. Some of these disease associated variants of suspected pleural effusions and as a guide to thoracentesis. When a
in sarcoidosis fall in human leukocyte antigen (HLA) regions, in regions patient is found to have a pleural effusion, an effort should be made to
of genes involved in immune regulation (e.g., interleukin 12B [IL12B]) determine the cause (Fig. 288-1). The first step is to determine whether
in regions of genes that are less well understood (butroyrophilin-like the effusion is a transudate or an exudate. A transudative pleural effusion
2 [BTNL2]) but also appear to be involved in T-cell activation. LAM is occurs when systemic factors that influence the formation and absorp-
often associated with genetic variants in the tuberous sclerosis complex tion of pleural fluid are altered. The leading causes of transudative
genes (e.g., TSC1 and TSC2), consistent with the known evidence that pleural effusions in the United States are left ventricular failure and
this disease can occur in isolation but also in patients with known cirrhosis. An exudative pleural effusion occurs when local factors that
tuberous sclerosis. Many genetic factors for rare diseases such as influence the formation and absorption of pleural fluid are altered. The
Hermansky-Pudlak syndrome (a rare autosomal recessive disorder that leading causes of exudative pleural effusions are bacterial pneumonia,
results in pulmonary fibrosis but also includes oculocutaneous albi- malignancy, viral infection, and pulmonary embolism. The primary
nism, bleeding diatheses, and horizontal nystagmus) have also been reason for making this differentiation is that additional diagnostic
discovered (e.g., HSP1, and HSP3-7). procedures are indicated with exudative effusions to define the cause
of the local disease.
■■GLOBAL CONSIDERATIONS Transudative and exudative pleural effusions are distinguished
The prevalence, clinical presentation, and natural history of by measuring the lactate dehydrogenase (LDH) and protein levels in
most ILDs in European countries resemble that described in the pleural fluid. Exudative pleural effusions meet at least one of the
the United States. However, as expected, there is growing following criteria, whereas transudative pleural effusions meet none:
evidence for racial differences in clinical (rate of acute exacerbations) or
genetic (MUC5B) attributes between Caucasian and Asian populations. 1. Pleural fluid protein/serum protein >0.5
To date there are limited data on the prevalence of ILD in Hispanics, 2. Pleural fluid LDH/serum LDH >0.6
subjects of African descent and many other ethnic groups. 3. Pleural fluid LDH more than two-thirds the normal upper limit for
serum
Acknowledgment These criteria misidentify ~25% of transudates as exudates. If one
The authors gratefully acknowledge Talmadge King, Jr. for his contribution in or more of the exudative criteria are met and the patient is clinically
the prior version of this chapter. thought to have a condition producing a transudative effusion, the
difference between the protein levels in the serum and the pleural fluid
should be measured. If this gradient is >31 g/L (3.1 g/dL), the exuda-
■■FURTHER READING
tive categorization by these criteria can be ignored because almost all
American Thoracic Society/European Respiratory Society Consensus
such patients have a transudative pleural effusion.
Classification of the Idiopathic Interstitial Pneumonias: Am J
If a patient has an exudative pleural effusion, the following tests on
Respir Crit Care Med 165:277, 2002.
the pleural fluid should be obtained: description of the appearance of
Raghu G et al and ATS/ERS/JRS/ALAT Committee on Idiopathic
the fluid, glucose level, differential cell count, microbiologic studies,
Pulmonary Fibrosis: An official ATS/ERS/ JRS/ALAT statement:
and cytology.
Idiopathic pulmonary fibrosis: Evidence-based guidelines for the
diagnosis and management. Am J Respir Crit Care Med 183:788, 2011. Effusion Due to Heart Failure The most common cause of
Travis WD et al: Idiopathic nonspecific interstitial pneumonia: Report pleural effusion is left ventricular failure. The effusion occurs because
of an American Thoracic Society project. Am J Respir Crit Care Med the increased amounts of fluid in the lung interstitial spaces exit in
177:1338, 2008. part across the visceral pleura; this overwhelms the capacity of the
Travis WD et al: An official American Thoracic Society/European lymphatics in the parietal pleura to remove fluid. In patients with heart
Respiratory Society statement: Update of the international multidis- failure, a diagnostic thoracentesis should be performed if the effusions
ciplinary classification of the idiopathic interstitial pneumonias. Am J are not bilateral and comparable in size, if the patient is febrile, or
Respir Crit Care Med. 188:733, 2013. if the patient has pleuritic chest pain to verify that the patient has a

mild anemia, and a history of some factor that predisposes them to 2007
DIAGNOSTIC ALGORITHM OF PLEURAL EFFUSION aspiration.
Pleural effusion The possibility of a parapneumonic effusion should be considered
whenever a patient with bacterial pneumonia is initially evaluated.
The presence of free pleural fluid can be demonstrated with a lateral
Perform diagnostic thoracentesis
decubitus radiograph, computed tomography (CT) of the chest, or
Measure pleural fluid protein and LDH
ultrasound. If the free fluid separates the lung from the chest wall by
>10 mm, a therapeutic thoracentesis should be performed. Factors
Any of following met? indicating the likely need for a procedure more invasive than a tho-
PF/serum protein > 0.5 racentesis (in increasing order of importance) include the following:
PF/serum LDH > 0.6
CHAPTER 288 Disorders of the Pleura

PF LDH > 2/3 upper normal serum limit 1. Loculated pleural fluid
2. Pleural fluid pH <7.20
Yes No
3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL)
4. Positive Gram stain or culture of the pleural fluid
Exudate Transudate 5. Presence of gross pus in the pleural space
Further diagnostic procedures Treat CHF, cirrhosis, nephrosis
If the fluid recurs after the initial therapeutic thoracentesis and if any
of these characteristics is present, a repeat thoracentesis should be per-
Measure PF glucose formed. If the fluid cannot be completely removed with the therapeutic
Obtain PF cytology thoracentesis, consideration should be given to inserting a chest tube
Obtain differential cell count and instilling the combination of a fibrinolytic agent (e.g., tissue plas-
Culture, stain PF minogen activator, 10 mg) and deoxyribonuclease (5 mg) or performing
PF marker for TB
a thoracoscopy with the breakdown of adhesions. Decortication should
be considered when these measures are ineffective.
Glucose < 60 mg/dL
Consider: Malignancy Effusion Secondary to Malignancy Malignant pleural effu-
Bacterial infections sions secondary to metastatic disease are the second most common
Rheumatoid
pleuritis
type of exudative pleural effusion. The three tumors that cause ~75%
of all malignant pleural effusions are lung carcinoma, breast carcinoma,
and lymphoma. Most patients complain of dyspnea, which is fre-
No diagnosis
quently out of proportion to the size of the effusion. The pleural fluid
is an exudate, and its glucose level may be reduced if the tumor burden
Consider pulmonary Yes in the pleural space is high.
embolus (spiral CT Treat for PE The diagnosis usually is made via cytology of the pleural fluid. If
or lung scan) the initial cytologic examination is negative, thoracoscopy is the best
No
Yes next procedure if malignancy is strongly suspected. At the time of
Treat for TB
thoracoscopy, a procedure such as pleural abrasion should be per-
PF marker for TB
formed to effect a pleurodesis. An alternative to thoracoscopy is CT- or
No ultrasound-guided needle biopsy of pleural thickening or nodules.
Yes
SYMPTOMS IMPROVING Observe
Patients with a malignant pleural effusion are treated symptomatically
for the most part, since the presence of the effusion indicates dissemi-
No nated disease and most malignancies associated with pleural effusion
are not curable with chemotherapy. The only symptom that can be
Consider thoracoscopy
or image-guided attributed to the effusion itself is dyspnea. If the patient’s lifestyle is
pleural biopsy compromised by dyspnea and if the dyspnea is relieved with a thera-
peutic thoracentesis, one of the following procedures should be consid-
FIGURE 288-1 Approach to the diagnosis of pleural effusions. CHF, congestive ered: (1) insertion of a small indwelling catheter or (2) tube thoracostomy
heart failure; CT, computed tomography; LDH, lactate dehydrogenase; with the instillation of a sclerosing agent such as doxycycline (500 mg).
PE, pulmonary embolism; PF, pleural fluid; TB, tuberculosis.
Mesothelioma Malignant mesotheliomas are primary tumors that
transudative effusion. Otherwise the patient’s heart failure is treated. If arise from the mesothelial cells that line the pleural cavities; most are
the effusion persists despite therapy, a diagnostic thoracentesis should related to asbestos exposure. Patients with mesothelioma present with
be performed. A pleural fluid N-terminal pro-brain natriuretic peptide chest pain and shortness of breath. The chest radiograph reveals a
(NT-proBNP) >1500 pg/mL is virtually diagnostic that the effusion is pleural effusion, generalized pleural thickening, and a shrunken hem-
secondary to congestive heart failure. ithorax. The diagnosis is usually established with image-guided needle
biopsy or thoracoscopy.
Hepatic Hydrothorax Pleural effusions occur in ~5% of patients
with cirrhosis and ascites. The predominant mechanism is the direct Effusion Secondary to Pulmonary Embolization The diag-
movement of peritoneal fluid through small openings in the dia- nosis most commonly overlooked in the differential diagnosis of a
phragm into the pleural space. The effusion is usually right-sided and patient with an undiagnosed pleural effusion is pulmonary embolism.
frequently is large enough to produce severe dyspnea. Dyspnea is the most common symptom. The pleural fluid is almost
always an exudate. The diagnosis is established by spiral CT scan or
Parapneumonic Effusion Parapneumonic effusions are associ- pulmonary arteriography (Chap. 273). Treatment of a patient with a
ated with bacterial pneumonia, lung abscess, or bronchiectasis and are pleural effusion secondary to pulmonary embolism is the same as it is
probably the most common cause of exudative pleural effusion in the for any patient with pulmonary emboli. If the pleural effusion increases
United States. Empyema refers to a grossly purulent effusion. in size after anticoagulation, the patient probably has recurrent emboli
Patients with aerobic bacterial pneumonia and pleural effusion or another complication, such as a hemothorax or a pleural infection.
present with an acute febrile illness consisting of chest pain, spu-
tum production, and leukocytosis. Patients with anaerobic infections Tuberculous Pleuritis (See also Chap. 173) In many parts of
present with a subacute illness with weight loss, a brisk leukocytosis, the world, the most common cause of an exudative pleural effusion

2008 is tuberculosis (TB), but tuberculous effusions are relatively uncom- TABLE 288-1 Differential Diagnoses of Pleural Effusions
mon in the United States. Tuberculous pleural effusions usually are
Transudative Pleural Effusions
associated with primary TB and are thought to be due primarily to a
hypersensitivity reaction to tuberculous protein in the pleural space. 1. Congestive heart failure
Patients with tuberculous pleuritis present with fever, weight loss, 2. Cirrhosis
dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate 3. Nephrotic syndrome
with predominantly small lymphocytes. The diagnosis is established 4. Peritoneal dialysis
by demonstrating high levels of TB markers in the pleural fluid (ade- 5. Superior vena cava obstruction
nosine deaminase >40 IU/L or interferon γ >140 pg/mL). Alternatively, 6. Myxedema
the diagnosis can be established by culture of the pleural fluid, needle 7. Urinothorax
biopsy of the pleura, or thoracoscopy. The recommended treatments of Exudative Pleural Effusions
pleural and pulmonary TB are identical (Chap. 173).
PART 7
1. Neoplastic diseases

Effusion Secondary to Viral Infection Viral infections are a. Metastatic disease
probably responsible for a sizable percentage of undiagnosed exuda- b. Mesothelioma
tive pleural effusions. In many series, no diagnosis is established for 2. Infectious diseases
~20% of exudative effusions, and these effusions resolve spontaneously
a. Bacterial infections

with no long-term residua. The importance of these effusions is that b. Tuberculosis
one should not be too aggressive in trying to establish a diagnosis
c. Fungal infections
for the undiagnosed effusion, particularly if the patient is improving
d. Viral infections
clinically.
e. Parasitic infections
Chylothorax A chylothorax occurs when the thoracic duct is dis- 3. Pulmonary embolization
rupted and chyle accumulates in the pleural space. The most common 4. Gastrointestinal disease
cause of chylothorax is trauma (most frequently thoracic surgery), but a. Esophageal perforation
it also may result from tumors in the mediastinum. Patients with chy-
b. Pancreatic disease
lothorax present with dyspnea, and a large pleural effusion is present
c. Intraabdominal abscesses
on the chest radiograph. Thoracentesis reveals milky fluid, and bio-
chemical analysis reveals a triglyceride level that exceeds 1.2 mmol/L d. Diaphragmatic hernia
(110 mg/dL). Patients with chylothorax and no obvious trauma should e. After abdominal surgery
have a lymphangiogram and a mediastinal CT scan to assess the medi- f. Endoscopic variceal sclerotherapy
astinum for lymph nodes. The treatment of choice for most chylotho- g. After liver transplant
raxes is insertion of a chest tube plus the administration of octreotide. If 5. Collagen vascular diseases
these modalities fail, percutaneous transabdominal thoracic duct block- a. Rheumatoid pleuritis
age effectively controls most chylothoraces. An alternative treatment b. Systemic lupus erythematosus
is ligation of the thoracic duct. Patients with chylothoraxes should c. Drug-induced lupus
not undergo prolonged tube thoracostomy with chest tube drainage d. Sjögren syndrome
because this will lead to malnutrition and immunologic incompetence.
e. Granulomatosis with polyangiitis (Wegener)
Hemothorax When a diagnostic thoracentesis reveals bloody pleu- f. Churg-Strauss syndrome
ral fluid, a hematocrit should be obtained on the pleural fluid. If the 6. Post-coronary artery bypass surgery
hematocrit is more than one-half of that in the peripheral blood, the 7. Asbestos exposure
patient is considered to have a hemothorax. Most hemothoraxes are 8. Sarcoidosis
the result of trauma; other causes include rupture of a blood vessel or 9. Uremia
tumor. Most patients with hemothorax should be treated with tube tho-
10. Meigs’ syndrome
racostomy, which allows continuous quantification of bleeding. If the
11. Yellow nail syndrome
bleeding emanates from a laceration of the pleura, apposition of the two
pleural surfaces is likely to stop the bleeding. If the pleural hemorrhage 12. Drug-induced pleural disease
exceeds 200 mL/h, consideration should be given to angiographic coil a. Nitrofurantoin
embolization, thoracoscopy or thoracotomy. b. Dantrolene
c. Methysergide
Miscellaneous Causes of Pleural Effusion There are many
d. Bromocriptine
other causes of pleural effusion (Table 288-1). Key features of some
e. Procarbazine
of these conditions are as follows: If the pleural fluid amylase level is
elevated, the diagnosis of esophageal rupture or pancreatic disease is f. Amiodarone
likely. If the patient is febrile, has predominantly polymorphonuclear g. Dasatinib
cells in the pleural fluid, and has no pulmonary parenchymal abnor- 13. Trapped lung
malities, an intraabdominal abscess should be considered. 14. Radiation therapy
The diagnosis of an asbestos pleural effusion is one of exclusions. 15. Post-cardiac injury syndrome
Benign ovarian tumors can produce ascites and a pleural effusion 16. Hemothorax
(Meigs’ syndrome), as can the ovarian hyperstimulation syndrome. 17. Iatrogenic injury
Several drugs can cause pleural effusion; the associated fluid is usu- 18. Ovarian hyperstimulation syndrome
ally eosinophilic. Pleural effusions commonly occur after coronary 19. Pericardial disease
artery bypass surgery. Effusions occurring within the first weeks are
20. Chylothorax
typically left-sided and bloody, with large numbers of eosinophils, and
respond to one or two therapeutic thoracenteses. Effusions occurring
after the first few weeks are typically left-sided and clear yellow, with ■■PNEUMOTHORAX
predominantly small lymphocytes, and tend to recur. Other medical Pneumothorax is the presence of gas in the pleural space. A spontane-
manipulations that induce pleural effusions include abdominal sur- ous pneumothorax is one that occurs without antecedent trauma to the
gery; radiation therapy; liver, lung, or heart transplantation; and the thorax. A primary spontaneous pneumothorax occurs in the absence of
intravascular insertion of central lines. underlying lung disease, whereas a secondary pneumothorax occurs in

its presence. A traumatic pneumothorax results from penetrating or non- 2009
penetrating chest injuries. A tension pneumothorax is a pneumothorax
in which the pressure in the pleural space is positive throughout the
respiratory cycle.
289 Disorders of the
Mediastinum
Primary Spontaneous Pneumothorax Primary spontaneous Richard W. Light
pneumothoraxes are usually due to rupture of apical pleural blebs,
small cystic spaces that lie within or immediately under the visceral
pleura. Primary spontaneous pneumothoraxes occur almost exclu- The mediastinum is the region between the pleural sacs. It is sepa-
sively in smokers; this suggests that these patients have subclinical rated into three compartments (Table 289-1). The anterior mediastinum
lung disease. Approximately one-half of patients with an initial pri- extends from the sternum anteriorly to the pericardium and brachio-
CHAPTER 289 Disorders of the Mediastinum

mary spontaneous pneumothorax will have a recurrence. The initial cephalic vessels posteriorly. It contains the thymus gland, the anterior
recommended treatment for primary spontaneous pneumothorax is mediastinal lymph nodes, and the internal mammary arteries and
simple aspiration. If the lung does not expand with aspiration or if veins. The middle mediastinum lies between the anterior and posterior
the patient has a recurrent pneumothorax, thoracoscopy with stapling mediastina and contains the heart; the ascending and transverse arches
of blebs and pleural abrasion is indicated. Thoracoscopy or thoraco- of the aorta; the venae cavae; the brachiocephalic arteries and veins;
tomy with pleural abrasion is almost 100% successful in preventing the phrenic nerves; the trachea, the main bronchi, and their contiguous
recurrences. lymph nodes; and the pulmonary arteries and veins. The posterior medi-
astinum is bounded by the pericardium and trachea anteriorly and the
Secondary Pneumothorax Most secondary pneumothoraxes
vertebral column posteriorly. It contains the descending thoracic aorta,
are due to chronic obstructive pulmonary disease, but pneumothoraxes
the esophagus, the thoracic duct, the azygos and hemiazygos veins,
have been reported with virtually every lung disease. Pneumothorax in
and the posterior group of mediastinal lymph nodes.
patients with lung disease is more life-threatening than it is in normal
individuals because of the lack of pulmonary reserve in these patients.
■■MEDIASTINAL MASSES
Nearly all patients with secondary pneumothorax should be treated
The first step in evaluating a mediastinal mass is to place it in one of the
with tube thoracostomy. Most should also be treated with thoracoscopy
three mediastinal compartments, since each has different characteristic
or thoracotomy with the stapling of blebs and pleural abrasion. If the
lesions (Table 289-1).
patient is not a good operative candidate or refuses surgery, pleurod-
Computed tomography (CT) scanning is the most valuable imaging
esis should be attempted by the intrapleural injection of a sclerosing
technique for evaluating mediastinal masses and is the only imaging
agent such as doxycycline.
technique that should be done in most instances. Barium studies of
Traumatic Pneumothorax Traumatic pneumothoraxes can the gastrointestinal tract are indicated in many patients with posterior
result from both penetrating and nonpenetrating chest trauma. Trau- mediastinal lesions, because hernias, diverticula, and achalasia are
matic pneumothoraxes should be treated with tube thoracostomy readily diagnosed in this manner. An iodine-131 scan can efficiently
unless they are very small. If a hemopneumothorax is present, one establish the diagnosis of intrathoracic goiter.
chest tube should be placed in the superior part of the hemithorax to A definite diagnosis can be obtained with mediastinoscopy or
evacuate the air and another should be placed in the inferior part of the anterior mediastinotomy in many patients with masses in the anterior
hemithorax to remove the blood. Iatrogenic pneumothorax is a type of or middle mediastinal compartments. A diagnosis can be established
traumatic pneumothorax that is becoming more common. The leading without thoracotomy via percutaneous fine-needle aspiration biopsy
causes are transthoracic needle aspiration, thoracentesis, and the inser- or endoscopic transesophageal or endobronchial ultrasound-guided
tion of central intravenous catheters. Most can be managed with sup- biopsy of mediastinal masses in most cases. An alternative way to
plemental oxygen or aspiration, but if these measures are unsuccessful, establish the diagnosis is video-assisted thoracoscopy. In many cases,
a tube thoracostomy should be performed. the diagnosis can be established and the mediastinal mass removed
with video-assisted thoracoscopy.
Tension Pneumothorax This condition usually occurs during
mechanical ventilation or resuscitative efforts. The positive pleural ■■ACUTE MEDIASTINITIS
pressure is life-threatening both because ventilation is severely com- Cases of acute mediastinitis are usually due to esophageal perforation,
promised and because the positive pressure is transmitted to the medi- occur after median sternotomy for cardiac surgery, or are infections
astinum, resulting in decreased venous return to the heart and reduced descending from the neck, oral cavity, or facial area. Patients with
cardiac output. esophageal rupture are acutely ill with chest pain and dyspnea due
Difficulty in ventilation during resuscitation or high peak inspi- to the mediastinal infection. The esophageal rupture can occur spon-
ratory pressures during mechanical ventilation strongly suggest the taneously or as a complication of esophagoscopy or the insertion of a
diagnosis. The diagnosis is made by physical examination showing an Blakemore tube. Appropriate treatment consists of exploration of the
enlarged hemithorax with no breath sounds, hyperresonance to per- mediastinum with primary repair of the esophageal tear and drainage
cussion, and shift of the mediastinum to the contralateral side. Tension of the pleural space and the mediastinum.
pneumothorax must be treated as a medical emergency. If the tension The incidence of mediastinitis after median sternotomy is 0.4–5.0%.
in the pleural space is not relieved, the patient is likely to die from Patients most commonly present with wound drainage. Other pre-
inadequate cardiac output or marked hypoxemia. A large-bore needle sentations include sepsis and a widened mediastinum. The diagnosis
should be inserted into the pleural space through the second anterior usually is established with mediastinal needle aspiration. Treatment
intercostal space. If large amounts of gas escape from the needle after includes immediate drainage, debridement, and parenteral antibiotic
insertion, the diagnosis is confirmed. The needle should be left in place therapy, but the mortality rate still exceeds 20%.
until a thoracostomy tube can be inserted.
■■CHRONIC MEDIASTINITIS
■■FURTHER READING The spectrum of chronic mediastinitis ranges from granulomatous
Bhatnagar R et al: Advanced medical interventions in pleural disease. inflammation of the lymph nodes in the mediastinum to fibrosing
Eur Respir Rev 25:199, 2016. mediastinitis. Most cases are due to histoplasmosis or tuberculosis, but
Light RW: Pleural Diseases, 6th ed. Lippincott, Williams and Wilkins, sarcoidosis, silicosis, and other fungal diseases are at times causative.
Baltimore, 2013. Patients with granulomatous mediastinitis are usually asymptomatic.
Rahman NM et al: Intrapleural use of tissue plasminogen activator Those with fibrosing mediastinitis usually have signs of compression of
and DNase in pleural infection. N Engl J Med 365:518, 2011. a mediastinal structure such as the superior vena cava or large airways,

2010 TABLE 289-1 The Three Compartments of the Mediastinum
ANTERIOR COMPARTMENT MIDDLE COMPARTMENT POSTERIOR COMPARTMENT
Anatomical boundaries Manubrium and sternum anteriorly, Anterior mediastinum anteriorly, posterior Pericardium and trachea anteriorly; vertebral
pericardium, aorta, and brachiocephalic mediastinum posteriorly column posteriorly
vessels posteriorly
Contents Thymus gland, anterior mediastinal Pericardium, heart, ascending and Descending thoracic aorta, esophagus,
lymph nodes, internal mammary transverse arch of aorta, superior and thoracic duct, azygos and hemiazygos veins,
arteries, and veins inferior vena cavae, brachiocephalic sympathetic chains, and the posterior group
arteries and veins, phrenic nerves, of mediastinal lymph nodes
trachea, and main bronchi and their
contiguous lymph nodes, pulmonary
arteries, and veins
PART 7
Common abnormalities Thymoma, lymphomas, teratomatous Metastatic lymph node enlargement, Neurogenic tumors, meningocele,
neoplasms, thyroid masses, granulomatous lymph node enlargement, meningomyelocele, gastroenteric cysts,
parathyroid masses, mesenchymal pleuropericardial cysts, bronchogenic esophageal diverticula, hernia through
tumors, giant lymph node hyperplasia, cysts, masses of vascular origin foramen of Bochdalek, extramedullary
hernia through foramen of Morgagni hematopoiesis
phrenic or recurrent laryngeal nerve paralysis, or obstruction of the where the dead space fraction Vd/Vt represents the portion of a tidal
pulmonary artery or proximal pulmonary veins. If veins or arteries breath that remains within the conducting airways at the conclusion of
are involved, the placement of stents has relieved the symptoms in inspiration and so does not contribute to alveolar ventilation. As such,
many patients. all disturbances of Paco2 must reflect altered CO2 production, minute
ventilation, or dead space fraction.
■■PNEUMOMEDIASTINUM ·
Diseases that alter Vco2 are often acute (sepsis, burns, or pyrexia,
In this condition, there is gas in the interstices of the mediastinum. for example) and their contribution to ventilatory abnormalities and/
The three main causes are (1) alveolar rupture with dissection of air or respiratory failure is reviewed elsewhere. Chronic ventilatory dis-
into the mediastinum; (2) perforation or rupture of the esophagus, orders typically involve inappropriate levels of minute ventilation
trachea, or main bronchi; and (3) dissection of air from the neck or or increased dead space fraction. Characterization of these disorders
the abdomen into the mediastinum. Typically, there is severe subster- requires a review of the normal respiratory cycle.
nal chest pain with or without radiation into the neck and arms. The The spontaneous cycle of inspiration and expiration is automatically
physical examination usually reveals subcutaneous emphysema in the generated in the brainstem. Two groups of neurons located within
suprasternal notch and Hamman’s sign, which is a crunching or click- the medulla are particularly important: the dorsal respiratory group
ing noise synchronous with the heartbeat and is best heard in the left (DRG) and the ventral respiratory column (VRC). These neurons have
lateral decubitus position. The diagnosis is confirmed with the chest widespread projections including the descending projections into the
radiograph. Usually no treatment is required, but the mediastinal air contralateral spinal cord where they perform many functions. They
will be absorbed faster if the patient inspires high concentrations of initiate activity in the phrenic nerve/diaphragm, project to the upper
oxygen. If mediastinal structures are compressed, the compression can airway muscle groups and spinal respiratory neurons, and innervate
be relieved with needle aspiration. the intercostal and abdominal muscles that participate in normal
respiration. The DRG acts as the initial integration site for many of
the afferent nerves relaying information about Pao2, Paco2, pH, and
Jabłoński S et al: Acute mediastinitis: evaluation of clinical risk factors
blood pressure from the carotid and aortic chemoreceptors and barore-
for death in surgically treated patients. ANZ J Surg 83:657, 2013.
ceptors to the central nervous system (CNS). In addition, the vagus
Ponamgi SP et al: Catheter-based intervention for pulmonary vein
nerve relays information from stretch receptors and juxtapulmonary-
stenosis due to fibrosing mediastinitis: The Mayo Clinic experience.
capillary receptors in the lung parenchyma and chest wall to the DRG.
Int J Cardiol Heart Vasc 8:103, 2015.
The respiratory rhythm is generated within the VRC as well as the
more rostrally located parafacial respiratory group (pFRG), which is
particularly important for the generation of active expiration. One par-
ticularly important area within the VRC is the so called pre-Bötzinger
complex. This area is responsible for the generation of various forms of
290 Disorders of Ventilation

inspiratory activity, and lesioning of the pre-Bötzinger complex leads to
the complete cessation of breathing. The neural output of these medul-
lary respiratory networks can be voluntarily suppressed or augmented
John F. McConville, Julian Solway,
by input from higher brain centers and the autonomic nervous system.
Babak Mokhlesi
During normal sleep there is an attenuated response to hypercapnia
and hypoxemia resulting in mild nocturnal hypoventilation that cor-
rects upon awakening.
DEFINITION AND PHYSIOLOGY Once neural input has been delivered to the respiratory pump
In health the arterial level of carbon dioxide (Paco2) is maintained muscles, normal gas exchange requires an adequate amount of respi-
between 37 and 43 mmHg at sea level. All disorders of ventilation ratory muscle strength to overcome the elastic and resistive loads of
result in abnormal measurements of Paco2. This chapter reviews the respiratory system (Fig. 290-1A) (also see Chap. 279). In health,
chronic ventilatory disorders. the strength of the respiratory muscles readily accomplishes this and
The continuous production of CO2 by cellular metabolism necessi- normal respiration continues indefinitely. Reduction in respiratory
tates its efficient elimination by the respiratory system. The relation- drive or neuromuscular competence or substantial increase in respi-
ship between CO2 production and Paco2 is described by the equation: ratory load can diminish minute ventilation, resulting in hypercapnia
· · ·
Paco2 = (k) (Vco2)/VA, where Vco2 represents the carbon dioxide (Fig. 290-1B). Alternatively, if normal respiratory muscle strength is
·
production, k is a constant and VA is fresh gas alveolar ventilation (see coupled with excessive respiratory drive, then alveolar hyperventila-
·
Chap. 279). VA can be calculated as minute ventilation × (1 – Vd/Vt), tion ensues and leads to hypocapnia (Fig. 290-1C).

Excess respiratory muscle strength in health TABLE 290-1 Signs and Symptoms of Hypoventilation 2011
Dyspnea during activities of daily living
Chest wall Adequate neural
elastic transmission to motor Orthopnea in diseases affecting diaphragm function
loads units Poor-quality sleep
Daytime hypersomnolence
Early morning headaches
Anxiety
Impaired cough in neuromuscular diseases
Lung resistive Respiratory
Load Strength
loads muscle strength
CHAPTER 290 Disorders of Ventilation

the underlying disorder. Patients with parenchymal lung or chest wall
disease typically present with shortness of breath and diminished exer-
cise tolerance. Episodes of increased dyspnea and sputum production
Lung elastic Respiratory
are hallmarks of obstructive lung diseases such as COPD, whereas
A loads drive progressive dyspnea and cough are common in interstitial lung dis-
eases. Excessive daytime somnolence, poor-quality sleep and snoring
Load > Strength are common among patients with sleep-disordered breathing. Sleep
Impaired neuromuscular
Chest wall disease
disturbance and orthopnea are also described in neuromuscular disor-
transmission
Kyphoscoliosis Amyotrophic lateral sclerosis ders. As neuromuscular weakness progresses, the respiratory muscles,
Obesity Myasthenia gravis including the diaphragm, are placed at a mechanical disadvantage in
Abdominal distention (ascites) Phrenic nerve injury
Spinal cord lesion
the supine position due to the upward movement of the abdominal
contents. New onset orthopnea is frequently a sign of reduced respi-
ratory muscle force generation. More commonly however, extremity
weakness or bulbar symptoms develop prior to sleep disturbance in
Sleep-disordered Muscle neuromuscular diseases such as amyotrophic lateral sclerosis (ALS)
breathing weakness or muscular dystrophy. Patients with respiratory drive disorders do
Upper airway Load Strength Myopathy
obstruction Malnutrition
not have symptoms distinguishable from other causes of chronic
Intermittent hypoxemia Fatigue hypoventilation.
The clinical course of patients with chronic hypoventilation from
neuromuscular or chest wall disease follows a characteristic sequence:
An asymptomatic stage where daytime Pao2 and Paco2 are normal
Lung disease Diminished drive followed by nocturnal hypoventilation, initially during rapid eye
Interstitial lung disease Sleep disordered breathing movement (REM) sleep and later in non-REM sleep. Finally, if vital
Airflow obstruction Narcotic/sedative use capacity drops further, daytime hypercapnia develops. Symptoms can
Atelectasis Brainstem stroke
Pulmonary embolus Hypothyroidism develop at any point along this time-course and often depend on the
B 1º Alveolar hypoventilation pace of respiratory muscle functional decline. Regardless of cause, the
hallmark of all alveolar hypoventilation syndromes is an increase in
Increased drive with acceptable strength alveolar Pco2 (PAco2) and therefore in Paco2. The resulting respiratory
No chest wall Normal neural acidosis eventually leads to a compensatory increase in plasma bicar-
disease transmission bonate concentration. The increase in Paco2 results in an obligatory
decrease in PAo2, often resulting in hypoxemia. If severe, the hypox-
emia manifests clinically as cyanosis and can stimulate erythropoiesis
and so induce secondary erythrocytosis. The combination of chronic
hypoxemia and hypercapnia may also induce pulmonary vasoconstric-
Increased drive
Numerous initiating and tion, leading eventually to pulmonary hypertension, right ventricular
Load Strength
sustaining factors (see text) hypertrophy, and right heart failure.
■■DIAGNOSIS
Elevated plasma bicarbonate in the absence of volume depletion is sug-
gestive of hypoventilation. An arterial blood gas demonstrating elevated
No lung disease Normal respiratory Paco2 with a normal pH confirms chronic alveolar hypoventilation. The
C muscle strength subsequent evaluation to identify an etiology should initially focus on
FIGURE 290-1 Examples of balance between respiratory system strength and whether the patient has lung disease or chest wall abnormalities. Phys-
load. A. Excess respiratory muscle strength in health. B. Load greater than ical examination, imaging studies (chest x-ray and/or CT scan) and
strength. C. Increased drive with acceptable strength. pulmonary function tests are sufficient to identify most lung/chest
wall disorders leading to hypercapnia. If these evaluations are unre-
vealing then the clinician should screen for obesity hypoventilation
HYPOVENTILATION syndrome (OHS), the most frequent sleep disorder leading to chronic
hypoventilation, which is typically accompanied by obstructive sleep
■■CLINICAL FEATURES apnea (OSA). Several screening tools have been developed to identify
Diseases that reduce minute ventilation or increase dead space fall patients at risk for OSA. The Berlin Questionnaire has been validated
into four major categories: parenchymal lung and chest wall disease, in a primary care setting and identifies patients likely to have OSA.
sleep disordered breathing, neuromuscular disease, and respiratory The Epworth Sleepiness Scale (ESS) and the STOP-Bang questionnaires
drive disorders (Fig. 290-1B). The clinical manifestations of hypoven- have not been validated in outpatient primary care settings but are
tilation syndromes are nonspecific (Table 290-1) and vary depending quick and easy to use. The ESS measures daytime sleepiness, with a
on the severity of hypoventilation, the rate at which hypercapnia score of ≥10 identifying individuals who warrant additional investiga-
develops, the degree of compensation for respiratory acidosis, and tion. The STOP-Bang survey has been used in preoperative anesthesia

2012 clinics to identify patients at risk of having OSA. In this population it Phrenic nerve or diaphragm pacing is a potential therapy for
has 93% sensitivity and 90% negative predictive value. Additionally, patients with hypoventilation from high cervical spinal cord lesions
the STOP-Bang questionnaire has been validated as a screening tool or respiratory drive disorders. Prior to surgical implantation patients
for OSA in sleep and surgical clinics. The probability of moderate and should have nerve conduction studies to ensure normal bilateral
severe OSA steadily increases with higher STOP-Bang scores. phrenic nerve function. Small case series suggest that effective
If the ventilatory apparatus (lung, airways, chest wall) is not respon- diaphragmatic pacing can improve quality of life in these patients.
sible for chronic hypercapnia then the focus should shift to respiratory
drive and neuromuscular disorders. There is an attenuated increase
in minute ventilation in response to elevated CO2 and/or low O2 in
HYPOVENTILATION SYNDROMES
respiratory drive disorders. These diseases are difficult to diagnose ■■OBESITY HYPOVENTILATION SYNDROME
and should be suspected when patients with hypercapnia are found The diagnosis of OHS requires: BMI ≥30 kg/m2 and chronic daytime
to have normal respiratory muscle strength, normal pulmonary func-
PART 7
alveolar hypoventilation, defined as Paco2 ≥45 mmHg at sea level in

tion, and normal alveolar-arterial Po2 difference. Hypoventilation is the absence of other known causes of hypercapnia. In almost 90% of
more marked during sleep in patients with respiratory drive defects cases the sleep disordered breathing is in the form of OSA. Several
and polysomnography often reveals central apneas, hypopneas, or international studies in different populations confirm that the overall
hypoventilation. Brain imaging (CT scan or MRI) can sometimes prevalence of OSA syndrome, defined by an apnea hypopnea index
identify structural abnormalities in the pons or medulla that result in ≥5 AND daytime sleepiness, is ~3–4% in middle-aged men and 2% in
hypoventilation. Chronic narcotic use or significant hypothyroidism middle-aged women. Thus, the population at risk for the development
can depress the central respiratory drive and lead to chronic hyper- of OHS continues to rise as the world-wide obesity epidemic persists.
capnia as well. Although no population-based prevalence studies of OHS have been
Respiratory muscle weakness has to be profound before lung vol- performed, some estimates suggest there may be as many as 500,000
umes are compromised and hypercapnia develops. Typically physical individuals with OHS in the United States.
examination reveals decreased strength in major muscle groups prior Some, but not all, studies suggest that severe obesity (BMI >40 kg/m2)
to the development of hypercapnia. Measurement of maximum inspi- and severe OSA (AHI >30 events per h) are risk factors for the
ratory and expiratory pressures or forced vital capacity (FVC) can be development of OHS. The pathogenesis of hypoventilation in these
used to monitor for respiratory muscle involvement in diseases with patients is the result of multiple physiologic variables and conditions
progressive muscle weakness. These patients also have increased including OSA, increased work of breathing, respiratory muscle
risk for sleep-disordered breathing, including hypopneas, central and impairment, ventilation-perfusion mismatching, and depressed cen-
obstructive apneas, and hypoxemia. Nighttime oximetry and capnom- tral ventilatory responsiveness to hypoxemia and hypercapnia. These
etry during polysomnography are helpful in better characterizing sleep defects in central respiratory drive often improve with treatment which
disturbances in this patient population. suggest that decreased ventilatory responsiveness is a consequence
rather than a primary cause of OHS. The treatment of OHS is similar
TREATMENT to that for OSA: weight reduction and nocturnal non-invasive positive
pressure ventilation (NIPPV). There is evidence that weight loss alone
Hypoventilation lowers Paco2 in patients with OHS. However, treatment with NIPPV
should never be delayed while the patient attempts to lose weight.
Nocturnal non-invasive positive-pressure ventilation (NIPPV) has
Continuous positive airway pressure (CPAP) improves daytime hyper-
been used successfully in the treatment of hypoventilation and
capnia and hypoxemia in more than half of patients with OHS and con-
apneas, both central and obstructive, in patients with neuromus-
comitant OSA. Bi-level positive airway pressure should be reserved for
cular and chest wall disorders. Nocturnal NIPPV has been shown
patients not able to tolerate high levels of CPAP support or patients that
to improve daytime hypercapnia, prolong survival, and improve
remain hypoxemic despite resolution of obstructive respiratory events.
health-related quality of life when daytime hypercapnia is docu-
NIPPV with bi-level PAP should be strongly considered if hypercapnia
mented. ALS guidelines recommend consideration of nocturnal
persists after several weeks of CPAP therapy with objectively proven
NIPPV if symptoms of hypoventilation exist and one of the follow-
adherence. Patients with OHS and no evidence of OSA are typically
ing criteria is present: Paco2 ≥45 mmHg; nocturnal oximetry dem-
started on bi-level positive airway pressure, as are patients presenting
onstrates oxygen saturation ≤88% for 5 consecutive min; maximal
with acute decompensated OHS. Finally, comorbid conditions that
inspiratory pressure <60 cmH2O; FVC <50% predicted; sniff nasal
impair ventilation, such as chronic obstructive pulmonary disease,
pressure <40 cmH2O. However, at present there is inconclusive evi-
should be aggressively treated in conjunction with co-existing OHS.
dence to support pre-emptive nocturnal NIPPV use in all patients
with neuromuscular and chest wall disorders who demonstrate ■■CENTRAL HYPOVENTILATION SYNDROME
nocturnal but not daytime hypercapnia. Nevertheless, at some point, This syndrome can present later in life or in the neonatal period where
the institution of full-time ventilatory support with either pressure it is often called Ondine’s curse or congenital central hypoventilation
or volume-preset modes is required in progressive neuromuscular syndrome (CCHS). Abnormalities in the gene encoding PHOX2b, a tran-
disorders. There is less evidence to direct the timing of this decision, scription factor with a role in neuronal development, have been impli-
but ventilatory failure requiring mechanical ventilation and chest cated in the pathogenesis of CCHS. Regardless of the age of onset, these
infections related to ineffective cough are frequent triggers for the patients have absent respiratory response to hypoxia or hypercapnia,
institution of full-time ventilatory support. mildly elevated Paco2 while awake, and markedly elevated Paco2 during
Treatment of chronic hypoventilation from lung or neuro- non-REM sleep. Interestingly these patients are able to augment their
muscular diseases should be directed at the underlying disorder. ventilation and “normalize” Paco2 during exercise and during REM
Pharmacologic agents that stimulate respiration, such as medroxy- sleep. These patients typically require NIPPV or mechanical ventilation
progesterone and acetazolamide, have been poorly studied in as therapy and should be considered for phrenic nerve or diaphragmatic
chronic hypoventilation and should not replace treatment of the pacing at centers with experience performing these procedures.
underlying disease process. Regardless of the cause, excessive met-
abolic alkalosis should be corrected, as plasma bicarbonate levels HYPERVENTILATION
elevated out of proportion for the degree of chronic respiratory
acidosis can result in additional hypoventilation. When indicated, ■■CLINICAL FEATURES
administration of supplemental oxygen is effective in attenuating Hyperventilation is defined as ventilation in excess of metabolic
hypoxemia, polycythemia, and pulmonary hypertension. However, requirements (CO2 production) leading to a reduction in Paco2.
in some patients supplemental oxygen can worsen hypercapnia. The physiology of patients with chronic hyperventilation is poorly

understood and there is no typical clinical presentation. Symptoms Gardner WN: The pathophysiology of hyperventilation disorders. 2013
can include dyspnea, paresthesias, tetany, headache, dizziness, visual Chest 109:516, 1996.
disturbances, and atypical chest pain. Because symptoms can be so Mokhlesi B: Obesity hypoventilation syndrome: A state-of-the-art
diverse, patients with chronic hyperventilation present to a variety of review. Respir Care 55:1347. Discussion 1363, 2010.
health care providers, including internists, neurologists, psychologists, Nagappa M et al: Validation of the STOP-Bang questionnaire as a
psychiatrists, and pulmonologists. screening tool for obstructive sleep apnea among different popula-
It is helpful to think of hyperventilation as having initiating and tions: A systematic review and meta-analysis. PLoS One 10:e0143697,
sustaining factors. Some investigators believe that an initial event leads 2015.
to increased alveolar ventilation and a drop in Paco2 to ~20 mmHg. The Piper AJ, Grunstein RR: Obesity hypoventilation syndrome, mech-
ensuing onset of chest pain, breathlessness, paresthesia, or altered con- anisms and management. Am J Respir Crit Care Med 183:292, 2011.
sciousness can be alarming. The resultant increase in minute volume Simonds AK: Recent advances in respiratory care for neuromuscular
CHAPTER 291 Sleep Apnea

to relieve these acute symptoms only serves to exacerbate symptoms disease. Chest 130:1879, 2006.
that are often misattributed by the patient and health care workers to
cardiopulmonary disorders. An unrevealing evaluation for causes of
these symptoms often results in patients being anxious and fearful of
additional attacks. It is important to note that anxiety disorders and
panic attacks are NOT synonymous with hyperventilation. Anxiety
291 Sleep Apnea

disorders can be both an initiating and sustaining factor in the patho-
genesis of chronic hyperventilation, but these are not necessary for the
development of chronic hypocapnia.
Andrew Wellman, Susan Redline
■■DIAGNOSIS
Respiratory symptoms associated with acute hyperventilation can be
the initial manifestation of systemic illnesses such as diabetic ketoaci- Obstructive sleep apnea/hypopnea syndrome (OSAHS) and central
dosis. Causes of acute hyperventilation need to be excluded before a sleep apnea (CSA) are both classified as sleep-related breathing dis-
diagnosis of chronic hyperventilation is considered. Arterial blood gas orders. OSAHS and CSA share some risk factors and physiological
sampling that demonstrates a compensated respiratory alkalosis with bases but also have unique features. Each disorder is associated with
a near normal pH, low Paco2, and low calculated bicarbonate are nec- impaired ventilation during sleep and disruption of sleep, and each
essary to confirm chronic hyperventilation. Other causes of respiratory diagnosis requires careful elicitation of the patient’s history, physical
alkalosis, such as mild asthma, need to be diagnosed and treated before examination, and physiological testing. OSAHS, the more common
chronic hyperventilation can be considered. A high index of suspicion disorder, causes daytime sleepiness, impairs daily function, and is a
is required as increased minute ventilation can be difficult to detect on major contributor to cardiovascular disease in adults and to behavioral
physical examination. Once chronic hyperventilation is established, a problems in children. CSA is less common and may occur in combina-
sustained 10% increase in alveolar ventilation is enough to perpetuate tion with obstructive sleep apnea, as a primary condition, or secondary
hypocapnia. This increase can be accomplished with subtle changes to a medical condition (such as heart failure) or medication. Patients
in the respiratory pattern, such as occasional sigh breaths or yawning with CSA often report frequent awakenings and daytime fatigue and
2–3 times per min. are at increased risk for heart failure and atrial fibrillation.
■■OBSTRUCTIVE SLEEP APNEA/HYPOPNEA

TREATMENT SYNDROME
Hyperventilation Definition OSAHS is defined on the basis of nocturnal and day-
There are few well-controlled treatment studies of chronic hyper- time symptoms as well as sleep study findings. Diagnosis requires
ventilation owing to its diverse features and the lack of a universally the patient to have (1) either symptoms of nocturnal breathing distur-
accepted diagnostic process. Clinicians often spend considerable bances (snoring, snorting, gasping, or breathing pauses during sleep)
time identifying initiating factors, excluding alternative diagnoses, or daytime sleepiness or fatigue that occurs despite sufficient oppor-
and discussing the patient’s concerns and fears. In some patients, tunities to sleep and is unexplained by other medical problems; and
reassurance and frank discussion about hyperventilation can be lib- (2) five or more episodes of obstructive apnea or hypopnea per hour
erating. Identifying and eliminating habits that perpetuate hypocap- of sleep (the apnea-hypopnea index [AHI], calculated as the number
nia, such as frequent yawning or sigh breathing, can be helpful. of episodes divided by the number of hours of sleep) documented
Some evidence suggests that breathing exercises and diaphragmatic during a sleep study. OSAHS also may be diagnosed in the absence
retraining may be beneficial for some patients. The evidence for of symptoms if the AHI is >15 episodes/h. Each episode of apnea
using medications to treat hyperventilation is scant. Beta-blockers or hypopnea represents a reduction in breathing for at least 10 s and
may be helpful in patients with sympathetically mediated symp- commonly results in a ≥3% drop in oxygen saturation and/or a brain
toms such as palpitations and tremors. cortical arousal. OSAHS severity is based on the frequency of breathing
disturbances (AHI), the amount of oxyhemoglobin desaturation with
respiratory events, the duration of apneas and hypopneas, the degree
Acknowledgment of sleep fragmentation, and the level of daytime sleepiness or func-
We acknowledge Jan-Marino Ramirez for his careful critique and helpful tional impairment.
suggestions.
Pathophysiology During inspiration, intraluminal pharyngeal
■■FURTHER READING pressure becomes increasingly negative, creating a “suctioning” force.
Anderson PM et al: EFNS guidelines on the clinical management if Because the pharyngeal airway has no bone or cartilage, airway
amyotrophic lateral sclerosis-revised report of the EFNS task force. patency is dependent on the stabilizing influence of the pharyngeal
Eur J Neurol 19:360, 2012. dilator muscles. Although these muscles are continuously activated
Chung F et al: STOP Questionnaire: A tool to screen patients for during wakefulness, neuromuscular output declines with sleep onset.
obstructive sleep apnea. Anesthesiology 108:812, 2008. In patients with a collapsible airway, the reduction in neuromuscular
Douglas IS: Acute-on-chronic respiratory failure, in Principles of output results in transient episodes of pharyngeal collapse (manifest-
Critical Care, 4th ed. JB Hall, GS Schmidt, JP Kress (eds). New York, ing as an “apnea”) or near collapse (manifesting as a “hypopnea”).
McGraw-Hill, 2015, pp 482–495. The episodes of collapse are terminated when ventilatory reflexes are

2014 pharyngeal muscle compensation and prevent airway stabilization. A
high arousal threshold, conversely, may prevent appropriate termina-
tion of apneas, prolonging apnea duration, and exacerbating oxyhe-
moglobin desaturation severity. Finally, any impairment in the ability
of the muscles to compensate during sleep can contribute to collapse
of the pharynx. The relative contributions of risk factors vary among
individuals. Approaches to the measurement of these factors in clinical
settings, with consequent enhancement of “personalized” therapeutic
Palate
interventions, are being actively investigated.
Risk Factors and Prevalence The major risk factors for OSAHS
Lateral are obesity and male sex. Additional risk factors include mandibular
PART 7
pharyngeal retrognathia and micrognathia, a positive family history of OSAHS,

Tongue
walls
genetic syndromes that reduce upper airway patency (e.g., Down
syndrome, Treacher-Collins syndrome), adenotonsillar hypertrophy
Epiglottis (especially in children), menopause (in women), and various endocrine
syndromes (e.g., acromegaly, hypothyroidism).

Approximately 40–60% of cases of OSAHS are attributable to excess
weight. Obesity predisposes to OSAHS through the narrowing effects of
upper airway fat on the pharyngeal lumen. Obesity also reduces chest
wall compliance and decreases lung volumes, resulting in a loss of cau-
dal traction on upper airway structures. Obese individuals are at a four-
fold or greater risk for OSAHS than their normal-weight counterparts. A
10% weight gain is associated with a >30% increase in AHI. Even modest
FIGURE 291-1 The structures causing airway collapse in OSAHS include the
palate, the tongue, and/or the epiglottis. In addition, collapse can also occur due weight loss or weight gain can influence the risk and severity of OSAHS.
to the lateral pharyngeal walls. However, the absence of obesity does not exclude this diagnosis.
The prevalence of OSAHS is two- to fourfold higher among men
than among women. Factors that predispose men to OSAHS include
android patterns of obesity (resulting in upper-airway and abdom-
activated and cause arousal, thus stimulating an increase in neuromus- inal fat deposition) and relatively greater pharyngeal length, which
cular activity and opening of the airway. The airway may collapse at exacerbates collapsibility. Premenopausal women are relatively pro-
different sites, such as the soft palate (most common), tongue base, tected from OSAHS by the influence of sex hormones on ventilatory
lateral pharyngeal walls, and/or epiglottis (Fig. 291-1). OSAHS may drive. The decline in sex differences in older age is associated with an
be most severe during REM (rapid eye movement) sleep, when neuro- increased OSAHS prevalence in women after menopause.
muscular output to the skeletal muscles is particularly low, and in the Variations in craniofacial morphology that reduce the size of the
supine position due to gravitational forces. posterior airway space increase OSAHS risk. The contribution of
Individuals with a small pharyngeal lumen require relatively high hard-tissue structural features to OSAHS is most evident in nonobese
levels of neuromuscular innervation to maintain patency during wake- patients. Identification of features such as retrognathia can influence
fulness and thus are predisposed to excessive airway collapsibility therapeutic decision making.
during sleep. The airway lumen may be narrowed with enlargement OSAHS has a strong genetic basis, as evidenced by its significant
of soft tissue structures (tongue, palate, and uvula) due to fat depo- familial aggregation and heritability. For a first-degree relative of a
sition, increased lymphoid tissue, or genetic variation. Craniofacial patient with OSAHS, the odds ratio of having OSAHS is approximately
factors such as mandibular retroposition or micrognathia, reflecting twofold higher than that for someone without an affected relative. Sev-
genetic variation or developmental influences, also can reduce lumen eral genetic variants have been associated with prevalence of OSAHS
dimensions. In addition, lung volumes influence the caudal traction or with related traits, such as duration of apneas and hypopneas and
on the pharynx and consequently the stiffness of the pharyngeal wall. overnight levels of hypoxemia.
Accordingly, low lung volume in the recumbent position, which is OSAHS prevalence varies with age, from 2 to 15% among middle-
particularly pronounced in the obese, contributes to collapse. A high aged adults to >20% among elderly individuals. There is a peak due
degree of nasal resistance (e.g., due to nasal septal deviation or polyps) to lymphoid hypertrophy among children between the ages of 3 and
can contribute to airway collapse by increasing the negative intralu- 8 years; with airway growth and lymphoid tissue regression during
minal suction pressure. High-level nasal resistance also may trigger later childhood, prevalence declines. Then, as obesity prevalence
mouth opening during sleep, which breaks the seal between the tongue increases in middle life and women enter menopause, OSAHS again
and the teeth and allows the tongue to fall posteriorly and occlude the increases.
airway. The prevalence of OSAHS is especially high among patients with
Pharyngeal muscle activation is integrally linked to ventilatory diabetes or hypertension. Individuals of Asian ancestry appear to be at
drive. Thus, factors related to ventilatory control, particularly ventila- increased risk of OSAHS at relatively low levels of body mass index,
tory sensitivity, arousal threshold, and neuromuscular responses to possibly because of the influence of craniofacial risk factors that narrow
CO2, contribute to the pathogenesis of OSAHS. A buildup in CO2 dur- the nasopharynx. In the United States, African Americans, especially
ing sleep activates both the diaphragm and the pharyngeal muscles, children and young adults, are at higher risk for OSAHS than their
which stiffen the upper airway and can counteract inspiratory suction Caucasian counterparts. In a majority of adults with OSAHS, the dis-
pressures and maintain airway patency to an extent that depends on order is undiagnosed.
the anatomic predisposition to collapse. However, pharyngeal collapse
can occur when the ventilatory control system is overly sensitive to Course of the Disorder The precise onset of OSAHS is usually
CO2, with resultant wide fluctuations in ventilation and ventilatory hard to identify. A person may snore for many years, often beginning in
drive and in upper airway instability. Moreover, increasing levels of childhood, before OSAHS is identified. Weight gain may precipitate an
CO2 during sleep result in central nervous system arousal, causing increase in symptoms, which in turn may lead the patient to pursue an
the individual to move from a deeper to a lighter level of sleep or evaluation. OSAHS may become less severe with weight loss, particu-
to awaken. A low arousal threshold (i.e., awaken to a low level of larly after bariatric surgery. Marked increases and decreases in the AHI
CO2 or ventilatory drive) can preempt the CO2-mediated process of are uncommon unless accompanied by weight change.

2015
APPROACH TO THE PATIENT TABLE 291-1 Respiratory Event Definitions
• Apnea: Cessation of airflow for ≥10 s during sleep, accompanied by:
Obstructive Sleep Apnea/Hypopnea Syndrome • Persistent respiratory effort (obstructive apneas, Fig. 291-2A), or
An evaluation for OSAHS should be considered in patients with • Absence of respiratory effort (central apneas, Fig. 291-2B)
symptoms of OSAHS and one or more risk factors. Screening also • H ypopnea: A ≥30% reduction in airflow for at least 10 s during sleep that is
should be considered in patients who report symptoms consistent accompanied by either a ≥3% desaturation or an arousal (Fig. 291-2C)
with OSAHS and who are at high risk for OSAHS-related mor- • R espiratory effort-related arousal (RERA): Partial obstruction that does not
bidities, such as hypertension, diabetes mellitus, and cardiac and meet the criteria for hypopnea but provides evidence of increasing
cerebrovascular diseases. inspiratory effort (usually through pleural pressure monitoring) punctuated
by an arousal (Fig. 291-2D)
SYMPTOMS AND HISTORY

• F low-limited breath: A partially obstructed breath, typically within a hypopnea
When possible, a sleep history should be obtained with assistance or RERA, identified by a flattened or “scooped-out” inspiratory flow shape
from a bed partner or household member. Snoring is the most com- (Fig. 291-3)
mon complaint; however, its absence does not exclude the diagnosis,
as pharyngeal collapse may occur without tissue vibration. Gasping
or snorting during sleep may also be reported, reflecting termina- or in individuals experiencing hypopneas with arousals rather than
tion of individual apneas with abrupt airway opening. Dyspnea is oxyhemoglobin desaturation. Further evaluation may therefore be
unusual, and its absence generally distinguishes OSAHS from par- required.
oxysmal nocturnal dyspnea, nocturnal asthma, and acid reflux with The key physiological information collected during a sleep study
laryngospasm. Patients also may describe frequent awakening or for OSAHS assessment includes measurement of breathing (changes
sleep disruption, which is more common among women and older in airflow, respiratory excursion), oxygenation (hemoglobin oxygen
adults. The most common daytime symptom is excessive sleepiness, saturation), body position, and cardiac rhythm. In addition, PSGs
identified by a history of difficulty maintaining alertness or invol- and some home sleep studies measure sleep continuity and sleep
untary periods of dozing. However, many women preferentially stages (by electroencephalography, chin electromyography, elec-
report fatigue rather than sleepiness. Other symptoms include a tro-oculography, and actigraphy), limb movements (by leg sensors),
dry mouth, nocturnal heartburn, diaphoresis of the chest and neck, and snoring intensity. This information is used to quantify the fre-
nocturia, morning headaches, trouble concentrating, irritability, and quency and subtypes of abnormal respiratory events during sleep
mood disturbances. Although difficulty falling sleep and maintain- as well as associated changes in oxygen hemoglobin saturation,
ing sleep are characteristics of insomnia disorders, they also may arousals, and sleep stage distributions. Tables 291-1 and 291-2 define
occur with OSAHS, especially in women. Several questionnaires the respiratory events scored and the severity guidelines employed
that evaluate snoring frequency, self-reported apneas, and daytime during a sleep study. Fig. 291-2 shows examples of sleep-related
sleepiness can facilitate OSAHS screening. The predictive ability of respiratory events. A typical sleep study report provides quanti-
a questionnaire can be enhanced by a consideration of whether the tative data such as the AHI and the profile of oxygen saturation
patient is male or has risk factors such as obesity or hypertension. over the night (mean, nadir, time at low levels). Reports may also
include the respiratory disturbance index, which includes the num-
PHYSICAL FINDINGS ber of respiratory effort-related arousals in addition to the number
Physical findings often reflect the etiologic factors for the disorder of apneas plus hypopneas. In-laboratory, PSG also quantifies sleep
as well as comorbid conditions, particularly vascular disease. On latency (time from “lights off” to first sleep onset), sleep efficiency
examination, patients may exhibit hypertension and regional (cen- (percentage of time asleep relative to time in bed), arousal index
tral) obesity, as indicated by a large waist and neck circumference. (number of cortical arousals per hour of sleep), time in each sleep
The oropharynx may reveal a small orifice with crowding due to stage, and periodic limb movement index. OSAHS severity can be
an enlarged tongue, a low-lying soft palate with a bulky uvula, further characterized according to the degree of sleep fragmentation
large tonsils, a high-arched palate, and/or micro/retrognathia. Since associated with respiratory disturbances. Relevant metrics include
nasal resistance can increase the propensity to pharyngeal collapse, the frequency of cortical micro-arousals or awakenings per sleep
the nasal cavity should be inspected for polyps, septal deviation, hour (arousal index), reduction in sleep continuity (low sleep effi-
and other signs of obstruction. Because patients with heart failure ciency), reduction of time in deeper stages of sleep (stage N3 and
are at increased risk for both OSAHS and CSA, a careful cardiac REM sleep), and increases in light sleep (stage N1). The detection
examination should be conducted to detect possible left- or right- of autonomic arousals, such as surges in blood pressure, changes
sided cardiac dysfunction. Evidence of cor pulmonale suggests a in heart rate, and abnormalities in cardiac rhythm, also provides
comorbid cardiopulmonary condition; OSAHS alone is not thought relevant information on OSAHS severity.
to cause right-heart failure. A neurologic evaluation is needed to
Other Laboratory Findings Various imaging studies, including
evaluate for conditions such as neuromuscular and cerebrovascular
cephalometric radiography, MRI, CT, and fiberoptic endoscopy, can
diseases, which increase OSAHS risk.
be used to identify anatomic risk factors for OSAHS. Cardiac testing
LABORATORY FINDINGS may yield evidence of impaired systolic or diastolic ventricular
Diagnostic Findings Since symptoms and signs do not accurately function or abnormal cardiac structure. Overnight blood pressure
predict the severity of sleep-related breathing disturbances, specific monitoring often displays a “non-dipping” pattern (absence of the
diagnosis and categorization of OSAHS severity requires objective
measurement of breathing during sleep. The gold standard for TABLE 291-2 Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS):
diagnosis of OSAHS is an overnight polysomnogram (PSG). A Quantification and Severity Scale
negative in-laboratory PSG usually rules out OSAHS. However, • A
pnea-hypopnea index (AHI)a: Number of apneas plus hypopneas per hour
false-negative studies can result if the study did not collect repre- of sleep
sentative information on the patient’s usual sleep, particularly if • R
espiratory disturbance index (RDI): Number of apneas plus hypopneas plus
there was insufficient REM sleep or inadequate supine sleep during RERAs per hour of sleep
testing. Home sleep tests that record only a few respiratory and • Mild OSAHS: AHI of 5–14 events/h
cardiac channels commonly are used as a cost-effective means for • Moderate OSAHS: AHI of 15–29 events/h
diagnosing patients without significant comorbidity who have a
• Severe OSAHS: AHI of ≥30 events/h
high pretest probability of OSAHS. However, a home study may
yield a false-negative result if sleep time is not accurately estimated
a
Each level of AHI can be further quantified by level of sleepiness and associated
hypoxemia.

2016 A B
EEG
EEG
EOG
chin EOG
EKG
chin
snore
t. flow snore
PART 7
n. p. flow flow
chest chest
abdomen abdomen
SaO2 SaO2
C D
Hypnogram
EEG
Stage
EEG
EOG
chin
snore
EKG
flow Legs Ar
position
snore
t. flow
chest
n. p. flow
abdomen chest
abdomen
SaO2
SaO2
FIGURE 291-2 Obstructive apnea. A. There are 30 s of no airflow, as shown in the nasal pressure (n. p. flow) and thermistor-measured flow (t. flow). Note the presence
of chest-abdomen paradox, indicating respiratory effort against an occluded airway. B. Central apnea in a patient with Cheyne-Stokes respiration due to congestive
heart failure. The flat chest-abdomen tracings indicate the absence of inspiratory effort during the central apneas. C. Hypopnea. Partial obstruction of the pharyngeal
airway can limit ventilation, leading to desaturation (a mild decrease in this patient, from 93 to 90%) and arousal. D. Respiratory effort-related arousal (RERA). Minimal
flow reduction terminated by an arousal (Ar) without desaturation constitutes a RERA. EEG, electroencephalogram; EOG, electro-oculogram; EKG, electrocardiogram.
typical 10-mmHg fall of blood pressure during sleep compared and neurologic functions. OSAHS-related respiratory events stimulate
to wakefulness). Arterial blood gas measurements made during sympathetic overactivity, leading to acute blood pressure surges during
wakefulness are usually normal. Waking hypoxemia or hypercarbia sleep, endothelial damage, and nocturnal as well as daytime hyperten-
suggests coexisting cardiopulmonary disease or hypoventilation sion. OSAHS-related hypoxemia also stimulates release of acute-phase
syndromes. Patients with severe nocturnal hypoxemia may have proteins and reactive oxygen species that exacerbate insulin resistance
elevated hemoglobin values. A multiple sleep latency test or a main- and lipolysis and cause an augmented prothrombotic and proinflam-
tenance of wakefulness test can be useful in quantifying sleepiness matory state. Inspiratory effort against an occluded airway causes
and helping to distinguish OSAHS from narcolepsy. large intrathoracic negative pressure swings, altering cardiac preload
and afterload and resulting in cardiac remodeling and reduced cardiac
Health Consequences and Comorbidities OSAHS is a major function. Hypoxemia and sympathetic-parasympathetic imbalance also
contributor to cardiac, cerebrovascular, and metabolic disorders as well may cause electrical remodeling of the heart and myocyte injury.
as to premature death. It is the most common medical cause of daytime HYPERTENSION OSAHS can raise blood pressure to pre-hypertensive
sleepiness and negatively influences quality of life. This broad range of and hypertensive ranges, increase the prevalence of a non-dipping
health effects is attributable to the impact of sleep fragmentation, corti- overnight blood pressure pattern, and increase the risk of resistant
cal arousal, and intermittent hypoxemia on vascular, cardiac, metabolic, hypertension. Elevations in blood pressure are due to augmented
sympathetic nervous system activation as well as alterations in the
renin-angiotensin–aldosterone system and fluid balance. Treatment of
Normal Flow limitation
OSAHS with nocturnal continuous positive airway pressure (CPAP)
has been shown to reduce 24-h ambulatory blood pressure. Although
the overall impact of CPAP on blood pressure levels is relatively mod-
est (averaging 2–4 mmHg), larger improvements are observed among
patients who have a high AHI, report daytime sleepiness, or who have
resistant hypertension.
CARDIOVASCULAR, CEREBROVASCULAR, AND METABOLIC DISEASES Among
FIGURE 291-3 Example of flow limitation. The inspiratory flow pattern in a patent
airway is rounded and peaks in the middle. In contrast, a partially obstructed the most serious health consequences of OSAHS is its impact on cardiac
airway exhibits an early peak followed by mid-inspiratory flattening, yielding a and metabolic functions. Strong epidemiologic evidence indicates that
scooped-out appearance. OSAHS significantly increases the risk of coronary artery disease, heart

failure with and without reduced ejection fraction, atrial and ventric- 2017
TABLE 291-3 Side Effects of Continuous Positive Airway Pressure
ular arrhythmias, atherosclerosis and coronary artery disease, stroke, (CPAP) and Their Treatments
and diabetes. Treatment of OSAHS has been shown to reduce several SIDE EFFECT TREATMENT
markers of cardiovascular risk, improve insulin resistance, decrease the
Nasal congestion Provide heated humidification, administer saline/
recurrence rate of atrial fibrillation, and improve various outcomes in steroid nasal sprays
patients with active cardiovascular disease. Large-scale trials have not
Claustrophobia Change mask interface (e.g., to nasal prongs),
yet, however, demonstrated that OSAHS treatment with CPAP reduces promote habituation (i.e., practice breathing on
cardiac event rates and prolongs survival, perhaps due to limited CPAP while awake)
adherence with treatment among trial participants. Difficulty exhaling Temporarily reduce pressure, provide bilevel
SLEEPINESS More than 50% of patients with moderate to severe positive airway pressure

OSAHS report daytime sleepiness. Patients with OSAHS symptoms Bruised nasal ridge Change mask interface, provide protective padding
have a twofold increased risk of occupational accidents. Individuals Aerophagia Administer antacids
with elevated AHIs are involved in motor vehicle crashes as much as
seven times more often than persons with normal AHIs. Randomized
controlled trials have shown that treatment of OSAHS with nasal CPAP cardiovascular outcomes, cardiac ejection fraction, atrial fibrillation
therapy alleviates sleepiness as measured by either questionnaire or recurrence, and mortality risk.
objective testing in patients with both mild and more severe disease. Oral appliances for OSAHS work by advancing the mandible,
However, the degree of improvement varies widely. Residual sleep- thus opening the airway by repositioning the lower jaw and pull-
iness may be due to several factors, including suboptimal treatment ing the tongue forward. These devices generally work better when
adherence, insufficient sleep time, other sleep disorders, or prior customized for patient use; maximal adaptation can take several
hypoxic-mediated damage in brain areas involved in alertness. Visceral weeks. Efficacy studies show that these devices can reduce the AHI
adipose tissue, whose amounts are increased in patients with OSAHS, by ≥50% in two-thirds of individuals, although these data are based
releases somnogenic cytokines that may contribute to sleepiness. Thus, largely on patients with mild OSAHS. Some patients with moderate
even after treatment, it is important to assess and monitor patients or severe OSAHS respond to oral appliances as well, although no
for residual sleepiness and to evaluate the necessity of optimizing consistent predictors of success have been identified in these groups
treatment adherence, improving sleep patterns, and identifying other and thus follow-up PSG testing is recommended. Side effects of oral
disorders contributing to sleepiness. Careful and supervised use of appliances include temporomandibular joint pain and tooth move-
alerting agents may be administered as adjunctive treatment in patients ment. Oral appliances are most often used for treating patients with
in whom sleepiness does not respond to CPAP alone. mild OSAHS or patients who do not tolerate CPAP. However, since
QUALITY OF LIFE AND MOOD Reductions in health-related quality of adherence to the use of oral appliances sometimes exceeds CPAP
life are common in patients with OSAHS, with the largest decrements adherence, these devices are under investigation for treatment of
on the physical and vitality subscales. Numerous studies, including a more severe disease.
large-scale trial of minimally symptomatic patients, have shown that Upper airway surgery for OSAHS is less effective than CPAP and
treatment with CPAP can improve these patient-reported outcomes. is mostly reserved for the treatment of patients who snore, have
Depression, in particular symptoms of somatic depression (irritability, mild OSAHS, or cannot tolerate CPAP. Uvulopalatopharyngoplasty
fatigue, lack of energy), is commonly reported in OSAHS and improves (removal of the uvula and the margin of the soft palate) is the most
with CPAP. common surgery and, although results vary greatly, is generally
less successful than treatment with oral appliances. Upper airway
surgery is less effective in severe OSAHS and in obese patients.
TREATMENT Success rates may be higher for multilevel surgery (involving more
than one site/structure) performed by an experienced surgeon, but
Obstructive Sleep Apnea/Hypopnea Syndrome the selection of patients is an important factor and relies on careful
targeting of culprit areas for surgical resection. Bariatric surgery is
A comprehensive approach to the management of OSAHS is needed
an option for obese patients with OSAHS and can improve not only
to reduce risk factors and comorbidities. The clinician should seek to
OSAHS but also other obesity-associated health conditions. Other
identify and address lifestyle and behavioral factors as well as comor-
procedures that can decrease snoring but have minimal effects on
bidities that may be exacerbating OSAHS. As appropriate, treatment
OSAHS include injection of the soft palate (resulting in stiffening),
should aim to reduce weight; optimize sleep duration (7–9 h);
radiofrequency ablation, laser-assisted uvulopalatoplasty, and pala-
regulate sleep schedules (with similar bedtimes and wake times
tal implants.
across the week); encourage the patient to avoid sleeping in the
Upper airway neuro-stimulation is a recently tested alternative
supine position; treat nasal allergies; increase physical activity; elim-
treatment for OSAHS. Unilateral stimulation of the hypoglossal
inate alcohol ingestion (which impairs pharyngeal muscle activity)
nerve through a surgically implanted device was shown to signifi-
within 3 h of bedtime; and minimize use of sedating medications.
cantly decrease the AHI and improve a number of patient-reported
Patients should be counseled to avoid drowsy driving.
outcomes, such as sleepiness and quality of life, for a duration of at
CPAP is the standard medical therapy with the highest level
least 18 months after treatment. Initial studies enrolled patients with
of evidence for efficacy. Delivered through a nasal or nasal-oral
a BMI ≤32 kg/m2, moderate OSAHS, absence of complete concen-
mask, CPAP works as a mechanical splint to hold the airway
tric pharyngeal collapse (considered to decrease surgical efficacy)
open, thus maintaining airway patency during sleep. An overnight
and were unable to be treated successfully with CPAP. Additional
CPAP titration study, performed either in a laboratory or with a
research is underway to further evaluate longer-term effectiveness
home “auto-titrating” device, is required to determine the optimal
and potential utility of this treatment in other patient groups.
pressure setting that reduces the number of apneas/hypopneas
Supplemental oxygen can improve oxygen saturation, but there
during sleep, improves gas exchange, and reduces arousals. Rates of
is little evidence that it improves OSAHS symptoms or the AHI in
adherence to CPAP treatment are highly variable (average, 50–80%)
unselected patients.
and may be improved with support by a skilled health care team
who can address side effects, help the patient “problem solve,” and CENTRAL SLEEP APNEA
provide motivational education (Table 291-3). Despite the limita- CSA, which is less common than OSAHS, may occur in isolation
tions of CPAP, controlled studies have demonstrated its beneficial or, more often, in combination with obstructive events in the form
effect on blood pressure, alertness, mood, quality of life, and insulin of “mixed” apneas. CSA is often caused by an increased sensitivity
sensitivity. Uncontrolled studies also indicate a favorable effect on to pCO2, which leads to an unstable breathing pattern that manifests

2018 as hyperventilation alternating with apnea. A prolonged circulation improve as a result of the procedure. Survival rates after transplanta-
delay between the pulmonary capillaries and carotid chemore- tion can be compared with predictive indices for the patient’s disease,
ceptors is also a contributing cause; thus individuals with conges- but each patient’s individual clinical circumstances must be incorpo-
tive heart failure are at risk for CSA. With prolonged circulation rated into the assessment. Moreover, quality of life is a primary motive
delay, there is a crescendo-decrescendo breathing pattern known as for transplantation for many patients, and the prospect of improved
Cheyne-Stokes respiration (Fig. 291–2B). Other risk factors for CSA quality-adjusted survival is often attractive even if the survival advan-
include opioid medications (which appear to have a dose-dependent tage itself is questionable.
effect on CSA) and hypoxia (e.g., breathing at high altitude). In some Disease-specific consensus guidelines for referring patients for
individuals, CPAP—particularly at high pressures—seems to induce evaluation and for listing them for transplantation are summarized in
central apnea; this condition is referred to as complex sleep apnea. Table 292-1. Candidates for lung transplantation are also thoroughly
Rarely, CSA may be caused by blunted chemosensitivity due to con- screened for comorbidities that might affect the outcome adversely.
genital disorders (congenital central hypoventilation syndrome) or Conditions such as systemic hypertension, diabetes mellitus, gas-
PART 7
acquired factors. CSA is an independent risk factor for the develop- troesophageal reflux, and osteoporosis are not unusual, but if uncom-
ment of both heart failure and atrial fibrillation, possibly related to plicated and adequately managed, they do not disqualify patients from
elevations in sympathetic nervous system activity that accompany transplantation. The upper age limit is ~70–75 years at most centers,
this disorder. Patients with CSA may report symptoms of frequent and the proportion of older recipients has been increasing. In 2014, 29%
awakenings as well as daytime fatigue. Treatment of CSA is difficult of adult recipients in the United States were ≥65 years old.
and depends on the underlying cause. Limited data suggest that Standard exclusions include HIV infection, chronic active hepatitis
supplemental oxygen can reduce the frequency of central apneas, B or C infection, uncontrolled or untreatable pulmonary or extra-
particularly in patients with hypoxemia. Cheyne-Stokes respiration pulmonary infection, uncured malignancy, active cigarette smoking,
is treated by optimizing therapy for heart failure. At this time, there drug or alcohol dependency, irreversible physical deconditioning,
is no good evidence that CPAP, including adaptive servoventilation (a chronic nonadherence with medical care, significant disease of another
form of ventilatory support that attempts to regularize the breathing vital organ (e.g., heart, liver, or kidney), and psychiatric or psychosocial
pattern) improves health outcomes in patients with Cheyne-Stokes situations that could substantially interfere with post-transplantation
respiration without OSAHS. management. Other problems that may compromise the outcome
constitute relative contraindications. Some typical issues are ventilator-
■■FURTHER READING dependent respiratory failure, extracorporeal life support, obesity,
Berry R, Wagner M: Sleep Medicine Pearls, 3rd ed. Philadelphia, coronary artery disease, and previous thoracic surgical procedures.
Elsevier, 2015. Chronic infection with antibiotic-resistant Pseudomonas species, Burk-
Javaheri S et al: Sleep apnea: Types, mechanisms, and clinical cardio- holderia species, Aspergillus species, or nontuberculous mycobacteria is a
vascular consequences. J Am Coll Cardiol 769:841, 2017. unique concern in some patients with CF. The potential impact of these
Kapur VK et al: Clinical Practice Guideline for Diagnostic Testing for and other factors has to be judged in clinical context to determine an
Adult Obstructive Sleep Apnea: An American Academy of Sleep individual candidate’s suitability for transplantation.
Medicine Clinical Practice Guideline. J Clin Sleep Med 13:479, 2017.
McEvoy RD et al: CPAP for prevention of cardiovascular events in ■■WAITING LIST AND ORGAN ALLOCATION
obstructive sleep apnea. N Engl J Med 375:919, 2016. Organ allocation policies are influenced by medical, ethical, geographi-
Strollo PJ Jr et al: Upper-airway stimulation for obstructive sleep cal, and political factors, with systems varying from country to country.
apnea. N Engl J Med 370:139, 2014. Regardless of the system, potential recipients are placed on a waiting
list and must be matched for blood group compatibility and, with some
latitude, for lung size with an acceptable donor. If the potential recip-
ient is allosensitized with antibodies to any human leukocyte antigen
(HLA), the donor also has to be HLA compatible.
292 Lung Transplantation

Elbert P. Trulock, III
Most lungs are procured from deceased donors after brain death,
but only ~20% of brain-death organ donors yield either one or two
lungs suitable for transplantation. Lungs from donors after circulatory
death have been utilized to a limited extent (~2% of lung donors in the
United States in 2014). Ex vivo lung perfusion is being used by some
centers to assess donor lungs that are marginal for implantation by
Lung transplantation is a therapeutic consideration for many patients
standard criteria; if the results of ex vivo testing are satisfactory, these
with nonmalignant end-stage lung disease, and it prolongs survival
lungs have been transplanted successfully.
and improves quality of life in appropriately selected recipients. Since
In the United States, a lung allocation score (LAS) system has been
1985 more than 51,000 adult lung transplants have been recorded
used to prioritize patients on the waiting list since 2005. For the pur-
worldwide, and annual volume has reached ~4000 transplants per year.
poses of the LAS, patients are divided into four groups by diagnosis:
■■INDICATIONS A—COPD and emphysema; B—IPAH and other forms of pulmonary
The indications for lung transplantation span the gamut of lung diseases, hypertension; C—cystic fibrosis and other forms of bronchiectasis; D—
and the distribution reflects both the prevalence and prognosis of the IPF and other interstitial diseases. The LAS is based on the patient’s
diseases and the applicable organ allocation policies. According to inter- risk of death during 1 year on the waiting list and the patient’s like-
national registry data, the most common indications in recent years have lihood of survival for 1 year after transplantation. It can range from
been idiopathic pulmonary fibrosis (IPF), ~30%; chronic obstructive pul- 0 to 100, and priority for transplantation is ranked from highest to
monary disease (COPD), ~27%; cystic fibrosis (CF), ~15%; α1-antitrypsin lowest scores. Both the lung disease and its severity affect a patient’s
deficiency emphysema, ~3%; and idiopathic pulmonary arterial hyper- LAS; parameters in the LAS must be updated biannually, but can be
tension (IPAH), ~2.5%. Other lung diseases have comprised the balance submitted for recalculation whenever the patient’s condition changes.
of primary indications, and retransplantation has accounted for ~3% of Patients in group D usually have the highest scores, and those in group
procedures. Since 2001, IPF has increased from ~15 to ~30%, and COPD A, the lowest.
has decreased from ~40 to ~27% among the indications. In recent years, the U.S. national waiting list typically has contained
~1500 patients with a median LAS of ~35–36. In 2014, 50% of the
■■REFERRAL AND RECIPIENT SELECTION patients on the waiting list were in group D, and the median waiting
Transplantation should be considered when other therapeutic options time to transplantation was 3.7 months. The overall death rate (deaths
have been exhausted and when the patient’s prognosis is expected to per 100 waitlist years) on the waiting list was ~10, but the rate varied

TABLE 292-1 Disease-Specific Guidelines for Referral and considerably by diagnostic group (e.g., A, ~4; B, ~11; C, ~12; D, ~18) 2019
Transplantation and by LAS (e.g., 35–39, ~10; 40–49, ~22; ≥50, ~125). Because the LAS
Chronic Obstructive Pulmonary Disease system prioritizes patients with the highest risk of death on the waiting
list, many patients are now critically ill at the time of transplantation. In
Referral for Evaluation
2014, 25% of recipients were hospitalized (15% in intensive care), and
Progressive despite medications, oxygen, and pulmonary rehabilitation
9% were being supported by mechanical ventilation, extracorporeal life
FEV1 <25% support or both at the time of transplantation.
Pao2 <60 mmHg or Paco2 >50 mmHg
BODE index 5–6 ■■TRANSPLANT PROCEDURE
Listing for Transplantation Bilateral transplantation is mandatory for CF and other forms of
BODE index ≥7 bronchiectasis because the risk of spillover infection from a remaining
CHAPTER 292 Lung Transplantation

FEV1 <15–20% native lung precludes single-lung transplantation. Heart-lung trans-
Moderate to severe pulmonary hypertension
plantation is obligatory for Eisenmenger syndrome with complex
anomalies that cannot be readily repaired in conjunction with lung
Three or more severe exacerbations in preceding year
transplantation and for concomitant end-stage lung and heart disease.
One severe exacerbation with acute hypercapnic respiratory failure
However, cardiac replacement is not necessary for cor pulmonale
Cystic Fibrosis/Bronchiectasis because right ventricular function will recover when pulmonary vas-
Referral for Evaluation cular afterload is normalized by lung transplantation.
FEV1 <30% or rapidly declining despite optimal therapy Either bilateral or single-lung transplantation is an option for other
Pulmonary hypertension (in absence of hypoxemic exacerbation) diseases unless there is a special consideration, but for all indications,
6-min walk distance <400 m bilateral transplantation is performed most often. In 2014, 68% of all
Clinical deterioration with increasing frequency of exacerbations, with transplants in the United States were bilateral (68% of transplants for
– An episode of acute respiratory failure requiring ventilatory support COPD; 54% for IPF).
Living donor lobar transplantation has played a limited role in adult
– Increasing antibiotic resistance and poor recovery from exacerbations
lung transplantation, but is rarely performed anymore; only three cases
– Worsening nutritional status despite adequate supplementation
were recorded in the U.S. registry from 2010 through 2015. When per-
– Refractory or recurrent pneumothorax formed, it usually has been reserved for teenagers or young adults with
– Life-threatening hemoptysis despite bronchial artery embolization CF who were unlikely to survive the wait for a deceased organ donor.
Listing for Transplantation
Chronic hypoxemic or hypercapnic respiratory failure ■■POSTTRANSPLANTATION MANAGEMENT
Pulmonary hypertension Immunosuppression Induction therapy is increasingly utilized,
Rapid decline in lung function and in 2014, ~65% of recipients in both the U.S. and international
Long-term noninvasive ventilator support registries received an induction agent. The interleukin-2 receptor
Frequent hospitalization antagonist basiliximab has been the most widely used drug (~50% of
WHO functional class IV recipients), but the antilymphocyte globulins and alemtuzumab have
Idiopathic Pulmonary Fibrosis been used, as well. A three-drug maintenance immunosuppressive
Referral for Evaluation regimen that includes a calcineurin inhibitor (cyclosporine or tacroli-
mus), a purine synthesis antagonist (azathioprine or a mycophenolic
Pathologic or radiographic evidence of UIP or NSIP regardless of lung function
acid precursor), and prednisone is traditional; the triad of tacrolimus,
FVC <80% or DLCO <40%
mycophenolate, and prednisone is the most commonly prescribed reg-
Dyspnea or functional limitation attributable to lung disease imen. Subsequently, other drugs such as sirolimus or everolimus may
Any oxygen requirement (rest or exercise) be substituted for various reasons. Prophylaxis for Pneumocystis jiroveci
Listing for Transplantation pneumonia is standard, and prophylaxis against cytomegalovirus
Decrement in FVC ≥10% or in DLCO >15% during 6 months of follow-up (CMV) infection and fungal infection is part of many protocols. The
Pulmonary hypertension dose of cyclosporine, tacrolimus, sirolimus, or everolimus is adjusted
Desaturation to SpO2 <88% during 6-min walk test by blood-level monitoring. All of these agents are metabolized by the
6-min walk test distance <250 m or decrement >50 m over 6 months hepatic cytochrome P450 system, and interactions with medications
Hospitalization for acute exacerbation that affect this pathway can significantly alter their clearance and blood
Idiopathic Pulmonary Arterial Hypertension
level.
Referral for Evaluation Spirometry and Bronchoscopy Routine management focuses
NYHA functional class III or IV during escalating therapy on monitoring of the allograft, regulating immunosuppressive therapy,
Use of parenteral therapy regardless of NYHA functional class and detecting problems or complications expeditiously. Regular con-
Rapidly progressive disease tact with a nurse coordinator, physician follow-up, chest radiography,
Listing for Transplantation blood tests, and spirometry are customary. Surveillance bronchoscopy
with bronchoalveolar lavage and transbronchial biopsies is employed
NYHA functional class III or IV despite combination therapy with a
prostanoid by some programs to screen for occult acute cellular rejection (ACR)
Cardiac index <2 L/min/m2 or right atrial pressure >15 mmHg
or infection, and bronchoscopy is the standard invasive procedure to
investigate problems with the allograft. If recovery is uncomplicated,
6-minute walk test distance <350 m
lung function rapidly improves and then stabilizes by 3–6 months after
Progressive right heart failure or significant pericardial effusion or
transplantation. Subsequently, the variation in spirometric measure-
hemoptysis
ments is small, and a sustained decline of ≥10–15% signals a potentially
Abbreviations: BODE—body-mass index (B), airflow obstruction (O), dyspnea (D), significant problem.
exercise capacity (E); FVC, forced vital capacity; FEV1, forced expiratory volume in
1 s; DLCO, diffusing capacity for carbon monoxide; HRCT, high resolution computed
tomography; ICU, intensive care unit; NSIP, nonspecific interstitial pneumonitis; ■■OUTCOMES
NYHA, New York Heart Association; Paco2 and Pao2, partial pressures of carbon
dioxide and oxygen, respectively, in arterial blood; SpO2, arterial oxygen saturation by Survival Major registries publish survival rates (Table 292-2) and
pulse oximetry; UIP, usual interstitial pneumonitis; WHO, World Health Organization other outcomes annually (www.ishlt.org; www.srtr.org). In the interna-
Source: Summarized from D. Weill et al: J Heart Lung Transplant 34:1, 2015. For tional registry, for the cohort from 1990 to 2013, median survival for
BODE index, BR Celli et al: N Engl J Med 350:1005, 2004. recipients with IPF was 4.7 years; IPAH, 5.7 years; COPD, 5.5 years; CF,

2020 TABLE 292-2 Recipient Survival, by Pretransplantation Diagnosis
SURVIVAL RATE, %
DIAGNOSIS; TRANSPLANT TYPE 3 MONTHS 1 YEAR 3 YEARS 5 YEARS 10 YEARS 15 YEARS
Chronic obstructive pulmonary diseasea
Bilateral 93 86 71 59 37 16
Single 92 84 66 51 24 6
α1-antitrypsin deficiency emphysema
Bilateral 89 81 69 61 40 24
Single 88 78 62 52 29 13
Cystic fibrosisa 93 88 76 63 48 27
PART 7
Idiopathic pulmonary fibrosisa

Bilateral 89 82 66 55 34 16
Single 89 79 58 45 21 7
Idiopathic pulmonary arterial hypertension
Bilateral 80 74 62 55 40 28
Single 71 62 52 41 24 15
Sarcoidosis 86 76 62 55 35 22
a
Survival cohorts: 2009–2015 for 3 months, 1 year and 3 years; 1999–2008 for 5 years and 10 years; 1990–1998 for 15 years. For other diagnoses, cohort is 1990–
2013 for all survival rates.
Source: Data from www.ishlt.org/registries/slides.asp?slides=heartLungRegistry. Accessed March 10, 2016.
8.6 years; and sarcoidosis, 6.1 years. Transplant procedure and recipient admission was $1,037,700. The total charge included the following
age also have a significant impact on outcome. Long-term survival has components: all care during 30 days before transplantation, $30,700;
been significantly better after bilateral transplantation than after uni- organ procurement, $129,700; hospital transplant admission, $566,900;
lateral transplantation for all of the major indications. For recipients physician fees during transplant admission, $59,100; all inpatient and
18–49 years of age, the median survival is ~7.2 years, but it decreases outpatient care for 180 days after discharge, $219,800; and all outpatient
to ~5.5 years for those 50–59 years old and to ~4.5 years for those drugs, including immunosuppressants, for 180 days after discharge,
≥60 years old. In the U.S. registry, survival rates have been lowest for $31,500. However, Medicare does not fully reimburse billed charges,
recipients who were in group D, were ≥65 years old, or had an LAS ≥60. and in the era from 2008 to 2012, the average Medicare cost from trans-
The causes of death depend on the time period after transplantation. plantation through the first posttransplant year was ~$240,000.
In the first 30 days, the major causes have been infection (~19%), graft
failure (~24%), cardiovascular events (~11%) and technical problems ■■COMPLICATIONS
(~11%), and for the remainder of the first year, the main contributors Lung transplantation can be complicated by a variety of problems
have been infection (~37%) and graft failure (~17%). After the first year, (Table 292-3). The average length of stay after bilateral transplantation
bronchiolitis and other forms of late graft failure have accounted for in the United States in 2014 was 29.5 days, and the rehospitalization
~40–45% of deaths and infection for ~16–20%. rate in the first year has been ~50%, higher than after any other solid
Risk factors for mortality have been analyzed in the international organ transplant except intestine.
and U.S. registries. In these analyses, factors associated with an Primary Graft Dysfunction Primary graft dysfunction (PGD),
increased risk of death in the first year after transplantation have an acute lung injury, is a manifestation of multiple potential insults to
included the following: recipients hospitalized at the time of transplan- the donor organ inherent in harvesting, preserving, and implanting it
tation; recipients supported by mechanical ventilation, extracorporeal in the recipient. The principal clinical features are diffuse pulmonary
membrane oxygenation, or dialysis at the time of transplantation; and infiltrates and hypoxemia within 72 h of transplantation; however,
recipients undergoing retransplantation; however, other factors have the presentation can be mimicked by pulmonary venous obstruction,
contributed, too. The mortality risk has also been higher at centers with hyperacute rejection, pulmonary edema, and pneumonia.
an annual volume below ~30 transplants/year. The severity is graded by a standardized system that is based on
Function Regardless of the disease, successful transplantation an edema pattern on chest radiograph and the PaO2/FiO2 ratio (>300,
impressively restores cardiopulmonary function. After bilateral trans- grade 1; 200–300, grade 2; <200, grade 3). Up to 50% of recipients may
plantation, pulmonary function tests are typically normal; after unilat- have some degree of PGD, and ~10–20% have grade 3 PGD. The treat-
eral transplantation, a mild abnormality characteristic of the remaining ment follows the conventional, supportive paradigm for acute lung
diseased lung is still apparent. Formal exercise testing usually dem- injury. Inhaled nitric oxide, inhaled epoprostenol, and extracorporeal
onstrates some impairment in maximum work rate and maximum membrane oxygenation have been used in severe cases. Retransplanta-
oxygen uptake, but few recipients report any limitation to activities of tion has also been performed, but when undertaken in the first 30 days,
daily living. the 1-year survival rate has been only ~30%. Most recipients with mild
PGD recover, but the mortality rate for severe PGD has been ~40–60%.
Quality of Life Both overall and health-related quality of life PGD is also associated with longer postoperative ventilator support,
measurements have improved after transplantation. With multidimen- longer intensive care unit and hospital stays, higher costs, and excess
sional profiles, improvements have extended across most domains and morbidity. Finally, severe (grade 3) PGD is a risk factor for the later
have been sustained longitudinally unless chronic rejection or some development of chronic lung allograft dysfunction (CLAD).
other complication develops.
Airway Complications The bronchial blood supply to the donor
Cost The cost of transplantation depends on the health care lung is disrupted during procurement. Bronchial revascularization
system and economic factors that vary from country to country. In during transplantation is technically feasible in some cases, but it is
the United States in 2014, lung transplantation was covered by private not widely practiced. Consequently, after implantation, the donor
insurance for 49% of recipients, Medicare for 36%, and other government- bronchus is dependent on retrograde bronchial blood flow from the
sponsored programs for 8.5%. In 2014, the average total of billed pulmonary circulation and is vulnerable to ischemia.
charges for a bilateral transplant for the period from 30 days before The spectrum of airway problems includes anastomotic necrosis
transplantation until 180 days after discharge from the transplant and dehiscence, occlusive granulation tissue, anastomotic or bronchial

TABLE 292-3 Major Potential Complications of Lung Transplantation complex (MHC), and its incidence is highest in the first 6–12 months 2021
and Immunosuppression after transplantation. In the years 2008–2013, ~18% of recipients in the
CATEGORY COMPLICATION U.S. registry had an episode of ACR during the first year.
Allograft Primary graft dysfunction; anastomotic dehiscence or
ACR can be clinically silent or can be manifested by nonspecific
stenosis; ischemic airway injury with bronchostenosis symptoms or signs that may include cough, low-grade fever, dyspnea,
or bronchomalacia; rejection; infection; recurrence of hypoxemia, inspiratory crackles, interstitial infiltrates, and declining
primary disease (sarcoidosis, lymphangioleiomyomatosis, lung function; however, clinical impressions are not reliable. The
giant cell interstitial pneumonitis, diffuse panbronchiolitis, diagnosis is confirmed by transbronchial biopsies showing the char-
pulmonary alveolar proteinosis, Langerhans cell acteristic lymphocytic infiltrates around arterioles or bronchioles,
histiocytosis)
and a standardized pathologic scheme is used to grade the biopsies
Thoracic Phrenic nerve injury/diaphragmatic dysfunction; recurrent (grades A0–4 and B0–4 for the arteriolar and bronchiolar components,
CHAPTER 292 Lung Transplantation

laryngeal nerve injury/vocal cord dysfunction; cervical
ganglia injury/Horner’s syndrome; pneumothorax; pleural respectively).
effusion; chylothorax; empyema Minimal ACR (grade A1) on a surveillance biopsy in a clinically
Cardiovascular Intraoperative or perioperative air embolism; stable recipient is not treated always, but higher grades (≥A2) gener-
postoperative pericarditis; perioperative myocardial injury/ ally are treated regardless of the clinical situation. Treatment usually
infarction; venous thromboembolism; supraventricular includes a short course of high-dose steroid therapy and adjustment of
dysrhythmias; systemic hypertension the maintenance immunosuppressive regimen. Most episodes respond
Gastrointestinal Esophagitis (especially Candida, herpes or to this approach; however, more intensive therapy is sometimes neces-
cytomegalovirus [CMV]); gastroparesis; gastroesophageal sary for persistent or recurrent episodes.
reflux; diarrhea (C. difficile; medications, especially
mycophenolate mofetil and sirolimus); colitis (C. difficile; Chronic Lung Allograft Dysfunction CLAD is the preferred
CMV) term when lung function never reaches expected values because of an
Hepatobiliary Hepatitis (especially CMV or medications); acalculous early complication or, more often, when there is a sustained decrement
cholecystitis in lung function below previously normal baseline measurements.
Renal Calcineurin inhibitor nephropathy; hemolytic-uremic In the latter situation, two main forms of CLAD are recognized—
syndrome (thrombotic microangiopathy) bronchiolitis obliterans syndrome (BOS) and restrictive allograft syn-
Neurologic Perioperative stroke; tremors; seizures; reversible drome (RAS), and both alloimmune and nonalloimmune fibropro-
posterior leukoencephalopathy; headaches liferative reactions can contribute to the pathogenesis. CLAD is the
Musculoskeletal Steroid myopathy; rhabdomyolysis (cyclosporine + principal impediment to better long-term survival rates, and it is the
HMG co-A reductase inhibitor treatment); osteoporosis;
source of substantial morbidity because of its impact on performance
avascular necrosis
status and quality of life.
Metabolic Obesity; diabetes mellitus; hyperlipidemia; idiopathic
hyperammonemia
The distinguishing features of BOS and RAS are contrasted in
Table 292-4. By definition, the decrement in lung function must persist
Hematologic Anemia; leukopenia; thrombocytopenia; thrombotic
microangiopathy for ≥3 weeks, and other causes of graft dysfunction must be excluded
by an appropriate evaluation. Bronchoscopy with bronchoalveolar
Oncologic Lymphoproliferative disease and lymphoma; skin cancers;
other malignancies lavage and transbronchial biopsies is usually performed to exclude
bronchostenosis, ACR, and infection. Transbronchial biopsies, how-
ever, are insensitive for detecting obliterative bronchiolitis in BOS and
are nonspecific in RAS, and pathologic confirmation is not required for
stenosis, and bronchomalacia. The incidence has been in the range of diagnosis.
7–18%, but the associated mortality rate has been low. These problems BOS is the classic form of chronic rejection, and the prevalence
usually can be managed bronchoscopically with techniques such as approaches 50% by 5 years after transplantation. The severity is cat-
simple endoscopic debridement, laser photoresection, balloon dilation, egorized by the decrement in FEV1 from the average of the two best
and bronchial stenting. posttransplant values (20–35%, stage 1; 35–50%, stage 2; >50%, stage
Lung Allograft Dysfunction The transplanted lung is suscepti- 3). Risk factors include PGD, ACR, humoral rejection and anti-HLA
ble to a variety of conditions that can compromise graft function. Some antibodies, viral infections (CMV pneumonia; community-acquired
of these, such as the various forms of rejection, are unique to transrespiratory viral infections), airway colonization by Pseudomonas aerug-
plantation, but others are not. Acute lung allograft dysfunction is most inosa or Aspergillus fumigatus, and gastroesophageal reflux (GER).
often caused by rejection or infection and may be completely reversible BOS usually is treated with augmented immunosuppression, but
after diagnosis and treatment. CLAD can be the result of residual dam- there is no consensus about therapy. Strategies include adjustments to
age from an episode of acute allograft dysfunction, or it can develop the maintenance drug regimen, the addition of azithromycin, and treat-
separately in response to alloimmune and non-alloimmune injuries to ment with antilymphocyte globulin, photopheresis, or total lymphoid
the graft. irradiation; antireflux surgery should be considered if GER is present.
Although therapy may stabilize lung function, the overall results of
Acute Cellular Rejection ACR is caused by T lymphocyte inter- treatment have been disappointing; median survival period after onset
actions with donor alloantigens, mainly in the major histocompatibility has been ~3–4 years. Retransplantation is a consideration if clinical
TABLE 292-4 Chronic Lung Allograft Dysfunction: Clinical Features of Bronchiolitis Obliterans Syndrome (BOS) and Restrictive Allograft
Syndrome (RAS)
SYNDROME PULMONARY FUNCTION HRCT PATTERN PATHOLOGY
BOS Obstructive Air trapping usually present Obliterative bronchiolitis
FEV1 <80% of baseline Minimal, if any, infiltrates ± bronchiectasis Transbronchial biopsies insensitive
RAS Restrictive Infiltrates usually present Parenchymal/pleural fibrosis
TLC <90% of baseline, or ± air trapping ± obliterative bronchiolitis
FVC and FEV1 <80% of baseline ± bronchiectasis
Abbreviations: BOS, bronchiolitis obliterans syndrome; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HRCT, high-resolution computed tomography;
TLC, total lung capacity.
Source: Modified from GM Verleden et al: J Heart Lung Transplant 33:127, 2014.

2022 circumstances and other comorbidities are not prohibitive, but survival monitoring and with widespread prophylactic and preemptive proto-
rates have been inferior to that with primary transplantation. cols using valganciclovir. However, CMV viremia, pneumonia, hepa-
RAS is less common than BOS, and occasionally the two forms titis, and gastroenteritis/colitis still occur occasionally, and treatment
coexist. Risk factors for RAS have not been delineated yet. Treatment with ganciclovir is generally effective unless resistance has developed.
usually includes a trial of steroid therapy and, in some cases, the same The most problematic fungal infections are caused by Aspergillus
strategies that are used for BOS. Prognosis is worse than BOS, with a species. The spectrum encompasses simple pulmonary colonization,
median survival ~1.5 years. tracheobronchitis, invasive pulmonary aspergillosis, and disseminated
aspergillosis, and the clinical scenario dictates treatment.
Humoral Rejection The role of antibody-mediated rejection is
still evolving. Hyperacute rejection is caused by preformed HLA anti- Other Complications Other potential complications are listed
bodies in the recipient, but it is minimized by pretransplantation anti- in Table 292-3. Many of them are related to side effects or toxicities of
body screening coupled with virtual or direct cross-matching with any the immunosuppressive drugs, and the prevalence of some of them
PART 7
potential donor. Donor-specific HLA antibodies develop after trans- is high (hypertension—39% and 61%; renal dysfunction—16% and
plantation in ~35–50% of recipients, and their presence has been asso- 45%; hyperlipidemia—24% and 47%; diabetes mellitus—13% and
ciated with an increased risk of both ACR and BOS and with poorer 34%; malignancy—4% and 22%, at 1 year and 5 years, respectively,
overall survival. Criteria for antibody-mediated rejection include graft in the U.S. registry). Management of these general medical problems
dysfunction, serologic detection of donor-specific antibodies, and a is guided by standard practices, but the complex milieu of transplan-
pathologic pattern of graft injury with evidence of antibody deposition; tation requires close collaboration and good communication among
however, few cases in lung transplantation fulfill all of these criteria. health care providers.
Nonetheless, episodes of acute lung allograft dysfunction occasion-
ally have been attributed directly to antibody-mediated rejection. If
treatment is indicated, potential therapies include plasmapheresis and ■■FURTHER READING
administration of intravenous immune globulin, rituximab, borte- Levine DJ et al: Antibody-mediated rejection of the lung: A consensus
zomib, and eculizumab. report of the International Society for Heart and Lung Transplanta-
tion. J Heart Lung Transplant 35:397, 2016.
Infection The lung allograft is especially susceptible to infection. In Meyer KC et al: An international ISHLT/ATS/ERS practice guideline:
addition to a blunted immune response from the immunosuppressive Diagnosis and management of bronchiolitis obliterans syndrome. Eur
drugs, other normal defenses are compromised: the cough reflex is Respir J 44:1479, 2014.
diminished, and mucociliary clearance is impaired in the transplanted Valapour M et al: OPTN/SRTR 2014 annual data report: Lung. Am J
lung. The spectrum of infections includes both opportunistic and non- Transplant 16:141, 2016.
opportunistic pathogens. Verleden GM: A new classification system for chronic lung allograft
Bacterial bronchitis or pneumonia can occur at any time, but it is dysfunction. J Heart Lung Transplant 33:127, 2014.
very common in the perioperative period. Later, bronchitis occurs Weil D et al: A consensus document for the selection of lung transplant
frequently in recipients with BOS, and Pseudomonas aeruginosa or candidates: 2014—an update from the Pulmonary Transplant Council
methicillin-resistant Staphylococcus aureus is often the culprit. of the International Society for Heart and Lung Transplantation.
Community-acquired respiratory viruses (influenza, parainfluenza, J Heart Lung Transplant 34:1, 2015.
respiratory syncytial virus, metapneumovirus and others) are the most Yusen RD et al: The Registry of the International Society for Heart and
common viral infections and are easily identified with viral multiplex Lung Transplantation: Thirty-second official adult lung and heart-
PCR testing of a nasopharyngeal swab or washing. CMV infection lung transplantation report—2015; focus theme: early graft failure.
has become less problematic with highly sensitive blood CMV PCR J Heart Lung Transplant 34:1264, 2015.

Critical Care Medicine PART 8
not clear. SOI scoring systems are important for defining populations
Section 1 Respiratory Critical Care of critically ill patients. Such systematic scoring allows effective com-
parison of groups of patients enrolled in clinical trials. In verifying a
purported benefit of therapy, investigators must be confident that dif-
293 with
Approach to the Patient ferent groups involved in a clinical trial have similar illness severities.
SOI scores are also useful in guiding hospital administrative policies,
Critical Illness directing the allocation of resources such as nursing and ancillary care
and assisting in assessments of quality of ICU care over time. Scoring
John P. Kress, Jesse B. Hall system validations are based on the premise that age, chronic medical
illnesses, and derangements from normal physiology are associated
with increased mortality rates. All existing SOI scoring systems are
derived from patients who have already been admitted to the ICU.
The care of critically ill patients requires a thorough understanding of
SOI scoring systems cannot be used to predict survival in individual
pathophysiology and centers initially on the resuscitation of patients
patients. No established scoring systems that purport to direct clini-
at the extremes of physiologic deterioration. This resuscitation is
cians’ decision-making regarding criteria for admission to an ICU are
often fast-paced and occurs early, without a detailed awareness of the
available. Thus the use of SOI scoring systems to direct therapy and
patient’s chronic medical problems. While physiologic stabilization
clinical decision-making cannot be recommended. Instead, these tools
is taking place, intensivists attempt to gather important background
should be used as a source of important data to complement clinical
medical information to supplement the real-time assessment of the
bedside decision-making.
patient’s current physiologic conditions. Numerous tools are available
The most commonly utilized scoring systems are the SOFA (Sequen-
to assist intensivists in the accurate assessment of pathophysiology and
tial Organ Failure Assessment), the APACHE (Acute Physiology and
management of incipient organ failure, offering a window of opportu-
Chronic Health Evaluation), and the SAPS (Simplified Acute Physiology
nity for diagnosing and treating underlying disease(s) in a stabilized
Score) systems.
patient. Indeed, the use of invasive interventions such as mechanical
ventilation and renal replacement therapy is commonplace in the ■■THE SOFA SCORING SYSTEM
intensive care unit (ICU). An appreciation of the risks and benefits The SOFA scoring system is composed of scores from six organ systems,
of such aggressive and often invasive interventions is vital to ensure graded from 0 to 4 according to the degree of dysfunction (Table 293-1).
an optimal outcome. Nonetheless, intensivists must recognize when The score accounts for clinical interventions; it can be measured repeat-
a patient’s chances for recovery are remote or nonexistent and must edly (i.e., each day), and rising scores correlate well with increasing mor-
counsel and comfort dying patients and their significant others. Critical tality. Patients with suspected infection can be predicted to have poor
care physicians often must redirect the goals of care from resuscitation outcomes typical of sepsis if they have at least two of the following clin-
and cure to comfort when the resolution of an underlying illness is not ical criteria: respiratory rate >22, altered mental status, or systolic blood
possible. pressure <100 mmHg. Recently, a new bedside clinical score using two or
more of the above clinical criteria has emerged and is termed quickSOFA
ASSESSMENT OF ILLNESS SEVERITY (qSOFA). qSOFA is intended to screen patients for ICU admission from
In the ICU, illnesses are frequently categorized by degree of severity. out-of-hospital, emergency department, and hospital ward settings.
Numerous severity-of-illness (SOI) scoring systems have been devel-
oped and validated over the past three decades. Although these scoring ■■THE APACHE II SCORING SYSTEM
systems have been validated as tools to assess populations of critically The APACHE II system is the most commonly used SOI scoring system
ill patients, their utility in predicting individual patient outcomes is in North America. Age, type of ICU admission (after elective surgery
TABLE 293-1 Calculation of SOFA Scorea

SCORE
SYSTEM 0 1 2 3 4
Respiration
Pao2/Fio2, mmHg (kPa) ≥400 (53.3) <400 (53.3) <300 (40) <200 (26.7) with <100 (13.3) with
respiratory support respiratory support
Coagulation
Platelets, × 103/μL >150 <150 <100 <50 <20
Liver
Bilirubin, mg/dL <1.2 (20) 1.2–1.9 (20–32) 2.0–5.9 (33–101) 6.0–11.9 (102–204) >12.0 (204)
(μmol/L)
Cardiovascular MAP >70 mmHg MAP <70 mmHg Dopamine < 5 or Dopamine 5.1–15 or Dopamine >15 or
dobutamine (any dose)b epinephrine <0.1 or epinephrine >0.1 or
norepinephrine <0.1b norepinephrine >0.1b
Central Nervous System
Glasgow Coma Scalec 15 13–14 10–12 6–9 <6
Renal
Creatinine, mg/dL <1.2 (110) 1.2–1.9 (110–170) 2.0–3.4 (171–299) 3.5–4.9 (300–440) >5.0 (440)
(μmol/L)
Urine output, mL/dL <500 <200
a
Adapted from JL Vincent, R Moreno, J Takala, et al: Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-
related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 22(7):707, 1996. bCatecholamine doses are given as μg/kg per min
for at least 1 h. c Glasgow Coma Scale scores range from 3 to 15; higher score indicates better neurological function.
Abbreviations: Fio2, fraction of inspired oxygen; MAP, mean arterial pressure; Pao2, partial pressure of oxygen.

2024 vs nonsurgical or after emergency surgery), chronic health problems, ■■INITIAL EVALUATION
and 12 physiologic variables (the worst values for each in the first 24 h Shock, a common condition necessitating ICU admission or occurring
after ICU admission) are used to derive a score. The predicted hospital in the course of critical care, is defined by the presence of multisystem
mortality rate is derived from a formula that takes into account the end-organ hypoperfusion. Clinical indicators include reduced mean
APACHE II score, the need for emergency surgery, and a weighted, arterial pressure (MAP), tachycardia, tachypnea, cool skin and extrem-
disease-specific diagnostic category (Table 293-2). The relationship ities, acute altered mental status, and oliguria. Hypotension is usually,
between APACHE II score and mortality risk is illustrated in Fig. 293-1. though not always, present. The end result of multiorgan hypoperfu-
Updated versions of the APACHE scoring system (APACHE III and sion is tissue hypoxia, often with accompanying lactic acidosis. Since
APACHE IV) have been published. the MAP is the product of cardiac output and systemic vascular resis-
tance (SVR), reductions in blood pressure can be caused by decreases in
cardiac output and/or SVR. Accordingly, once shock is contemplated,
■■THE SAPS SCORING SYSTEM
the initial evaluation of a hypotensive patient should include an early
The SAPS II score, used more frequently in Europe than in the United
bedside assessment of the adequacy of cardiac output (Fig. 293-2).
States, was derived in a manner similar to the APACHE score. This
Clinical evidence of diminished cardiac output includes a narrow pulse
score is not disease-specific but rather incorporates three underlying
pressure (systolic BP minus diastolic BP)—a marker that correlates
disease variables: AIDS, metastatic cancer, and hematologic malig-
with stroke volume—and cool extremities with delayed capillary refill.
nancy. SAPS 3, which utilizes a 1-h rather than a 24-h window for
Signs of increased cardiac output include a widened pulse pressure
measuring physiologic derangement scores, was developed in 2005.
(particularly with a reduced diastolic pressure), warm extremities with
PART 8
bounding pulses, and rapid capillary refill. If a hypotensive patient

SHOCK has clinical signs of increased cardiac output, it can be inferred that the
See also Chap. 296. reduced blood pressure is from decreased SVR.
Critical Care Medicine
TABLE 293-2 Calculation of Acute Physiology and Chronic Health Evaluation II (APACHE II) Scorea
Acute Physiology Score
SCORE 4 3 2 1 0 1 2 3 4
Rectal temperature (°C) ≥41 39.0–40.9 38.5–38.9 36.0–38.4 34.0–35.9 32.0–33.9 30.0–31.9 ≤29.9
Mean blood pressure (mmHg) ≥160 130–159 110–129 70–109 50–69 ≤49
Heart rate (beats/min) ≥180 140–179 110–139 70–109 55–69 40–54 ≤39
Respiratory rate (breaths/min) ≥50 35–49 25–34 12–24 10–11 6–9 ≤5
Arterial pH ≥7.70 7.60–7.69 7.50–7.59 7.33–7.49 7.25–7.32 7.15–7.24 <7.15
Oxygenation
If FIo2 >0.5, use (A – a) Do2 ≥500 350–499 200–349 <200
If FIo2 ≤ 0.5, use Pao2 >70 61–70 55–60 <55
Serum sodium (meq/L) ≥180 160–179 155–159 150–154 130–149 120–129 111–119 ≤110
Serum potassium (meq/L) ≥7.0 6.0–6.9 5.5–5.9 3.5–5.4 3.0–3.4 2.5–2.9 <2.5
Serum creatinine (mg/dL) ≥3.5 2.0–3.4 1.5–1.9 0.6–1.4 <0.6
Hematocrit (%) ≥60 50–59.9 46–49.9 30–45.9 20–29.9 <20
WBC count (103/mL) ≥40 20–39.9 15–19.9 3–14.9 1–2.9 <1
Glasgow Coma Scoreb,c
Eye Opening Verbal (Nonintubated) Verbal (Intubated) Motor Activity
4—Spontaneous 5—Oriented and talks 5—Seems able to talk 6—Verbal command
3—Verbal stimuli 4—Disoriented and talks 3—Questionable ability to talk 5—Localizes to pain
2—Painful stimuli 3—Inappropriate words 1—Generally unresponsive 4—Withdraws from pain
1—No response 2—Incomprehensible sounds 3—Decorticate
1—No response 2—Decerebrate
1—No response
Points Assigned to Age and Chronic Disease
Age, Years Score
<45 0
45–54 2
55–64 3
65–74 5
≥75 6
Chronic Health (History of Chronic Conditions)d Score
None 0
If patient is admitted after elective surgery 2
If patient is admitted after emergency surgery or for reason other than after elective 5
surgery
a
The APACHE II score is the sum of the acute physiology score (vital signs, oxygenation, laboratory values), the Glasgow coma score, age, and chronic health points.
The worst values during the first 24 h in the ICU should be used. bGlasgow coma score (GCS) = eye-opening score + verbal (intubated or nonintubated) score + motor
score. cFor GCS component of acute physiology score, subtract GCS from 15 to obtain points assigned. dHepatic: cirrhosis with portal hypertension or encephalopathy;
cardiovascular: class IV angina (at rest or with minimal self-care activities); pulmonary: chronic hypoxemia or hypercapnia, polycythemia, ventilator dependence; renal:
chronic peritoneal or hemodialysis; immune: immunocompromised host.
Abbreviations: (A – a) Do2, alveolar-arterial oxygen difference; FIo2, fraction of inspired oxygen; Pao2, partial pressure of oxygen; WBC, white blood cell count.

100 pressure as a function of spontaneous respiration is a better predictor 2025
of fluid responsiveness (Fig. 293-3). Patients with fluid-responsive (i.e.,
90 hypovolemic) shock also may manifest large changes in pulse pressure
as a function of respiration during mechanical ventilation (Fig. 293-4).
80
A hypotensive patient with increased intravascular volume and cardiac
70 dysfunction may have S3 and/or S4 gallops on examination, increased
JVP, extremity edema, and crackles on lung auscultation. The chest
Mortality rate, %
60 x-ray may show cardiomegaly, widening of the vascular pedicle, Kerley

B lines, and pulmonary edema. Chest pain and electrocardiographic
50 changes consistent with ischemia may be noted (Chap. 298).
In hypotensive patients with clinical evidence of increased cardiac
40
output, a search for causes of decreased SVR is appropriate. The most
30 common cause of high-cardiac-output hypotension is sepsis (Chap. 297).
Other causes include liver failure, severe pancreatitis, burns, trauma,
20 anaphylaxis, thyrotoxicosis, and peripheral arteriovenous shunts.
In summary, the most common categories of shock are hypovolemic,
10
CHAPTER 293 Approach to the Patient with Critical Illness

cardiogenic, and high-cardiac-output with decreased SVR (high-output
hypotension). Certainly more than one category can occur simultane-
0
ously (e.g., hypovolemic and septic shock).
0–4 10–14 20–24 30–34
5–9 15–19 25–29 35+ The initial assessment of a patient in shock should take only a few
minutes. It is important that aggressive resuscitation is instituted on
APACHE II Score the basis of the initial assessment, particularly since early resuscitation
FIGURE 293-1 APACHE II survival curve. Blue, nonoperative; green, postoperative. from septic and cardiogenic shock may improve survival (see below).
If the initial bedside assessment yields equivocal or confounding data,
more objective assessments such as ultrasound/echocardiography may
In hypotensive patients with signs of reduced cardiac output, an be useful. In spontaneously breathing patients, inferior vena cava col-
assessment of intravascular volume status is appropriate. A hypoten- lapse seen on ultrasound predicts a fluid responsive state. Increasingly,
sive patient with decreased intravascular volume status may have a ultrasound of the thorax and abdomen is used by intensivists as an
history suggesting hemorrhage or other volume losses (e.g., vomiting, extension of the physical examination to assess rapidly imputed filling
diarrhea, polyuria). Although evidence of a reduced jugular venous volumes, adequacy of cardiac performance, and for indices of other
pressure (JVP) is often sought, static measures of right atrial pressure specific conditions (e.g., pericardial tamponade, pulmonary embolus,
do not predict fluid responsiveness reliably; the change in right atrial pulmonary edema, pneumothorax). The goal of aggressive resuscita-
tion is to reestablish adequate tissue perfusion and thus to prevent or
minimize end-organ injury.
APPROACH TO PATIENT IN SHOCK ■■MECHANICAL VENTILATORY SUPPORT

(See also Chap. 295) During the initial resuscitation of patients in
SHOCK shock, principles of advanced cardiac life support should be followed.
As such patients may be obtunded and unable to protect the airway,
Cold, clammy Warm, bounding an early assessment of the airway is mandatory. Early intubation and
extremities extremities mechanical ventilation often are required. Reasons for the institution
of endotracheal intubation and mechanical ventilation include acute
hypoxemic respiratory failure and ventilatory failure, which frequently
Low cardiac output High cardiac output accompany shock. Acute hypoxemic respiratory failure may occur in
patients with cardiogenic shock and pulmonary edema (Chap. 298)
May as well as in those who are in septic shock with pneumonia or acute
JVP, crackles JVP, orthostasis Septic shock,
convert
liver failure
to respiratory distress syndrome (ARDS) (Chaps. 294 and 297). Ventila-
tory failure often occurs as a consequence of an increased load on the
Heart is “full” respiratory system in the form of acute metabolic (often lactic) acidosis
(cardiogenic shock) Antibiotics, aggressive
resuscitation or decreased lung compliance due to pulmonary edema. Inadequate
perfusion to respiratory muscles in the setting of shock may be another
Evaluate for myocardial Heart is “empty” reason for early intubation and mechanical ventilation. Normally, the
ischemia (hypovolemic shock) respiratory muscles receive a very small percentage of the cardiac out-
put. However, in patients who are in shock with respiratory distress,
Consider echocardiogram, Intravenous fluids
the percentage of cardiac output dedicated to respiratory muscles may
invasive vascular monitoring increase by tenfold or more. Lactic acid production from inefficient
respiratory muscle activity presents an additional ventilatory load.
No improvement Mechanical ventilation may relieve the work of breathing and allow
Inotropes, afterload
reduction redistribution of a limited cardiac output to other vital organs. Patients
demonstrate respiratory distress by an inability to speak full sentences,
What does not fit?
accessory use of respiratory muscles, paradoxical abdominal muscle
activity, extreme tachypnea (>40 breaths/min), and decreasing respi-
Adrenal crisis, right heart syndrome, ratory rate despite an increasing drive to breathe due to exhaustion.
pericardial disease When patients with shock are treated with mechanical ventilation,
a major goal is for the ventilator to assume all or the majority of the
Consider echocardiogram, work of breathing, facilitating a state of minimal respiratory muscle
invasive vascular monitoring work. With the institution of mechanical ventilation for shock, further
declines in MAP are frequently seen. The reasons include impeded
FIGURE 293-2 Approach to the patient in shock. JVP, jugular venous pressure. venous return from positive-pressure ventilation, reduced endogenous

2026 Spontaneous inspiration multicenter, randomized, prospective
trial comparing traditional ventilator
strategies for ARDS (large tidal volume:
Pressure
12 mL/kg of ideal body weight) with

a low tidal volume (6 mL/kg of ideal
body weight). This study showed a
dramatic reduction in mortality rate
Time in the low-tidal-volume group from
that in the high-tidal-volume group
FIGURE 293-3 Right atrial pressure change during spontaneous respiration in a patient with shock whose cardiac
output will increase in response to intravenous fluid administration. The right atrial pressure decreases from 7 mmHg
(31 versus 39.8%). Other studies have
to 4 mmHg. The horizontal bar marks the time of spontaneous inspiration. shown that large tidal volumes may
lead to ARDS in patients who initially
do not have this problem. Neuromus-
catecholamine secretion once the stress associated with respiratory fail- cular blockade and prone positioning have been shown to
ure abates, and the actions of drugs used to facilitate endotracheal intu- improve survival in those with severe ARDS. In addition, a “fluid-
bation (e.g., propofol, opiates). Patients with right heart dysfunction or conservative” management strategy (maintaining a low central venous
preexiting pulmonary hypertension may also have diminished cardiac pressure [CVP] or pulmonary capillary wedge pressure [PCWP]) is
output related to the increases in right ventricular afterload resulting associated with fewer days of mechanical ventilation than a “fluid-
PART 8
from positive pressure ventilation. Accordingly, hypotension should liberal” strategy (maintaining a relatively high CVP or PCWP) in
be anticipated during and following endotracheal intubation. Because ARDS. There is growing interest in avoiding intubation in patients
many of these patients may be fluid responsive, IV volume adminis- with ARDS by the use of a variety of devices, such as masks, high
tration should be considered. Figure 293-2 summarizes the diagnosis flow oxygen delivery systems, and helmets for respiratory support;
and treatment of different types of shock. For further discussion of however, this is tempered by concern that higher tidal volumes during
individual forms of shock, see Chaps. 296, 297, and 298. spontaneous breathing with these devices could result in progression
of preexisting lung injury.
RESPIRATORY FAILURE
Respiratory failure is one of the most common reasons for ICU admis- ■■TYPE II RESPIRATORY FAILURE
sion. In some ICUs, ≥75% of patients require mechanical ventilation This type of respiratory failure is a consequence of alveolar hypoven-
during their stay. Respiratory failure can be categorized mechanisti- tilation and results from the inability to eliminate carbon dioxide
cally on the basis of pathophysiologic derangements in respiratory effectively. Mechanisms are categorized by impaired central nervous
function. system (CNS) drive to breathe, impaired strength with failure of neu-
romuscular function in the respiratory system, and increased load(s) on
■■TYPE I: ACUTE HYPOXEMIC RESPIRATORY FAILURE the respiratory system. Reasons for diminished CNS drive to breathe
This type of respiratory failure occurs with alveolar flooding and sub- include drug overdose, brainstem injury, sleep-disordered breathing,
sequent intrapulmonary shunt physiology. Alveolar flooding may be a and severe hypothyroidism. Reduced strength can be due to impaired
consequence of pulmonary edema, lung injury, pneumonia, or alveolar neuromuscular transmission (e.g., myasthenia gravis, Guillain-Barré
hemorrhage. Pulmonary edema can be further categorized as occurring syndrome, amyotrophic lateral sclerosis) or respiratory muscle weak-
due to elevated pulmonary microvascular pressures, as seen in heart ness (e.g., myopathy, electrolyte derangements, fatigue).
failure and intravascular volume overload or ARDS (“low-pressure The overall load on the respiratory system can be subclassified into
pulmonary edema,” Chap. 294). This syndrome is defined by acute resistive loads (e.g., bronchospasm), loads due to reduced lung compli-
onset (≤1 week) of bilateral opacities on chest imaging that are not fully ance (e.g., alveolar edema, atelectasis, intrinsic positive end-expiratory
explained by cardiac failure or fluid overload and of shunt physiology pressure [auto-PEEP]—see below), loads due to reduced chest wall
requiring positive end-expiratory pressure (PEEP). Type I respiratory compliance (e.g., pneumothorax, pleural effusion, abdominal disten-
failure occurs in clinical settings such as sepsis, gastric aspiration, tion), and loads due to increased minute ventilation requirements (e.g.,
pneumonia, near-drowning, multiple blood transfusions, and pancre- pulmonary embolus with increased dead-space fraction, sepsis).
atitis. The mortality rate among patients with ARDS was traditionally The mainstays of therapy for type II respiratory failure are directed
very high (50–70%), although changes in patient care have led to at reversing the underlying cause(s) of ventilatory failure. Noninva-
mortality rates closer to 30% (see below). sive positive-pressure ventilation with a tight-fitting facial or nasal
It is well established that mechanical ventilation of patients with mask, with avoidance of endotracheal intubation, often stabilizes these
ARDS may propagate lung injury. As seen in Fig. 293-5, the pressure- patients. This approach has been shown to be beneficial in treating
volume relationship of the lung in ARDS is not linear. Alveoli may patients with exacerbations of chronic obstructive pulmonary disease;
collapse at very low lung volumes. Animal studies have suggested it has been tested less extensively in other kinds of respiratory failure
that stretching and overdistention of injured alveoli during mechan- but may be attempted nonetheless in the absence of contraindications
ical ventilation can further injure the lung. Concern over this alve- (hemodynamic instability, inability to protect the airway, respiratory
olar overdistention, termed ventilator-induced “volutrauma,” led to a arrest).
■■TYPE III RESPIRATORY

FAILURE
90
Pressure (mmHg)
This form of respiratory failure results

from lung atelectasis. Because atelectasis
60 occurs so commonly in the perioperative
period, this form is also called periopera-
30 tive respiratory failure. After general anes-
thesia, decreases in functional residual
0 capacity lead to collapse of dependent
Time lung units. Such atelectasis can be treated
FIGURE 293-4 Pulse pressure change during mechanical ventilation in a patient with shock whose cardiac by frequent changes in position, chest
output will increase in response to intravenous fluid administration. The pulse pressure (systolic minus diastolic physiotherapy, upright positioning, and
blood pressure) changes during mechanical ventilation in a patient with septic shock. control of incisional and/or abdominal

in patients in whom extubation fails may be associated with worse 2027
Alveoli
outcomes than are obtained with immediate reintubation.
Mechanically ventilated patients frequently require sedatives and
analgesics. Opiates are the mainstay of therapy for analgesia in
D mechanically ventilated patients. After adequate pain control has
been ensured, additional indications for sedation include anxiolysis;
500 treatment of subjective dyspnea; reduction of autonomic hyperactivity,
C Upper deflection
point which may precipitate myocardial ischemia; and reduction of total O2
Volume, mL
consumption (Vo2). Non-benzodiazepine sedatives are preferred since

benzodiazepines are associated with worse patient outcomes.
250 The neuromuscular blocking agent cisatracurium is occasionally
B used to facilitate mechanical ventilation in patients with profound
ventilator dyssynchrony despite optimal sedation, particularly in the
Lower inflection
A point setting of severe ARDS. Use of these agents may result in prolonged
weakness—a myopathy known as the postparalytic syndrome. For this
0 15 30 reason, neuromuscular blocking agents typically are used as a last

Pressure, cmH2O resort when aggressive sedation fails to achieve patient-ventilator
synchrony. Because neuromuscular blocking agents result in phar-
FIGURE 293-5 Pressure-volume relationship in the lungs of a patient with acute macologic paralysis without altering mental status, sedative-induced
respiratory distress syndrome (ARDS). At the lower inflection point, collapsed amnesia is mandatory when these agents are administered.
alveoli begin to open and lung compliance changes. At the upper deflection point,
alveoli become overdistended. The shape and size of alveoli are illustrated at the
Amnesia can be achieved reliably with propofol and benzodi-
top of the figure. azepines such as lorazepam and midazolam. Outside the setting of
pharmacologic paralysis, few data support the idea that amnesia is
mandatory in all patients who require intubation and mechanical ven-
pain. Noninvasive positive-pressure ventilation may also be used to tilation. Since many of these critical patients have impaired hepatic and
reverse regional atelectasis. renal function, sedatives and opiates may accumulate when given for
prolonged periods. A nursing protocol–driven approach to sedation of
■■TYPE IV RESPIRATORY FAILURE mechanically ventilated patients or daily interruption of sedative infu-
This form results from hypoperfusion of respiratory muscles in sions paired with daily spontaneous breathing trials has been shown to
patients in shock. Normally, respiratory muscles consume <5% of total prevent excessive drug accumulation and shorten the duration of both
cardiac output and oxygen delivery. Patients in shock often experience mechanical ventilation and ICU stay.
respiratory distress due to pulmonary edema (e.g., in cardiogenic
shock), lactic acidosis, and anemia. In this setting, up to 40% of cardiac
output may be distributed to the respiratory muscles. Intubation and
MULTIORGAN SYSTEM FAILURE
Multiorgan system failure, which is commonly associated with crit-
mechanical ventilation can allow redistribution of the cardiac output
ical illness, is defined by the simultaneous presence of physiologic
away from the respiratory muscles and back to vital organs while the
dysfunction and/or failure of two or more organs. Typically, this syn-
shock is treated.
drome occurs in the setting of severe sepsis, shock of any kind, severe
CARE OF THE MECHANICALLY VENTILATED inflammatory conditions such as pancreatitis, and trauma. The fact that
multiorgan system failure occurs commonly in the ICU is a testament
PATIENT to our current ability to stabilize and support single-organ failure. The
(See also Chap. 295) Whereas a thorough understanding of the patho-
ability to support single-organ failure aggressively (e.g., by mechanical
physiology of respiratory failure is essential for optimal patient care,
ventilation or by renal replacement therapy) has reduced rates of early
recognition of a patient’s readiness to be liberated from mechanical
mortality in critical illness. As a result, it is uncommon for critically
ventilation is likewise important. Several studies have shown that daily
ill patients to die in the initial stages of resuscitation. Instead, many
spontaneous breathing trials can identify patients who are ready for
patients succumb to critical illness later in the ICU stay, after the initial
extubation. Accordingly, all intubated, mechanically ventilated patients
presenting problem has been stabilized.
should undergo daily screening of respiratory function. If oxygenation
Although there is debate regarding specific definitions of organ fail-
is stable (i.e., Pao2/FIo2 [partial pressure of oxygen/fraction of inspired
ure, several general principles governing the syndrome of multiorgan
oxygen] >200 and PEEP ≤5 cmH2O), cough and airway reflexes are
system failure apply. First, organ failure, no matter how it is defined,
intact, and no vasopressor agents or sedatives are being administered,
must persist beyond 24 h. Second, mortality risk increases with the
the patient has passed the screening test and should undergo a spon-
accrual of failing organs. Third, the prognosis worsens with increased
taneous breathing trial. This trial consists of a period of breathing
duration of organ failure. These observations remain true across vari-
through the endotracheal tube without ventilator support (continuous
ous critical care settings (e.g., medical versus surgical).
positive airway pressure [CPAP] of 5 cmH2O with or without low level
pressure support [e.g., 5 cmH2O] and an open T-piece breathing system
have all been validated) for 30–120 min. The spontaneous breathing MONITORING IN THE ICU
trial is declared a failure and stopped if any of the following occur: Because respiratory failure and circulatory failure are common in criti-
(1) respiratory rate >35/min for >5 min, (2) O2 saturation <90%, (3) heart cally ill patients, monitoring of the respiratory and cardiovascular sys-
rate >140/min or a 20% increase or decrease from baseline, (4) systolic tems is undertaken frequently. Evaluation of respiratory gas exchange
blood pressure <90 mmHg or >180 mmHg, or (5) increased anxiety is routine in critical illness. The “gold standard” remains arterial blood-
or diaphoresis. If, at the end of the spontaneous breathing trial, none gas analysis, in which pH, Pao2, partial pressure of carbon dioxide
of the above events has occurred and the ratio of the respiratory rate (Pco2), and O2 saturation are measured directly. With arterial blood-gas
and tidal volume in liters (f/VT) is <105, the patient can be extubated. analysis, the two main functions of the lung—oxygenation of arterial
Such protocol-driven approaches to patient care can have an important blood and elimination of CO2—can be assessed directly. In fact, the
impact on the duration of mechanical ventilation and ICU stay. In spite blood pH, which has a profound effect on the drive to breathe, can be
of such a careful approach to liberation from mechanical ventilation, assessed only by such sampling. Although sampling of arterial blood
up to 10% of patients develop respiratory distress after extubation is generally safe, it may be painful and cannot provide continuous
and may require resumption of mechanical ventilation. Many of these information. In light of these limitations, noninvasive monitoring of
patients will require reintubation. The use of noninvasive ventilation respiratory function is often employed.

2028 ■■PULSE OXIMETRY cmH2O Pressure–Time
The most commonly utilized noninvasive technique for monitoring 90
respiratory function, pulse oximetry takes advantage of differences
in the absorptive properties of oxygenated and deoxygenated hemo-
globin. At wavelengths of 660 nm, oxyhemoglobin reflects light more
effectively than does deoxyhemoglobin, whereas the reverse is true
in the infrared spectrum (940 nm). A pulse oximeter passes both
wavelengths of light through a perfused digit such as a finger, and
0 4
the relative intensity of light transmission at these two wavelengths
is recorded. From this information, the relative percentage of oxyhe- L/s Flow–Time
moglobin is derived. Since arterial pulsations produce phasic changes 1.2
in the intensity of transmitted light, the pulse oximeter is designed to
detect only light of alternating intensity. This feature allows distinction
of arterial and venous blood O2 saturations.
0 4
■■RESPIRATORY SYSTEM MECHANICS
Respiratory system mechanics can be measured in patients during
mechanical ventilation (Chap. 295). When volume-controlled modes of
PART 8
mechanical ventilation are used, accompanying airway pressures can –1.2

easily be measured as long as the patient is passive. The peak airway FIGURE 293-6 Increased airway resistance with auto-PEEP. The top waveform
pressure is determined by two variables: airway resistance and respira- (airway pressure vs. time) shows a large difference between the peak airway
tory system compliance. At the end of inspiration, inspiratory flow can pressure (80 cmH2O) and the plateau airway pressure (20 cmH2O). The bottom
be stopped transiently. This end-inspiratory pause (plateau pressure) is waveform (flow vs. time) demonstrates airflow throughout expiration (reflected by
a static measurement, affected only by respiratory system compliance the flow tracing on the negative portion of the abscissa) that persists up to the
next inspiratory effort.
and not by airway resistance. Therefore, during volume-controlled
ventilation, the difference between the peak (airway resistance +
respiratory system compliance) and plateau (respiratory system com- of O2 in mixed venous blood (C–vo2) is 15.76 mL/dL since the mixed
pliance only) airway pressures provides a quantitative assessment of venous blood is 75% saturated. Therefore, the normal tissue extraction
airway resistance. Accordingly, during volume-controlled ventilation, ratio for O2 is Cao2 – C–vo2/Cao2 ([21.16 – 15.76]/21.16) or ~25%. A
patients with increases in airway resistance typically have increased pulmonary artery catheter allows measurements of O2 delivery and the
peak airway pressures as well as abnormally high gradients between O2 extraction ratio.
peak and plateau airway pressures (typically >15 cmH2O) at a constant Information on the venous O2 saturation allows assessment of global
inspiratory flow rate of 1 L/sec. The compliance of the respiratory sys- tissue perfusion. A reduced venous O2 saturation may be caused by
tem is defined by the change in volume of the respiratory system per inadequate cardiac output, reduced hemoglobin concentration, and/or
unit change in pressure. reduced arterial O2 saturation. An abnormally high Vo2 may also lead
The respiratory system can be divided into two components: the to a reduced venous O2 saturation if O2 delivery is not concomitantly
lungs and the chest wall. Normally, respiratory system compliance increased. Abnormally increased Vo2 in peripheral tissues may be caused
is ~100 mL/cmH2O. Pathophysiologic processes such as pleural effu- by problems such as fever, agitation, shivering, and thyrotoxicosis.
sions, pneumothorax, and increased abdominal girth all reduce chest The pulmonary artery catheter originally was designed as a tool
wall compliance. Lung compliance may be reduced by pneumonia, to guide therapy for acute myocardial infarction but has been used in
pulmonary edema, interstitial lung disease, or auto-PEEP. Accordingly, the ICU for evaluation and treatment of a variety of other conditions,
patients with abnormalities in compliance of the respiratory system such as ARDS, septic shock, congestive heart failure, and acute renal
(lungs and/or chest wall) typically have elevated peak and plateau failure. This device has never been validated as a tool associated with
airway pressures but a normal gradient between these two pressures. reduction in morbidity and mortality rates. Indeed, despite numerous
Auto-PEEP occurs when there is insufficient time for emptying of prospective studies, mortality or morbidity rate benefits associated
alveoli before the next inspiratory cycle. Since the alveoli have not with use of the pulmonary artery catheter have never been reported in
decompressed completely, alveolar pressure remains positive at the any setting. Accordingly, it appears that routine pulmonary artery cath-
end of exhalation (functional residual capacity). This phenomenon results eterization is not indicated as a means of monitoring and characterizing
most commonly from obstruction of distal airways in disease pro- circulatory status in most critically ill patients.
cesses such as asthma and COPD. Auto-PEEP with resulting alveolar Static measurements of circulatory parameters (e.g., CVP, PCWP) do
overdistention may result in diminished lung compliance, reflected by not provide reliable information on the circulatory status of critically
abnormally increased plateau airway pressures. Modern mechanical ill patients. In contrast, dynamic assessments measuring the impact
ventilators allow breath-to-breath display of pressure and flow, per- of breathing on the circulation are more reliable predictors of respon-
mitting detection of problems such as patient-ventilator dyssynchrony, siveness to IV fluid administration. A decrease in CVP of >1 mmHg
airflow obstruction, and auto-PEEP (Fig. 293-6). during inspiration in a spontaneously breathing patient may predict
an increase in cardiac output after IV fluid administration. Similarly,
■■CIRCULATORY STATUS a changing pulse pressure during mechanical ventilation of a passive
Oxygen delivery (Qo2) is a function of cardiac output and the content patient has been shown to predict an increase in cardiac output after IV
of O2 in the arterial blood (Cao2). The Cao2 is determined by the hemo- fluid administration, assuming the R-R interval is stable.
globin concentration, the arterial hemoglobin saturation, and dissolved
O2 not bound to hemoglobin. For normal adults: PREVENTION OF COMPLICATIONS OF
Qo2 = 50 dL/min × (1.39 × 15 g/dL [hemoglobin concentration] CRITICAL ILLNESS
× 1.0 [hemoglobin % saturation] + 0.0031 × 100 [Pao2])
= 50 dL/min (cardiac output) × 21.6 mL O2 per dL blood (Cao2)
■■SEPSIS IN THE CRITICAL CARE UNIT
(See also Chap. 297) Sepsis, is defined as life-threatening organ dysfunc-
= 1058 mL O2 per min
tion (i.e., an increase in Sequential Organ Failure Assessment [SOFA]
It is apparent that nearly all of the O2 delivered to tissues is bound of 2 points or more) caused by a dysregulated response to infection.
to hemoglobin and that the dissolved O2 (Pao2) contributes very little Poor outcomes can be anticipated in patients with 2 or more of the fol-
to O2 content in arterial blood or to O2 delivery. Normally, the content lowing: respiratory rate >22 per min, altered mentation, systolic blood

pressure <100 mmHg. Sepsis is a leading cause of death in noncoronary ■■ICU-ACQUIRED WEAKNESS 2029
ICUs in the United States, with case rates expected to increase as the ICU-acquired weakness occurs frequently in patients who survive
population ages and a higher percentage of people are vulnerable to critical illness, particularly those with SIRS and/or sepsis. Both neu-
infection. ropathies and myopathies have been described, most commonly after
~1 week in the ICU. The mechanisms behind ICU-acquired weakness
■■NOSOCOMIAL INFECTIONS IN THE ICU syndromes are poorly understood, they are known to present with
Many therapeutic interventions in the ICU are invasive and predis- heterogeneous muscle pathophysiology. Intensive insulin therapy may
pose patients to infectious complications. These interventions include reduce polyneuropathy in critical illness. Very early physical and occu-
endotracheal intubation, indwelling vascular catheters, transurethral pational therapy in mechanically ventilated patients reportedly results
bladder catheters, and other catheters placed into sterile body cavities in significant improvements in functional independence at hospital
(e.g., tube thoracostomy, percutaneous intraabdominal drainage cath- discharge as well as in reduced durations of mechanical ventilation
eterization). The longer such devices remain in place, the more prone and delirium.
to these infections patients become. For example, ventilator-associated
events such as ventilator-associated pneumonia correlate strongly with ■■ANEMIA
the duration of intubation and mechanical ventilation. Therefore, an Studies have shown that most ICU patients are anemic as a result of
important aspect of preventive care is the timely removal of invasive chronic inflammation. Phlebotomy also contributes to ICU anemia.
devices as soon as they are no longer needed. Moreover, multidrug- A large multicenter study involving patients in many different ICU

resistant organisms are commonplace in the ICU. settings challenged the conventional notion that a hemoglobin level of
Infection control is critical in the ICU. Care bundles, which include 100 g/L (10 g/dL) is needed in critically ill patients, with similar out-
measures such as frequent hand washing, are effective but underuti- comes noted in those whose transfusion trigger was 7 g/dL. Red blood
lized strategies. Other components of care bundles, such as protective cell transfusion is associated with impairment of immune function and
isolation of patients colonized or infected by drug-resistant organisms, increased risk of infections as well as of ARDS and volume overload,
are also commonly used. Silver-coated endotracheal tubes reportedly all of which may explain the findings in this study. A conservative
reduce the incidence of ventilator-associated pneumonia. Studies transfusion strategy has shown similar outcomes in septic shock, post-
evaluating multifaceted, evidence-based strategies to decrease cath- cardiac surgery, and post-hip surgery patients. A conservative transfu-
eter-related bloodstream infections have shown improved outcomes sion strategy has been shown to enhance survival among patients with
with strict adherence to measures such as hand washing, full-barrier active upper gastrointestinal hemorrhage.
precautions during catheter insertion, chlorhexidine skin preparation,
avoidance of the femoral site, and timely catheter removal. ■■ACUTE KIDNEY FAILURE
(See also Chap. 304) Acute kidney failure occurs in a significant per-
■■DEEP-VENOUS THROMBOSIS (DVT) centage of critically ill patients. The most common underlying etiology
(See also Chap. 273) All ICU patients are at high risk for this complica- is acute tubular necrosis, usually precipitated by hypoperfusion and/
tion because of their predilection for immobility. Therefore, all should or nephrotoxic agents. Currently, no pharmacologic agents are avail-
receive some form of prophylaxis against DVT. The most commonly able for prevention of kidney injury in critical illness. Studies have
employed forms of prophylaxis are subcutaneous low-dose heparin shown convincingly that neither low-dose dopamine, fenoldapam
injections and sequential compression devices for the lower extrem- nor vasopressin are not effective in protecting the kidneys from acute
ities. Observational studies report an alarming incidence of DVTs injury.
despite the use of these standard prophylactic regimens. Furthermore,
heparin prophylaxis may result in heparin-induced thrombocytopenia, NEUROLOGIC DYSFUNCTION IN
another nosocomial complication in critically ill patients. CRITICALLY ILL PATIENTS
Low-molecular-weight heparins such as enoxaparin are more effec-
tive than unfractionated heparin for DVT prophylaxis in high-risk ■■DELIRIUM
patients (e.g., those undergoing orthopedic surgery) and are associ- (See also Chaps. 24 and 300) This state is defined by (1) an acute onset
ated with a lower incidence of heparin-induced thrombocytopenia. of changes or fluctuations in mental status, (2) inattention, (3) disorga-
Fondaparinux, a selective factor Xa inhibitor, is even more effective nized thinking, and (4) an altered level of consciousness (i.e., a state
than enoxaparin in high-risk orthopedic patients. other than alertness). Delirium is reported to occur in a wide range of
mechanically ventilated ICU patients and can be detected by the Con-
■■STRESS ULCERS fusion Assessment Method (CAM)-ICU or the Intensive Care Delirium
Prophylaxis against stress ulcers is not necessary for all ICU patients. Screening Checklist. These tools are used to ask patients to answer
It should only be administered to high-risk patients, such as those with simple questions and perform simple tasks and can be used readily at
coagulopathy or respiratory failure. Histamine receptor-2 antagonists the bedside. The differential diagnosis of delirium in ICU patients is
are preferred over proton pump inhibitors because the latter are asso- broad and includes infectious etiologies (including sepsis), medications
ciated with increased incidence of C. difficile colitis and pneumonia. (particularly sedatives and analgesics), drug withdrawal, metabolic/
electrolyte derangements, intracranial pathology (e.g., stroke, intracra-
■■NUTRITION AND GLYCEMIC CONTROL nial hemorrhage), seizures, hypoxia, hypertensive crisis, shock, and
These are important issues that may be associated with respiratory vitamin deficiencies (particularly thiamine). The etiology of a patient’s
failure, impaired wound healing, and dysfunctional immune response ICU delirium impacts the prognosis. Those with persistent ICU delir-
in critically ill patients. Early enteral feeding is reasonable, with some ium not related to sedatives have increases in length of hospital stay,
data suggesting that permissive underfeeding of nonprotein calories is time on mechanical ventilation, cognitive impairment at hospital
not inferior to full goal feeding. Certainly, enteral feeding, if possible, is discharge, and 6-month mortality rate. Interventions to reduce ICU
preferred over parenteral nutrition, which is associated with numerous delirium are limited. The sedative dexmedetomidine has been less
complications, including hyperglycemia, fatty liver, cholestasis, and strongly associated with ICU delirium than midazolam. In addition,
sepsis. When parenteral feeding is necessary to supplement enteral very early physical and occupational therapy in mechanically venti-
nutrition, delaying this intervention until day 8 in the ICU results in lated patients has been demonstrated to reduce delirium.
better recovery and fewer ICU-related complications. Tight glucose
control is an area of controversy in critical care. Although one study ■■ANOXIC CEREBRAL INJURY
showed a significant mortality benefit when glucose levels were (See also Chap. 301) This condition is common after cardiac arrest and
aggressively normalized in a large group of surgical ICU patients, other often results in severe and permanent brain injury in survivors. Active
studies of both medical and surgical ICU patients suggested that tight cooling of patients after cardiac arrest is controversial, with some stud-
glucose control resulted in increased rates of mortality. ies showing improved neurologic outcomes and others showing no

2030 such improvement. Certainly patients suffering cardiac arrest should achievable. Since all medical treatments are justified by their expected
have a temperature targeted to no higher than 36°C. benefits, the loss of such an expectation justifies the act of withdrawing
or withholding such treatment; these two actions are judged to be fun-
■■STROKE damentally similar. An underlying stipulation derived from this report
(See also Chap. 419) Stroke is a common cause of neurologic critical is that an informed patient should have his or her wishes respected
illness. Hypertension must be managed carefully, since abrupt reduc- with regard to life-sustaining therapy. Implicit in this stipulation is the
tions in blood pressure may be associated with further brain ischemia need to ensure that patients are thoroughly and accurately informed
and injury. Acute ischemic stroke treated with tissue plasminogen regarding the plausibility and expected results of various therapies.
activator (tPA) has an improved neurologic outcome when treatment The act of informing patients and/or surrogate decision-makers is
is given within 4.5 h of onset of symptoms. The mortality rate is not the responsibility of the physician and other health care providers. If
reduced when tPA is compared with placebo, despite the improved a patient or surrogate desires therapy deemed futile by the treating
neurologic outcome. The risk of cerebral hemorrhage is significantly physician, the physician is not obligated ethically to provide such treat-
higher in patients given tPA. No benefit is seen when tPA therapy is ment. Rather, arrangements may be made to transfer the patient’s care
given beyond 4.5 h after symptom onset. Heparin has not been con- to another care provider. Whether the decision to withdraw life sup-
vincingly shown to improve outcomes in patients with acute ischemic port should be initiated by the physician or left to surrogate decision-
stroke. Decompressive craniectomy is a surgical procedure that relieves makers alone is not clear. One study reported that slightly more than
increased intracranial pressure in the setting of space-occupying brain half of surrogate decision-makers preferred to receive such a recom-
lesions or brain swelling from stroke; available evidence suggests that mendation, whereas the rest did not. Critical care providers should
PART 8
this procedure may improve survival among select patients (≤55 years meet regularly with patients and/or surrogates to discuss prognosis
or age), albeit at a cost of increased disability for some. when the withholding or withdrawal of care is being considered. After
a consensus among caregivers has been reached, this information
■■SUBARACHNOID HEMORRHAGE should be relayed to the patient and/or surrogate decision-maker. If a
(See also Chap. 419) Subarachnoid hemorrhage may occur secondary
decision to withhold or withdraw life-sustaining care for a patient has

to aneurysm rupture and is often complicated by cerebral vasospasm, been made, aggressive attention to analgesia and anxiolysis is needed.
re-bleeding, and hydrocephalus. Vasospasm can be detected by either
transcranial Doppler assessment or cerebral angiography; it is typi- ■■FURTHER READING
cally treated with the calcium channel blocker nimodipine, aggres- Barr J et al: Clinical practice guidelines for the management of pain,
sive IV fluid administration, and therapy aimed at increasing blood agitation, and delirium in adult patients in the intensive care unit.
pressure, typically with vasoactive drugs such as phenylephrine. The Crit Care Med. 41:263, 2013.
IV fluids and vasoactive drugs (hypertensive hypervolemic therapy) Girard TD et al: An Official American Thoracic Society/American
are used to overcome the cerebral vasospasm. Early surgical clipping College of Chest Physicians Clinical Practice Guideline: Liberation
or endovascular coiling of aneurysms is advocated to prevent com- from Mechanical Ventilation in Critically Ill Adults. Rehabilitation
plications related to re-bleeding. Hydrocephalus, typically heralded Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests. Am J
by a decreased level of consciousness, may require ventriculostomy Respir Crit Care Med 195:120, 2017.
drainage. Guerin C et al: Prone positioning in severe acute respiratory distress
syndrome. N Engl J Med 368:2159, 2013.
■■STATUS EPILEPTICUS MacLaren R et al: Histamine-2 receptor antagonists vs proton
(See also Chap. 418) Recurrent or relentless seizure activity is a medical pump inhibitors on gastrointestinal tract hemorrhage and infectious
emergency. Cessation of seizure activity is required to prevent irrevers- complications in the intensive care unit. JAMA Intern Med 174:564,
ible neurologic injury. Lorazepam is the most effective benzodiazepine 2014.
for treating status epilepticus and is the treatment of choice for control- Moore CL, Copel JA: Point-of-care ultrasonography. N Engl J Med
ling seizures acutely. Phenytoin or fosphenytoin should be given con- 364:749, 2011.
comitantly since lorazepam has a short half-life. Other drugs, such as Papazian L et al: Neuromuscular blockers in early acute respiratory
gabapentin, carbamazepine, and phenobarbital, should be reserved for distress syndrome. N Engl J Med 363:1107, 2010.
patients with contraindications to phenytoin (e.g., allergy or pregnancy) Singer M et al: The third international consensus definitions for
or ongoing seizures despite phenytoin. sepsis and septic shock (Sepsis-3). JAMA 315:801, 2016.
■■BRAIN DEATH
(See also Chap. 301) Although deaths of critically ill patients usually
294
are attributable to irreversible cessation of circulatory and respiratory
function, a diagnosis of death also may be established by irreversible Acute Respiratory Distress
cessation of all functions of the entire brain, including the brainstem,
even if circulatory and respiratory functions remain intact on artificial Syndrome
life support. Such a diagnosis requires demonstration of the absence of
Rebecca M. Baron, Bruce D. Levy
cerebral function (no response to any external stimulus) and brainstem
functions (e.g., unreactive pupils, lack of ocular movement in response
to head turning or ice-water irrigation of ear canals, positive apnea
test [no drive to breathe]). Absence of brain function must have an Acute respiratory distress syndrome (ARDS) is a clinical syndrome
established cause and be permanent without possibility of recovery; of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary
a sedative effect, hypothermia, hypoxemia, neuromuscular paralysis, infiltrates leading to respiratory failure. ARDS is caused by diffuse
and severe hypotension must be ruled out. If there is uncertainty about lung injury from many underlying medical and surgical disorders. The
the cause of coma, studies of cerebral blood flow and electroencepha- lung injury may be direct, as occurs in toxic inhalation, or indirect, as
lography should be performed. occurs in sepsis (Table 294-1). The clinical features of ARDS are listed in
Table 294-2. By expert consensus, ARDS is defined by three categories
■■WITHHOLDING OR WITHDRAWING CARE based on the degrees of hypoxemia (Table 294-2). These stages of mild,
(See also Chap. 9) Withholding or withdrawal of care occurs com- moderate, and severe ARDS are associated with mortality risk and with
monly in the ICU setting. The Task Force on Ethics of the Society of the duration of mechanical ventilation in survivors.
Critical Care Medicine reported that it is ethically sound to withhold The annual incidence of ARDS is estimated to be as high as
or withdraw care if a patient or the patient’s surrogate makes such 60 cases/100,000 population. Approximately 10% of all intensive care
a request or if the physician judges that the goals of therapy are not unit (ICU) admissions involve patients with ARDS.

TABLE 294-1 Clinical Disorders Commonly Associated with ARDS Exudative Proliferative Fibrotic 2031
DIRECT LUNG INJURY INDIRECT LUNG INJURY

Hyaline
Pneumonia Sepsis Edema Membranes Interstitial Inflammation Fibrosis
Aspiration of gastric contents Severe trauma
Pulmonary contusion Multiple bone fractures
Near-drowning Flail chest Day: 0 2 7 14 21 . . .
Toxic inhalation injury Head trauma FIGURE 294-1 Diagram illustrating the time course for the development and
Burns resolution of ARDS. The exudative phase is notable for early alveolar edema and
Multiple transfusions neutrophil-rich leukocytic infiltration of the lungs, with subsequent formation of
hyaline membranes from diffuse alveolar damage. Within 7 days, a proliferative
Drug overdose
phase ensues with prominent interstitial inflammation and early fibrotic changes.
Pancreatitis Approximately 3 weeks after the initial pulmonary injury, most patients recover.
Postcardiopulmonary bypass However, some patients enter the fibrotic phase, with substantial fibrosis and
bullae formation.
■■ETIOLOGY alterations in alveolar spaces are exacerbated by microvascular occlu-
CHAPTER 294 Acute Respiratory Distress Syndrome

While many medical and surgical illnesses have been associated with sion that results in reductions in pulmonary arterial blood flow to
the development of ARDS, most cases (>80%) are caused by a relatively ventilated portions of the lung (and thus in increased dead space) and
small number of clinical disorders: pneumonia and sepsis (~40–60%), in pulmonary hypertension. Thus, in addition to severe hypoxemia,
followed in incidence by aspiration of gastric contents, trauma, multi- hypercapnia secondary to an increase in pulmonary dead space can be
ple transfusions, and drug overdose. Among patients with trauma, the prominent in early ARDS.
most frequently reported surgical conditions in ARDS are pulmonary The exudative phase encompasses the first 7 days of illness after
contusion, multiple bone fractures, and chest wall trauma/flail chest, exposure to a precipitating ARDS risk factor, with the patient experi-
whereas head trauma, near-drowning, toxic inhalation, and burns are encing the onset of respiratory symptoms. Although usually present-
rare causes. The risks of developing ARDS are increased in patients ing within 12–36 h after the initial insult, symptoms can be delayed by
with more than one predisposing medical or surgical condition. 5–7 days. Dyspnea develops, with a sensation of rapid shallow breath-
Several other clinical variables have been associated with the devel- ing and an inability to get enough air. Tachypnea and increased work
opment of ARDS. These include older age, chronic alcohol abuse, of breathing result frequently in respiratory fatigue and ultimately in
metabolic acidosis, pancreatitis, and severity of critical illness. Trauma respiratory failure. Laboratory values are generally nonspecific and
patients with an Acute Physiology and Chronic Health Evaluation are primarily indicative of underlying clinical disorders. The chest
(APACHE) II score ≥16 (Chap. 293) have a 2.5-fold increased risk of radiograph usually reveals opacities consistent with pulmonary edema
developing ARDS. and often involves at least three-quarters of the lung fields (Fig. 294-2).
■■CLINICAL COURSE AND PATHOPHYSIOLOGY While characteristic for ARDS, these radiographic findings are not
The natural history of ARDS is marked by three phases—exudative, specific and can be indistinguishable from cardiogenic pulmonary
proliferative, and fibrotic—that each have characteristic clinical and edema (Chap. 298). Unlike the latter, however, the chest x-ray in ARDS
pathologic features (Fig. 294-1). may not demonstrate cardiomegaly, pleural effusions, or pulmonary
vascular redistribution as is often present in pure cardiogenic pulmo-
Exudative Phase In this phase, alveolar capillary endothelial nary edema. If no ARDS risk factor is present, then some objective
cells and type I pneumocytes (alveolar epithelial cells) are injured, evaluation is required (e.g., echocardiography) to exclude a cardiac
with consequent loss of the normally tight alveolar barrier to fluid etiology for hydrostatic edema. Chest computed tomography (CT) in
and macromolecules. Edema fluid that is rich in protein accumulates ARDS also reveals the presence of bilateral pulmonary infiltrates and
in the interstitial and alveolar spaces (Fig. 294-2). Pro-inflammatory demonstrates extensive heterogeneity of lung involvement (Fig. 294-4).
cytokines (e.g., interleukin 1, interleukin 8, and tumor necrosis factor Because the early features of ARDS are nonspecific, alternative
α [TNF-α]) and lipid mediators (e.g., leukotriene B4) are increased in diagnoses must be considered. In the differential diagnosis of ARDS,
this acute phase, leading to the recruitment of leukocytes (especially the most common disorders are cardiogenic pulmonary edema, bilat-
neutrophils) into the pulmonary interstitium and alveoli. In addition, eral pneumonia, and alveolar hemorrhage. Less common diagnoses to
condensed plasma proteins aggregate in the air spaces with cellular consider include acute interstitial lung diseases (e.g., acute interstitial
debris and dysfunctional pulmonary surfactant to form hyaline mem- pneumonitis; Chap. 287), acute immunologic injury (e.g., hypersensi-
brane whorls. Pulmonary vascular injury also occurs early in ARDS, tivity pneumonitis; Chap. 282), toxin injury (e.g., radiation pneumoni-
with vascular obliteration by microthrombi and fibrocellular prolifer- tis; Chap. 71), and neurogenic pulmonary edema (Chap. 33).
ation (Fig. 294-3).
Alveolar edema predominantly involves dependent portions of the Proliferative Phase This phase of ARDS usually lasts from day
lung with diminished aeration. Collapse of large sections of depen- 7 to day 21. Most patients recover rapidly and are liberated from
dent lung can contribute to decreased lung compliance. Consequently, mechanical ventilation during this phase. Despite this improvement,
intrapulmonary shunting and hypoxemia develop and the work many patients still experience dyspnea, tachypnea, and hypoxemia.
of breathing increases, leading to dyspnea. The pathophysiologic Some patients develop progressive lung injury and early changes of
TABLE 294-2 Diagnostic Criteria for ARDS

ABSENCE OF LEFT ATRIAL
SEVERITY: OXYGENATIONa ONSET CHEST RADIOGRAPH HYPERTENSION
Mild: 200 mmHg < Pao2/Fio2 ≤ 300 Acute: Within 1 week of a clinical Bilateral opacities consistent with Hydrostatic edema is not the primary
mmHg insult or new or worsening respiratory pulmonary edema not fully explained cause of respiratory failure. If no
Moderate: 100 mmHg < Pao2/Fio2 symptoms. by effusions, lobar/lung collapse, or ARDS risk factor is present, then
≤ 200 mmHg nodules some objective evaluation is required
(e.g., echocardiography) to rule out
Severe: Pao2/Fio2 ≤ 100 mmHg
hydrostatic edema
As assessed on at least 5 cm H2O of positive end expiratory pressure (PEEP).
a
Abbreviations: ARDS, acute respiratory distress syndrome; Fio2, inspired O2 percentage; Pao2, arterial partial pressure of O2; PCWP, pulmonary capillary wedge pressure.

2032
FIGURE 294-4 A representative CT scan of the chest during the exudative

phase of acute respiratory distress syndrome (ARDS), in which dependent
PART 8
alveolar edema and atelectasis predominate.

FIGURE 294-2 A representative anteroposterior chest x-ray in the exudative
phase of ARDS shows bilateral opacities consistent with pulmonary edema that
can be difficult to distinguish from left ventricular failure. As part of the reparative process, type II pneumocytes proliferate
along alveolar basement membranes. These specialized epithelial cells
pulmonary fibrosis during the proliferative phase. Histologically, the synthesize new pulmonary surfactant and differentiate into type I
first signs of resolution are often evident in this phase, with the initi- pneumocytes.
ation of lung repair, the organization of alveolar exudates, and a shift Fibrotic Phase While many patients with ARDS recover lung
from neutrophil- to lymphocyte-predominant pulmonary infiltrates. function 3–4 weeks after the initial pulmonary injury, some enter a
Normal alveolus Injured alveolus during the acute phase
Sloghing of
bronchial epithelium
Inactivated
Surfactant
surfactant
layer
Necrotic or apoptotic
Epithelial type I cell
basement
membrane Red blood cell
Alveolar Protein-rich
air space edema fluid
Type I cell Denuded basement
Activated membrane
Interstitium neutrophil
Leukotrienes Intact type II cell
PAF
Type II cell Oxidants
Proteases Hyaline membrane
Alveolar
macrophages Cellular
debris Proteases Widened
edematous
interstitium
Fibrin
IL-6, IL-8
MIF Migrating
TNF-α
neutrophil
Red blood
cell Procollagen
Platelets
Endothelial
cell IL-8
IL-8 Swollen, injured
Capillary endothelial cell
Endothelial
basement Neutrophils
membrane
Fibroblasts Gap formation
FIGURE 294-3 The normal alveolus (left) and the injured alveolus in the acute phase of acute lung injury and the acute respiratory distress syndrome (right). In
the acute phase of the syndrome (right), there is sloughing of both the bronchial and alveolar epithelial cells, with the formation of protein-rich hyaline membranes on
the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and transmigrating through the interstitium into the air space,
which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting pro-inflammatory cytokines—i.e., interleukins 1, 6, 8 (IL-1, 6, 8)
and tumor necrosis factor α (TNF-α)—that act locally to stimulate chemotaxis and activate neutrophils. IL-1 can also stimulate the production of extracellular matrix
by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of
anti-inflammatory mediators are also present in the alveolar milieu, including the IL-1-receptor antagonist, soluble TNF-α receptor, autoantibodies to IL-8, and cytokines
such as IL-10 and IL-11 (not shown). The influx of protein-rich edema fluid into the alveolus can lead to the inactivation of surfactant. MIF, macrophage inhibitory factor.
(Adapted from LB Ware, MA Matthay: N Engl J Med 342:1334, 2000, with permission.)

fibrotic phase that may require long-term support on mechanical venti- consensus on the optimal method to set PEEP, because numerous 2033
lators and/or supplemental oxygen. Histologically, the alveolar edema trials have proved inconclusive. Possible approaches include using
and inflammatory exudates of earlier phases convert to extensive the table of PEEP-Fio2 combinations from the ARDS Network trial
alveolar-duct and interstitial fibrosis. Marked disruption of acinar group, generating a static pressure-volume curve for the respira-
architecture leads to emphysema-like changes, with large bullae. tory system and setting PEEP at the lower inflection point on this
Intimal fibroproliferation in the pulmonary microcirculation causes curve to maximize respiratory system compliance, and measuring
progressive vascular occlusion and pulmonary hypertension. The esophageal pressures to estimate transpulmonary pressure (which
physiologic consequences include an increased risk of pneumothorax, may be particularly helpful in patients with a stiff chest wall). Until
reductions in lung compliance, and increased pulmonary dead space. more data become available on how best to optimize PEEP settings
Patients in this late phase experience a substantial burden of excess in ARDS, clinicians can use these options or a practical approach to
morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase empirically measure “best PEEP” at the bed side to determine the
of ARDS is associated with increased mortality risk. optimal settings that best promotes alveolar recruitment, minimizes
alveolar overdistention and hemodynamic instability, and provides
adequate Pao2 while minimizing Fio2 (Chap. 295).
TREATMENT Prone Positioning While several prior trials demonstrated that
Acute Respiratory Distress Syndrome mechanical ventilation in the prone position improved arterial oxy-
CHAPTER 294 Acute Respiratory Distress Syndrome

genation without a mortality benefit, a recent trial demonstrated
GENERAL PRINCIPLES a significant reduction in 28-day mortality with prone positioning
Recent reductions in ARDS mortality rates are largely the result of (32.8 to 16%) for patients with severe ARDS (Pao2/Fio2 <150 mm
general advances in the care of critically ill patients (Chap. 293). Hg). Thus, many centers are increasing the use of prone position-
Thus, caring for these patients requires close attention to (1) the rec- ing in severe ARDS, with the understanding that this maneuver
ognition and treatment of underlying medical and surgical disorders requires a critical-care team that is experienced in “proning,” as
(e.g., pneumonia, sepsis, aspiration, trauma); (2) the minimization of repositioning critically ill patients can be hazardous, leading to
unnecessary procedures and their complications; (3) standardized accidental endotracheal extubation, loss of central venous catheters,
“bundled care” approaches for ICU patients, including prophylaxis and orthopedic injury.
against venous thromboembolism, gastrointestinal bleeding, aspira- OTHER STRATEGIES IN MECHANICAL VENTILATION
tion, excessive sedation, prolonged mechanical ventilation, and cen-
Recruitment maneuvers that transiently increase PEEP to high levels
tral venous catheter infections; (4) prompt recognition of nosocomial
to “recruit” atelectatic lung can increase oxygenation, but a mor-
infections; and (5) provision of adequate nutrition via the enteral
tality benefit has not been established. Alternate modes of mechanical
route when feasible.
ventilation, such as airway pressure release ventilation and high fre-
MANAGEMENT OF MECHANICAL VENTILATION quency oscillatory ventilation, have not been proven beneficial over
(See also Chap. 295) Patients meeting clinical criteria for ARDS fre- standard modes of ventilation in ARDS management and in many
quently become fatigued from increased work of breathing and pro- cases require specialized expertise at the bedside. Lung-replacement
gressive hypoxemia, requiring mechanical ventilation for support. therapy with extracorporeal membrane oxygenation (ECMO) was shown
to improve mortality for patients with ARDS in the United Kingdom
Minimizing Ventilator-Induced Lung Injury Despite its life-
who were referred to an ECMO center (though only 75% of referred
saving potential, mechanical ventilation can aggravate lung injury.
patients received ECMO) and thus may have utility in select adult
Experimental models have demonstrated that ventilator-induced
patients with severe ARDS as a rescue therapy.
lung injury can arise from at least two principal mechanisms:
“volutrauma” from repeated alveolar overdistention from excess FLUID MANAGEMENT
tidal volume and “atelectrauma” from recurrent alveolar collapse. (See also Chap. 293) Increased pulmonary vascular permeability
As is evident from chest CT (Fig. 294-4), ARDS is a heterogeneous leading to interstitial and alveolar edema fluid rich in protein is a
disorder, principally involving dependent portions of the lung central feature of ARDS. In addition, impaired vascular integrity
with relative sparing of other regions. Because compliance differs augments the normal increase in extravascular lung water that
in affected versus more “normal” areas of the lung, attempts to occurs with increasing left atrial pressure. Maintaining a low left
fully inflate the consolidated lung may lead to overdistention of atrial filling pressure minimizes pulmonary edema and prevents
and injury to the more normal areas. Ventilator-induced injury can further decrements in arterial oxygenation and lung compliance;
be demonstrated in experimental models of acute lung injury, in improves pulmonary mechanics; shortens ICU stay and the duration
particular with high-tidal-volume (VT) ventilation. of mechanical ventilation. Thus, aggressive attempts to reduce left
A large-scale, randomized controlled trial sponsored by the atrial filling pressures with fluid restriction and diuretics should be
National Institutes of Health and conducted by the ARDS Network an important aspect of ARDS management, limited only by hypoten-
compared low VT ventilation (6 mL/kg of predicted body weight) to sion and hypoperfusion of critical organs such as the kidneys.
conventional VT ventilation (12 mL/kg predicted body weight). Lower
NEUROMUSCULAR BLOCKADE
airway pressures were also targeted in the low tidal volume group (i.e.,
plateau pressure measured on the ventilator after a 0.5-s pause after In severe ARDS, sedation alone can be inadequate for the patient-
inspiration) ≤30 cm H2O versus ≤50 cm H2O in the high tidal volume ventilator synchrony required for lung-protective ventilation. In a
group. The mortality rate was significantly lower in the low VT patients multicenter, randomized, placebo-controlled trial of early neuro-
(31%) than in the conventional VT patients (40%). This improvement in muscular blockade (with cisatracurium besylate) for 48 h, patients
survival represents a substantial ARDS-mortality benefit. with severe ARDS had increased survival and ventilator-free days
without increasing ICU-acquired paresis. These promising findings
Minimizing Atelectrauma by Prevention of Alveolar Collapse In support the early administration of neuromuscular blockade if
ARDS, the presence of alveolar and interstitial fluid and the loss needed to facilitate mechanical ventilation in severe ARDS.
of surfactant can lead to a marked reduction of lung compliance.
Without an increase in end-expiratory pressure, significant alveolar GLUCOCORTICOIDS
collapse can occur at end-expiration, with consequent impairment Many attempts have been made to treat both early and late ARDS
of oxygenation. In most clinical settings, positive end-expiratory with glucocorticoids, with the goal of reducing potentially deleteri-
pressure (PEEP) is adjusted to minimize Fio2 (inspired O2 per- ous pulmonary inflammation. Few studies have shown any signifi-
centage) and provide adequate Pao2 (arterial partial pressure of cant mortality benefit. Current evidence does not support the routine
O2) without causing alveolar overdistention. Currently, there is no use of glucocorticoids in the care of ARDS patients.

2034 TABLE 294-3 Evidence-Based Recommendations for ARDS Therapies INITIAL MANAGEMENT OF ARDS
TREATMENT RECOMMENDATIONa
Goals and Limits:
Mechanical ventilation
Initiate
Low tidal volume A Tidal volume ≤ 6 ml/kg PBW
volume/pressure-limited
Plateau pressure ≤ 30 cmH2O
Minimized left atrial filling pressures B ventilation
RR ≤ 35 bpm
High-PEEP or “open lung” Bb
Prone position Bb
Recruitment maneuvers C FIO2 ≤ 0.6
Oxygenate SpO2 88 – 95%
High-frequency ventilation D
ECMO Bb
Early neuromuscular blockade Bb
Glucocorticoid treatment D pH ≥ 7.30
Minimize acidosis RR ≤ 35 bpm
Inhaled vasodilators (e.g., inhaled NO, inhaled C
epoprosteol)
Surfactant replacement, and other anti-inflammatory D
therapy (e.g., ketoconazole, PGE1, NSAIDs)
MAP ≥ 65 mmHg
PART 8
a
Key: A, recommended therapy based on strong clinical evidence from randomized Diuresis Avoid hypoperfusion
clinical trials; B, recommended therapy based on supportive but limited clinical
data; C, recommended only as alternative therapy on the basis of indeterminate
evidence; D, not recommended on the basis of clinical evidence against efficacy
of therapy. bAs described in the text, there is no consensus on optimal PEEP FIGURE 294-5 Algorithm for the initial management of ARDS. Clinical trials have
setting in ARDS, but general consensus supports an open lung strategy that provided evidence-based therapeutic goals for a stepwise approach to the early
minimizes alveolar distention; prone positioning was shown to improve mortality mechanical ventilation, oxygenation, and correction of acidosis and diuresis of
in severe ARDS in one randomized controlled clinical trial; ECMO may be critically ill patients with ARDS. Fio2, inspired O2 percentage; MAP, mean arterial
beneficial in select patients with severe ARDS; early neuromuscular blockade pressure; PBW, predicted body weight; RR, respiratory rate; Spo2, arterial
demonstrated a mortality benefit in one randomized controlled trial in patients oxyhemoglobin saturation measured by pulse oximetry.
with severe ARDS
Abbreviations: ARDS, acute respiratory distress syndrome; ECMO, extracorporeal
membrane oxygenation; NO, nitric oxide; NSAIDs, nonsteroidal anti-inflammatory
drugs; PEEP, positive end-expiratory pressure; PGE1, prostaglandin E1. indirect causes of lung injury, while surgical and trauma patients with
ARDS—especially those without direct lung injury—generally have a
higher survival rate than other ARDS patients.
OTHER THERAPIES Increasing severity of ARDS, as defined by the consensus Berlin
Clinical trials of surfactant replacement and multiple other medical definition, predicts increased mortality. Surprisingly, there is little
therapies have proved disappointing. Pulmonary vasodilators such additional value in predicting ARDS mortality from other parameters
as inhaled nitric oxide and inhaled epoprostenol sodium can tran- of lung injury, including the level of PEEP (≥10 cm H2O), respiratory
siently improve oxygenation but have not been shown to improve system compliance (≤40 mL/cm H2O), the extent of alveolar infiltrates
survival or decrease time on mechanical ventilation. on chest radiography, and the corrected expired volume per minute
(≥10 L/min) (as a surrogate measure of dead space).
RECOMMENDATIONS
Many clinical trials have been undertaken to improve the outcome Functional Recovery in ARDS Survivors While it is common
of patients with ARDS; most have been unsuccessful in modifying for patients with ARDS to experience prolonged respiratory failure and
the natural history. While results of large clinical trials must be judi- remain dependent on mechanical ventilation for survival, it is a testa-
ciously applied to individual patients, evidence-based recommenda- ment to the resolving powers of the lung that the majority of patients
tions are summarized in Table 294-3, and an algorithm for the initial who survive regain nearly normal lung function. Patients usually
therapeutic goals and limits in ARDS management is provided in recover maximal lung function within 6 months. One year after endo-
Fig. 294-5. tracheal extubation, more than one-third of ARDS survivors have nor-
mal spirometry values and diffusion capacity. Most of the remaining
■■PROGNOSIS patients have only mild abnormalities in pulmonary function. Unlike
mortality risk, recovery of lung function is strongly associated with the
Mortality In the recent report from the Large Observational Study extent of lung injury in early ARDS. Low static respiratory compliance,
to Understand the Global Impact of Severe Acute Respiratory Failure high levels of required PEEP, longer durations of mechanical ventila-
(LUNG SAFE) trial, hospital mortality estimates for ARDS range tion, and high lung injury scores are all associated with less recovery
from 34.9% for mild ARDS, 40.3% for moderate ARDS, and 46.1% of pulmonary function. Of note, when physical function is assessed
with severe ARDS. There is substantial variability, but a trend toward 5 years after ARDS, exercise limitation and decreased physical quality
improved ARDS outcomes over time appears evident. Of interest, of life are often documented despite normal or nearly normal pulmo-
mortality in ARDS is largely attributable to nonpulmonary causes, with nary function. When caring for ARDS survivors, it is important to be
sepsis and nonpulmonary organ failure accounting for >80% of deaths. aware of the potential for a substantial burden of psychological prob-
Thus, improvement in survival is likely secondary to advances in the lems in patients and family caregivers, including significant rates of
care of septic/infected patients and those with multiple organ failure depression and posttraumatic stress disorder.
(Chap. 293).
The major risk factors for ARDS mortality are nonpulmonary. Acknowledgment
Advanced age is an important risk factor. Patients aged >75 years have The authors acknowledge the contributions to this chapter by the previous
a substantially higher mortality risk (~60%) than those <45 (~20%). authors, Drs. Augustine Choi and Steven D. Shapiro.
Moreover, patients >60 years of age with ARDS and sepsis have a three-
fold higher mortality risk than those <60. Other risk factors include ■■FURTHER READING
preexisting organ dysfunction from chronic medical illness—in par- ARDS Definition Task Force: Acute respiratory distress syndrome:
ticular, chronic liver disease, cirrhosis, chronic alcohol abuse, chronic The Berlin Definition. JAMA 307:2526, 2012.
immunosuppression (Chap. 293). Patients with ARDS arising from ARDS Network: Ventilation with lower tidal volumes as compared
direct lung injury (including pneumonia, pulmonary contusion, and with traditional tidal volumes for acute lung injury and the acute
aspiration; Table 294-1) are nearly twice as likely to die as those with respiratory distress syndrome. N Engl J Med 342:1301, 2000.

Bellani G et al: Epidemiology, patterns of care, and mortality for tight-fitting face mask, a nasal mask similar to that used for treatment 2035
patients with acute respiratory distress syndrome in intensive care of sleep apnea and in some cases with the use of a helmet or a hood.
units in 50 countries. JAMA 315:788, 2016. NIV has proved highly effective in patients with respiratory failure
Tomashefski JF Jr: Pulmonary pathology of acute respiratory distress arising from exacerbations of COPD. It is most frequently implemented
syndrome. Clin Chest Med 21:435, 2000. as bilevel positive airway pressure ventilation or pressure-support
Ware LB, Matthay MA: The acute respiratory distress syndrome. ventilation (PSV). Both modes, which apply a preset positive pres-
N Engl J Med 342:1334, 2000. sure during inspiration and a lower pressure during expiration, are
well tolerated by a conscious patient and optimize patient-ventilator
■■WEBSITES synchrony. The major limitation to the widespread application of NIV
ARDS Support Center for patient-oriented education: www.ards.org has been patient intolerance: the interface required for NIV can cause
NHLBI ARDS Clinical Trials information: www.ardsnet.org both physical and psychological discomfort. In addition, NIV has had
ARDS Foundation: www.ardsusa.org limited success in patients with acute hypoxemic respiratory failure,
for whom endotracheal intubation and conventional MV remain the
ventilatory method of choice.
The most important group of patients who benefit from a trial of
295 Mechanical
NIV are those with COPD exacerbations and respiratory acidosis
Ventilatory
CHAPTER 295 Mechanical Ventilatory Support

(pH <7.35). Several randomized trials have shown that, in patients
Support with ventilatory failure characterized by blood pH levels between 7.25
and 7.35, NIV is associated with low failure rates (15–20%) and good
outcomes (as judged by intubation rate, length of stay in intensive care,
Bartolome R. Celli
and—in some series—mortality rates). In more severely ill patients
with a blood pH <7.25, the rate of NIV failure is inversely related to
the severity of respiratory acidosis, with higher failure rates as the pH
MECHANICAL VENTILATORY SUPPORT decreases. In patients with milder acidosis (pH >7.35), NIV is not better
Mechanical ventilation (MV) is used to assist or replace spontaneous than conventional treatment that includes controlled oxygen delivery
breathing. It is implemented with special devices that can support and pharmacotherapy for exacerbations of COPD (systemic glucocorti-
ventilatory function and improve oxygenation through the applica- coids, bronchodilators, and, if needed, antibiotics).
tion of high-oxygen-content gas and positive pressure. The primary NIV is not useful in the majority of cases of respiratory failure and
indication for initiation of MV is respiratory failure, of which there is contraindicated in patients with the conditions listed in Table 295-1.
are two basic types: (1) hypoxemic, which is present when arterial O2 NIV can delay lifesaving ventilatory support in those cases and, in
saturation (Sao2) <90% occurs despite an increased inspired O2 fraction fact, can actually result in aspiration or hypoventilation. Once NIV
and usually results from ventilation-perfusion mismatch or shunt; is initiated, patients should be monitored; a reduction in respiratory
and (2) hypercarbic, which is characterized by elevated arterial carbon frequency and a decrease in the use of accessory muscles (scalene,
dioxide partial pressure (PCO2) values (usually >50 mmHg) resulting sternomastoid, and intercostals) are good clinical indicators of ther-
from conditions that decrease minute ventilation or increase physio- apeutic benefit. Arterial blood gases should be determined at least
logic dead space such that alveolar ventilation is inadequate to meet within hours of the initiation of therapy to ensure that NIV is having
metabolic demands. When respiratory failure is chronic, neither of the the desired effect. Lack of benefit within that time frame should alert
two types is obligatorily treated with MV, but when it is acute, MV may the physician to the possible need for conventional MV.
be lifesaving.
Conventional MV Conventional MV is implemented once a
■■INDICATIONS cuffed tube is inserted into the trachea to allow conditioned gas
The most common reasons for instituting MV are acute respiratory (warmed, oxygenated, and humidified) to be delivered to the airways
failure with hypoxemia (acute respiratory distress syndrome, heart and lungs at pressures above atmospheric pressure. Care should be
failure with pulmonary edema, pneumonia, sepsis, complications taken during intubation to avoid brain-damaging hypoxia. In most
of surgery and trauma), which accounts for ~65% of all ventilated cases, the administration of mild sedation may facilitate the proce-
cases, and hypercarbic ventilatory failure—e.g., due to coma (15%), dure. Opiates and benzodiazepines are good choices but can have a
exacerbations of chronic obstructive pulmonary disease (COPD; 13%), deleterious effect on hemodynamics in patients with depressed cardiac
and neuromuscular diseases (5%). The primary objectives of MV are function or low systemic vascular resistance. Morphine can promote
to decrease the work of breathing, thus avoiding respiratory muscle histamine release from tissue mast cells and may worsen broncho-
fatigue, and to reverse life-threatening hypoxemia and progressive spasm in patients with asthma; fentanyl, sufentanil, and alfentanil
respiratory acidosis. are acceptable alternatives. Ketamine may increase systemic arterial
In some cases, MV is used as an adjunct to other forms of therapy. pressure and has been associated with hallucinatory responses. The
For example, it is used to reduce cerebral blood flow in patients with shorter-acting agents—etomidate and propofol—have been used for
increased intracranial pressure. MV also is used frequently in conjunc- both induction and maintenance of anesthesia in ventilated patients
tion with endotracheal intubation for airway protection to prevent because they have fewer adverse hemodynamic effects, but both are
aspiration of gastric contents in otherwise unstable patients during significantly more expensive than older agents. Great care must be
gastric lavage for suspected drug overdose or during gastrointestinal taken to avoid the use of neuromuscular paralysis during intubation of
endoscopy. In critically ill patients, intubation and MV may be indi-
cated before the performance of essential diagnostic or therapeutic TABLE 295-1 Contraindications for Noninvasive Ventilation
studies if it appears that respiratory failure may occur during those Cardiac or respiratory arrest
maneuvers. Severe encephalopathy
Severe gastrointestinal bleed
■■TYPES OF MECHANICAL VENTILATION Hemodynamic instability
There are two basic methods of MV: noninvasive ventilation (NIV) and
Unstable angina and myocardial infarction
invasive (or conventional mechanical) ventilation (MV).
Facial surgery or trauma
Noninvasive Ventilation NIV has gained acceptance because it Upper airway obstruction
is effective in certain conditions, such as acute or chronic respiratory High-risk aspiration and/or inability to protect airways
failure, and is associated with fewer complications—namely, pneu- Inability to clear secretions
monia and tracheolaryngeal trauma. NIV usually is provided with a

2036 specified time window, by a timer signal within the ventilator. Every
breath delivered, whether patient- or timer-triggered, consists of the
Alveolar operator-specified tidal volume. Ventilatory rate is determined either
overdistention by the patient or by the operator-specified backup rate, whichever is
1 of higher frequency. ACMV is commonly used for initiation of MV
because it ensures a backup minute ventilation in the absence of an
B
intact respiratory drive and allows for synchronization of the ventilator
0.8 cycle with the patient’s inspiratory effort.
Tidal volume (mL)
Problems can arise when ACMV is used in patients with tachypnea

0.6 Alveolar due to nonrespiratory or nonmetabolic factors, such as anxiety, pain,
collapse and airway irritation. Respiratory alkalemia may develop and trigger
myoclonus or seizures. Dynamic hyperinflation leading to increased
0.4
Protective alveolar intrathoracic pressures (so-called auto-PEEP) may occur if the patient’s
ventilation respiratory mechanics are such that inadequate time is available for
0.2 complete exhalation between inspiratory cycles. Auto-PEEP can limit
A venous return, decrease cardiac output, and increase airway pressures,
predisposing to barotrauma.
0
PART 8
0 10 20 30 40 50 Intermittent Mandatory Ventilation With this mode, the

Pressure (cm of water) operator sets the number of mandatory breaths of fixed volume to
FIGURE 295-1 Hypothetical pressure-volume curve of the lung in a patient be delivered by the ventilator; between those breaths, the patient can
undergoing mechanical ventilation. Alveoli tend to close if the distending breathe spontaneously. In the most frequently used synchronized
pressure falls below the lower inflection point A, whereas they overstretch if the mode (SIMV), mandatory breaths are delivered in synchrony with the
pressure within them is higher than that of the upper inflection point B. Collapse patient’s inspiratory efforts at a frequency determined by the operator.
and opening of ventilated alveoli are associated with poor outcomes in patients If the patient fails to initiate a breath, the ventilator delivers a fixed-
with acute respiratory failure. Protective ventilation (purple shaded area), using a
lower tidal volume (6 mL/kg of ideal body weight) and maintaining positive end- tidal-volume breath and resets the internal timer for the next inspira-
expiratory pressure to prevent overstretching and collapse/opening of alveoli, tory cycle. SIMV differs from ACMV in that only a preset number of
has resulted in improved survival rates among patients receiving mechanical breaths are ventilator-assisted.
ventilatory support. SIMV allows patients with an intact respiratory drive to exercise
inspiratory muscles between assisted breaths; thus it is useful for both
supporting and weaning intubated patients. SIMV may be difficult to
patients with renal failure, tumor lysis syndrome, crush injuries, med- use in patients with tachypnea because they may attempt to exhale
ical conditions associated with elevated serum potassium levels, and during the ventilator-programmed inspiratory cycle. Consequently,
muscular dystrophy syndromes; in particular, the use of agents whose the airway pressure may exceed the inspiratory pressure limit, the
mechanism of action includes depolarization at the neuromuscular ventilator-assisted breath will be aborted, and minute volume may
junction, such as succinylcholine chloride, must be avoided. drop below that programmed by the operator. In this setting, if the
■■PRINCIPLES OF MV tachypnea represents a response to respiratory or metabolic acidosis, a
Once the patient has been intubated, the basic goals of MV are to change in ACMV will increase minute ventilation and help normalize
optimize oxygenation while avoiding ventilator-induced lung injury due the pH while the underlying process is further evaluated and treated.
to overstretch and collapse/re-recruitment. This concept, known as the Pressure-Support Ventilation This form of ventilation is
“protective ventilatory strategy” (see below and Fig. 295-1) is sup- patient-triggered, flow-cycled, and pressure-limited. It provides
ported by evidence linking high airway pressures and volumes and graded assistance and differs from the other two modes in that the
overstretching of the lung as well as collapse/re-recruitment to poor operator sets the pressure level (rather than the volume) to augment
clinical outcomes (barotrauma and volume trauma). Although normal- every spontaneous respiratory effort. The level of pressure is adjusted
ization of pH through elimination of CO2 is desirable, the risk of lung by observing the patient’s respiratory frequency. During PSV, the
damage associated with the large volume and high pressures needed inspiration is terminated when inspiratory airflow falls below a cer-
to achieve this goal has led to the acceptance of permissive hypercap- tain level; in most ventilators, this flow rate cannot be adjusted by the
nia. This condition is well tolerated when care is taken to avoid excess operator. With PSV, patients receive ventilator assistance only when
acidosis by pH buffering. the ventilator detects an inspiratory effort. PSV is often used in combi-
■■MODES OF VENTILATION nation with SIMV to ensure volume-cycled backup for patients whose
Mode refers to the manner in which ventilator breaths are triggered, respiratory drive is depressed. PSV is well tolerated by most patients
cycled, and limited. The trigger, either an inspiratory effort or a time- who are being weaned from MV; PSV parameters can be set to provide
based signal, defines what the ventilator senses to initiate an assisted full ventilatory support and can be withdrawn to load the respiratory
breath. Cycle refers to the factors that determine the end of inspiration. muscles gradually.
For example, in volume-cycled ventilation, inspiration ends when a Other Modes of Ventilation There are other modes of ventila-
specific tidal volume is delivered. Other types of cycling include pres- tion, each with its own acronym and each with specific modifications
sure cycling and time cycling. The limiting factors are operator-specified of the manner and duration in which pressure is applied to the airway
values, such as airway pressure, that are monitored by transducers and lungs and of the interaction between the mechanical assistance pro-
internal to the ventilator circuit throughout the respiratory cycle; if vided by the ventilator and the patient’s respiratory effort. Although
the specified values are exceeded, inspiratory flow is terminated, and their use in acute respiratory failure is limited, the following modes
the ventilator circuit is vented to atmospheric pressure or the specified have been used with varying levels of enthusiasm and adoption.
pressure at the end of expiration (positive end-expiratory pressure,
PRESSURE-CONTROL VENTILATION (PCV) This form of ventilation is
or PEEP). Most patients are ventilated with assist-control ventilation
time-triggered, time-cycled, and pressure-limited. A specified pressure
(ACMV), intermittent mandatory ventilation (IMV), or PSV, with the
is imposed at the airway opening throughout inspiration. Since the
latter two modes often used simultaneously (Table 295-2).
inspiratory pressure is specified by the operator, tidal volume and
Assist-Control Ventilation ACMV is the most widely used inspiratory flow rate are dependent, rather than independent, variables
mode of ventilation. In this mode, an inspiratory cycle is initiated and are not operator-specified. PCV is the preferred mode of ven-
either by the patient’s inspiratory effort or, if none is detected within a tilation for patients in whom it is desirable to regulate peak airway

TABLE 295-2 Characteristics of the Most Commonly Used Forms of Mechanical Ventilation 2037
VARIABLES SET BY VARIABLES MONITORED

VENTILATORY MODE USER (INDEPENDENT) BY USER (DEPENDENT) TRIGGER CYCLE LIMIT ADVANTAGES DISADVANTAGES
ACMV (assist-control Tidal volume Peak, mean, and plateau Patient effort Patient control Potential hyperventilation
ventilation) Ventilator rate airway pressures Timer Guaranteed ventilation Barotrauma and volume
Fio2 VE Pressure limit trauma
PEEP level ABG Every effective breath
I/E ratio generates a ventilator
Pressure limit
volume

IMV (intermittent Tidal volume Peak, mean, and plateau Patient effort Timer Patient control Potential dysynchrony
mandatory ventilation) Mandatory ventilator rate airway pressures Pressure limit Comfort from Potential hypoventilation
Fio2 VE spontaneous breaths
PEEP level ABG Guaranteed ventilation
Pressure limit I/E ratio
Spontaneous breaths
CHAPTER 295 Mechanical Ventilatory Support

between assisted
breaths
PSV (pressure-support Inspiratory pressure level Tidal volume Pressure limit Patient control No timer backup
ventilation) Fio2 Respiratory rate Inspiratory flow Comfort Potential hypoventilation
PEEP VE Assures synchrony
Pressure limit ABG
NIV (noninvasive Inspiratory and expiratory Tidal volume Pressure limit Patient control Mask interface may
ventilation) pressure level Respiratory rate Inspiratory flow cause discomfort and
Fio2 facial bruising
VE
Leaks are common
ABG
Hypoventilation
Abbreviations: ABG, arterial blood gases; Fio2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; I/E, inspiratory to expiratory time ratio; VE, minute
ventilation.
pressures, such as those with preexisting barotrauma, and for post– small series and uncontrolled trials, the use of ECMO has increased
thoracic surgery patients, in whom the shear forces across a fresh world-wide. Guidelines for ECMO centers have been published, and
suture line should be limited. When PCV is used, minute ventilation is if considered in patients with severe respiratory failure refractory to
altered through changes in rate or in the pressure-control value, with conventional therapy, the patient should be referred to a center familiar
consequent changes in tidal volume. with the procedure. The second of these techniques, prone position-
INVERSE-RATIO VENTILATION (IRV) This mode is a variant of PCV that ing, should be available in all units caring for these patients. Several
incorporates the use of a prolonged inspiratory time with the appro- multi-center randomized trials in patients with acute lung injury and
priate shortening of the expiratory time. IRV has been used in patients refractory hypoxemia have shown that prone positioning improves
with severe hypoxemic respiratory failure. This approach increases ventilation-perfusion matching and provides short- and long-term
mean distending pressures without increasing peak airway pressures. survival advantage.
It is thought to work in conjunction with PEEP to open collapsed The design of new ventilator modes reflects attempts to improve
alveoli and improve oxygenation. However, no clinical-trial data have patient-ventilator synchrony—a major practical issue during MV—by
shown that IRV improves outcomes. allowing patients to trigger the ventilator with their own effort while
also incorporating flow algorithms that terminate the cycles once cer-
CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) CPAP is not a true tain preset criteria are reached; this approach has greatly improved
support mode of ventilation because all ventilation occurs through the patient comfort. New modes of ventilation that synchronize not only
patient’s spontaneous efforts. The ventilator provides fresh gas to the the timing but also the levels of assistance to match the patient’s effort
breathing circuit with each inspiration and sets the circuit to a constant, have been developed. Proportional assist ventilation (PAV) and neu-
operator-specified pressure. CPAP is used to assess extubation poten- rally adjusted ventilatory-assist ventilation (NAV) are two modes that
tial in patients who have been effectively weaned and who require are designed to deliver assisted breaths through algorithms incorpo-
little ventilatory support and in patients with intact respiratory system rating not only pressure, volume, and time but also overall respira-
function who require an endotracheal tube for airway protection. tory resistance as well as compliance (in the case of PAV) and neural
Nonconventional Ventilatory Strategies Several nonconven- activation of the diaphragm (in the case of NAV). Although these
tional strategies have been evaluated for their ability to improve gas modes enhance patient-ventilator synchrony, their practical use in the
exchange and survival rates in severe hypoxemic respiratory fail- everyday management of patients undergoing MV needs further study.
ure. These strategies include high-frequency oscillatory ventilation
(HFOV), airway pressure release ventilation (APRV), partial liquid ■■PROTECTIVE VENTILATORY STRATEGY
ventilation (PLV) using perfluorocarbons and the administration of Whichever mode of MV is used in acute respiratory failure, the evi-
nitric oxide gas delivered through the airways. Although case reports dence from several important controlled trials indicates that a pro-
and small uncontrolled cohort studies have shown benefit, randomized tective ventilation approach guided by the following principles (and
controlled trials have failed to demonstrate consistent improvements in summarized in Fig. 295-1) is safe and offers the best chance of a good
outcome with these strategies. outcome: (1) Set a target tidal volume close to 6 mL/kg of ideal body
Some “salvage” techniques have gained acceptance given recent weight. (2) Prevent plateau pressure (static pressure in the airway at the
positive clinical outcomes. A randomized trial of extracorporeal mem- end of inspiration) exceeding 30 cm H2O. (3) Use the lowest possible
brane oxygenation (ECMO) documented positive outcomes, although fraction of inspired oxygen (Fio2) to keep the Sao2 at ≥90%. (4) Adjust
older studies had failed to document positive results. However, with the PEEP to maintain alveolar patency while preventing overdistention
the popularity of venous-venous access, and encouraging reports in and closure/reopening. With the application of these techniques, the

2038 mortality rate among patients with acute hypoxemic respiratory failure failure on the basis of alveolar edema but in whom the cardiac or
has decreased to ~30% from close to 50% a decade ago. pulmonary origin of the edema is unclear, hemodynamic monitoring
with a pulmonary arterial catheter may be of value in helping to clarify
■■PATIENT MANAGEMENT the cause of the edema. Gastrointestinal effects of positive-pressure
Once the patient’s gas exchange has been stabilized, definitive therapy ventilation include stress ulceration and mild to moderate cholestasis.
for the underlying process responsible for respiratory failure is contin-
ued. Subsequent modifications in ventilator therapy must be provided ■■WEANING FROM MECHANICAL VENTILATION
in parallel with changes in the patient’s clinical status. As improvement
The Decision to Wean It is important to consider discontinua-
in respiratory function is noted, the first priority is to reduce the level
tion of MV once the underlying respiratory disease begins to reverse.
of mechanical ventilatory support. Patients on full ventilatory support
Although the predictive capacities of multiple clinical and physiologic
should be monitored frequently, with the goal of switching to a mode
variables have been explored, the consensus from a ventilatory wean-
that allows for weaning as soon as possible. Protocols and guidelines
ing task force cites the following conditions as indicating amenability
that can be applied by paramedical personnel when physicians are not
to weaning: (1) Lung injury is stable or resolving; (2) gas exchange is
readily available have proved to be of value in shortening ventilator
adequate, with low PEEP (<8 cmH2O) and Fio2 (<0.5); (3) hemodynamic
and intensive care unit (ICU) time, with very good outcomes. Patients
variables are stable, and the patient is no longer receiving vasopressors;
whose condition continues to deteriorate after ventilatory support
and (4) the patient is capable of initiating spontaneous breaths. A
is initiated may require increased O2, PEEP, or one of the alternative
“wean screen” based on these variables should be done at least daily. If
modes of ventilation.
PART 8
the patient is deemed capable of beginning to wean, the recommenda-

tion is to perform a spontaneous breathing trial (SBT), whose value is
GENERAL SUPPORT DURING VENTILATION supported by several randomized trials (Fig. 295-2). The SBT involves
Patients for whom MV has been initiated usually require sedation an integrated patient assessment during spontaneous breathing with
and analgesia to maintain an acceptable level of comfort. Often, this little or no ventilatory support. The SBT is usually implemented with
treatment consists of a combination of a benzodiazepine and an opi- a T-piece using 1–5 cmH2O CPAP with 5–7 cmH2O or PSV from the
ate administered intravenously. Medications commonly used for this ventilator to offset resistance from the endotracheal tube. Once it is
purpose include lorazepam, midazolam, diazepam, morphine, and determined that the patient can breathe spontaneously, a decision must
fentanyl. Oversedation must be avoided in the ICU because most stud- be made about the removal of the artificial airway, which should be
ies show that daily interruption of sedation in patients with improved undertaken only when it is concluded that the patient has the ability
ventilatory status results in a shorter time on the ventilator and a to protect the airway, is able to cough and clear secretions, and is alert
shorter ICU stay. enough to follow commands. In addition, other factors must be taken
Immobilized patients receiving mechanical ventilatory support are into account, such as the possible difficulty of replacing the tube if that
at risk for deep venous thrombosis and decubitus ulcers. Venous throm- maneuver is required. If upper airway difficulty is suspected, an eval-
bosis should be prevented with the use of subcutaneous heparin and/ uation using a “cuff-leak” test (assessing the presence of air movement
or pneumatic compression boots. Fractionated low-molecular-weight around a deflated endotracheal tube cuff) is supported by current evi-
heparin appears to be equally effective for this purpose. To help dence. If the “cuff-leak test” suggests a risk of post-extubation stridor,
prevent decubitus ulcers, frequent changes in body position and the the administration of systemic corticosteroids should be considered
use of soft mattress overlays and air mattresses are employed. Early prior to extubation. Despite all precautions, ~10–15% of extubated
mobilization is recommended for patients on MV, since this approach patients require reintubation. Several studies suggest that NIV can be
is associated with better outcomes. Prophylaxis against diffuse gas- used to obviate reintubation, particularly in patients with ventilatory
trointestinal mucosal injury is indicated for patients undergoing MV.
Histamine-receptor (H2-receptor) antagonists, antacids, and cytopro-
tective agents such as sucralfate have all been used and appear to
be effective. Nutritional support by enteral feeding through either a Daily wean screen
(resolving disease,
nasogastric or an orogastric tube should be initiated and maintained
adequate gas exchange,
whenever possible. Delayed gastric emptying is common in critically ill
stable hemodynamics,
patients taking sedative medications but often responds to promotility spontaneous breathing ability)
agents such as metoclopramide. Parenteral nutrition is an alternative
to enteral nutrition in patients with severe gastrointestinal pathology
who need prolonged MV.
Yes No
■■COMPLICATIONS OF MECHANICAL VENTILATION
Endotracheal intubation and MV have direct and indirect effects on the SBT
lung and upper airways, the cardiovascular and the gastrointestinal
system. Pulmonary complications include barotrauma, nosocomial
pneumonia, oxygen toxicity, tracheal stenosis, and deconditioning of Pass Fail
Continue MV
respiratory muscles. Barotrauma and volutrauma overdistend and dis- Treat reversible elements
rupt lung tissue; may be clinically manifest by pneumomediastinum,
interstitial and subcutaneous emphysema, or pneumothorax; and can Assess for
result in the liberation of cytokines from overdistended tissues, further extubation
Repeat daily screen
promoting tissue injury. Clinically significant pneumothorax requires
tube thoracostomy. Intubated patients are at high risk for ventila-
tor-associated pneumonia as a result of aspiration from the upper air- Pass Fail
ways through small leaks around the endotracheal tube cuff; the most
common organisms responsible for this condition are Pseudomonas Consider
aeruginosa, enteric gram-negative rods, and Staphylococcus aureus. Given Extubate
tracheostomy
the high associated mortality rates, when suspected, early initiation
of empirical antibiotics directed against likely pathogens is recom- FIGURE 295-2 Flowchart to guide the daily approach to management of patients
mended. Hypotension resulting from elevated intrathoracic pressures being considered for weaning off mechanical ventilation (MV). If attempts
with decreased venous return is almost always responsive to intravas- at extubation fail, a tracheostomy should be considered. SBT, spontaneous
cular volume repletion. In patients who are judged to have respiratory breathing trial.

failure secondary to COPD exacerbation or congestive heart failure; in multisystem organ dysfunction (MSOF). The clinician is required to 2039
this setting, earlier extubation with the use of prophylactic NIV has identify the patient with shock promptly, make a preliminary assess-
yielded good results. ment of the type of shock present, and initiate therapy to prevent
irreversible organ dysfunction and death. In this chapter, we review
Prolonged MV and Tracheostomy From 5 to 13% of patients a commonly used classification system that organizes shock into four
undergoing MV will go on to require prolonged MV (>21 days). In
major types based on the underlying physiologic derangement. We
these instances, critical care personnel must decide whether and when
discuss the initial assessment utilizing the history, physical examina-
to perform a tracheostomy. This decision is individualized and is based
tion, and initial diagnostic testing to confirm the presence of shock and
on the risk and benefits of tracheostomy and prolonged intubation as
determine the type of shock causing the organ dysfunction. Finally, we
well as the patient’s preferences and expected outcomes. A tracheo-
will discuss key principles of initial therapy with the aim of reducing
stomy is thought to be more comfortable, to require less sedation, and
the high morbidity and mortality associated with shock.
to provide a more secure airway and may also reduce weaning time.
However, tracheostomy carries the risk of complications, which occur ■■PATHOPHYSIOLOGY OF SHOCK
in 5–40% of these procedures and include bleeding, cardiopulmonary The cellular oxygen imbalance of shock is most commonly related to
arrest, hypoxia, structural damage, pneumothorax, pneumomediasti- impaired oxygen delivery in the setting of circulatory failure. Shock
num, and wound infection. In patients with long-term tracheostomy, can also develop during states of increased oxygen consumption or
complex complications include tracheal stenosis, granulation, and impaired oxygen utilization. An example of the impaired oxygen uti-
CHAPTER 296 Approach to the Patient with Shock

erosion of the innominate artery. In general, if a patient needs MV for lization is cyanide poisoning, which causes uncoupling of oxidative
>10–14 days, a tracheostomy, planned under optimal conditions, is phosphorylation. This chapter will focus on the approach to the patient
indicated. Whether it is completed at the bedside or as an operative with shock related to inadequate oxygen delivery.
procedure depends on local resources and experience. Some 5–10% In the setting of insufficient oxygen supply, the cell is no longer able
of patients are deemed unable to wean in the ICU. These patients to support aerobic metabolism. With adequate oxygen, the cell metab-
may benefit from transfer to special units where a multidisciplinary olizes glucose to pyruvate, which then enters the mitochondria where
approach, including nutrition optimization, physical therapy with ATP is generated via oxidative phosphorylation. Without sufficient
rehabilitation, and slower weaning methods (including SIMV with oxygen supply, the cell is forced into anaerobic metabolism, in which
PSV), results in successful weaning rates of up to 30%. Unfortunately, pyruvate is metabolized to lactate with much less ATP generation (per
close to 2% of ventilated patients may ultimately become dependent on mole of glucose). Maintenance of the homeostatic environment of the
ventilatory support to maintain life. Most of these patients remain in cell is dependent on an adequate supply of ATP. ATP-dependent ion
chronic care institutions, although some with strong social, economic, pumping systems, such as the Na+/K+ ATPase, consume 20–80%
and family support may live a relatively fulfilling life with at-home of the cell’s energy. Inadequate oxygen delivery and subsequent
ventilation. decreased ATP disrupt the cell’s ability to maintain osmotic, ionic, and
intracellular pH homeostasis. Influx of calcium can lead to activation
■■FURTHER READING of calcium-dependent phospholipases and proteases, causing cellular
The Acute Respiratory Distress Syndrome Network: Ventilation swelling and death. In addition to direct cell death, cellular hypoxia can
with lower tidal volumes as compared with traditional tidal volumes cause damage at the organ system level via leakage of the intracellular
for acute lung injury and the acute respiratory distress syndrome. contents into the extracellular space activating inflammatory cascades
N Engl J Med 342:1301, 2000. and altering the microvascular circulation.
Guérin C et al: Prone positioning in severe Acute Respiratory Distress
Syndrome. N Engl J Med 368:2159, 2013. ■■DETERMINANTS OF OXYGEN DELIVERY
Mercat A et al for the Expiratory Pressure Study Group: Positive Since shock is the clinical manifestation of inadequate oxygen delivery
end-expiratory pressure settings in adults with acute lung injury and compared to cellular needs, we will review determinants of oxygen
ARDS: A randomized controlled trial. JAMA 299:646, 2008. delivery (DO2). Disease processes affecting any of the components of
Schmidt GA et al: Liberation from mechanical ventilation in critically oxygen delivery have the potential to lead to the development of shock.
ill adults: Executive Summary of an Official American College of Disturbances to key determinants of oxygen delivery form the basis of
Chest Physicians/American Thoracic Society Clinical Practice Guide- the four major shock types described below.
line. Chest 151;166, 2017. The two major components of DO2 are cardiac output (CO) and
Squiers J et al: Contemporary extracorporeal membrane oxygenation arterial oxygen content (CaO2):
therapy in adults: Fundamental principles and systematic review of
the evidence. J Thorac Cardiovasc Surg 152:20, 2016. DO2 = CO × CaO2
The two components of CO are heart rate (HR) and stroke volume
(SV), which can be substituted in the above equation as
Section 2 Shock and Cardiac Arrest DO2 = (HR × SV) × CaO2

The major determinants of SV are preload, afterload (systemic vascular
resistance, SVR), and cardiac contractility. The relationship can be
296 Approach to the Patient

with Shock
represented as
SV α (Preload × contractility)/SVR
In this equation, preload refers to the myocardial fiber length before
Anthony F. Massaro contraction (the ventricular end-diastolic volume). Contractility refers
to the ability of the ventricle to contract independent of preload and
afterload. The SVR represents the afterload, or the force against which
Shock is the clinical condition of organ dysfunction resulting from the ventricle must contract.
an imbalance between cellular oxygen supply and demand. This The CaO2 is composed of oxygen carried by convection with hemo-
life-threatening condition is common in the intensive care unit (ICU). globin and oxygen dissolved in blood, given as
There are a multitude of heterogeneous disease processes that can lead
CaO2 = (Hb × 1.39 × SaO2) + (PaO2 × 0.03)
to shock. The organ dysfunction seen in early shock is reversible with
restoration of adequate oxygen supply. Left untreated, shock transi- A disease process that affects these variables (HR, preload, contractil-
tions from this reversible phase to an irreversible phase and death from ity, SVR, SaO2, or Hb) has the potential to reduce oxygen delivery and

2040 cause cellular hypoxia. Each of the shock types described below has TABLE 296-2 Hemodynamic Characteristics of the Major Types of
a distinctive physiologic hemodynamic profile corresponding with Shock
alterations in one of the variables affecting oxygen delivery described CARDIAC SYSTEMIC VASCULAR
above. TYPE OF SHOCK CVP PCWP OUTPUT RESISTANCE
Distributive ↓ ↓ ↑ ↓
■■CLASSIFICATION OF SHOCK
While there is a heterogeneous list of specific conditions that can Cardiogenic ↑ ↑ ↓ ↑
cause shock, it is helpful to categorize these processes into four major Obstructive ↑ ↓↑ ↓ ↑
shock types based on the primary physiologic derangement leading to Hypovolemic ↓ ↓ ↓ ↑
reduced oxygen delivery and cellular hypoxia. The four major shock Abbreviations: CVP, central venous pressure; PCWP, pulmonary capillary wedge
types are distributive, cardiogenic, hypovolemic, and obstructive. pressure.
Table 296-1 outlines these major shock types as well as specific disease
processes that can result in that physiologic derangement. Each shock
type has a distinct hemodynamic profile (Table 296-2). Familiarity with histamine release. In this setting, there is evidence of both venous and
the major shock types and their unique hemodynamic profile is essen- arterial vasodilation. Studies have demonstrated extravasation of up
tial so that when evaluating a patient presenting with shock, the clini- to 35% of the circulating blood volume within 10 min. Patients with
cian can use the history, physical examination, and laboratory testing severe brain or spinal cord injury may have a reduction of SVR related
to determine the type of shock present and promptly begin appropriate to disruption of the autonomic pathways that regulate vascular tone.
PART 8
initial therapy to restore oxygen delivery. In these patients, there is pooling of blood in the venous system with a
resulting decreased venous return and decreased CO. A final category
Distributive Shock Distributive shock is the condition of reduced of patients who present with distributive shock are those with adrenal
oxygen delivery where the primary physiologic disturbance is a reduc- insufficiency. Adrenal insufficiency may be related to chronic steroid
tion in SVR. It is unique among the types of shock in that there is a com-
use, metastatic malignancy, adrenal hemorrhage, infection (tubercu-

pensatory increase in CO (Table 296-2). The central venous pressure losis, HIV), autoimmune adrenalitis, or amyloidosis. In conditions of
(CVP) and pulmonary capillary wedge pressure (PCWP) are usually stress (such as infection or surgery), the deficit may become apparent
reduced. The most common cause of distributive shock is sepsis. Sepsis with an inability to increase cortisol leading to vasodilation as well as
has recently been redefined as the dysregulated host response to infec- aldosterone deficiency-mediated hypovolemia.
tion resulting in life-threatening organ dysfunction. When this process
is accompanied by persistent hypotension requiring vasopressor sup- Cardiogenic Shock Cardiogenic shock is characterized by
port, it is classified as septic shock. Other processes that are manifest reduced oxygen delivery related to a reduction in CO owing to a pri-
as cellular hypoxia related to a primary reduction of SVR include mary cardiac problem. There is usually a compensatory increase in SVR
pancreatitis, severe burns, and liver failure. Anaphylaxis is predomi- in cardiogenic shock. When the cardiac process (e.g., myocardial infarc-
nantly an IgE-mediated allergic reaction that can rapidly develop after tion) affects the left ventricle (LV), there will be elevation of the PCWP
exposure to an allergen (food, medication, or insect bite), in which there and when it affects the right ventricle (RV), the CVP will be elevated.
is a profound distributive type of shock possibly mediated through As detailed above, the CO (and accordingly the DO2) can be reduced
by alterations in the SV or HR. In cardiogenic shock, the SV may be
reduced by processes that affect myocardial contractility (myocardial
TABLE 296-1 Pathophysiologic Classification of Shock infarction, ischemic cardiomyopathies, and primary myocarditis) or
1. Distributive mechanical valvular disease (acute mitral insufficiency or aortic insuf-
a. Septic shock ficiency). Both bradyarrhythmias and tachyarrhythmias (from either
an atrial or ventricular source) may have associated hemodynamic
b. Pancreatitis
consequence with a reduction in CO.
c. Severe burns
d. Anaphylactic shock Hypovolemic Shock Hypovolemic shock encompasses disease
e. Neurogenic shock processes that reduce CO (and oxygen delivery) via a reduction in
f. Endocrine shock preload. In addition to the reduced CO, this shock type is character-
i. Adrenal crisis ized by an elevated SVR and low CVP and PCWP related to decreased
intravascular volume. Any process causing a reduction in intravascular
2. Cardiogenic
volume can cause shock of this type. Hypovolemic shock most com-
a. Myocardial infarction monly is related to hemorrhage, that may be external (secondary to
b. Myocarditis trauma) or internal (most commonly upper or lower gastrointestinal
c. Arrhythmia [GI]) bleeding. Hypovolemic shock can also be seen with nonhem-
d. Valvular orrhagic processes. Examples include GI illnesses causing profound
i. Severe aortic valve insufficiency emesis or diarrhea, renal losses (osmotic diuresis associated with
ii. Severe mitral valve insufficiency diabetic ketoacidosis or diabetes insipidus), or skin loss (severe burns,
3. Obstructive
inflammatory conditions such as Stevens-Johnson).
a. Tension pneumothorax Obstructive Shock Obstructive shock is also characterized by a
b. Cardiac tamponade reduction in oxygen delivery related to reduced CO, but in this case
c. Restrictive pericarditis the etiology of the reduced CO is an extracardiac processes impairing
d. Pulmonary embolism blood flow. Processes that can impede venous return to the heart and
e. Aortic dissection reduce CO include tension pneumothorax (PTX), cardiac tamponade,
and restrictive pericarditis. Similarly processes that obstruct cardiac
4. Hypovolemic
outflow, such as pulmonary embolism (right heart) or aortic dissection
a. Hemorrhagic (left heart), are included in this shock type category.
b. GI losses
c. Burns Mixed Shock The types of shock outlined in this classification
d. Polyuria scheme are not mutually exclusive; not uncommonly, a patient will
i. Diabetic ketoacidosis
present with more than one type of shock. The initial physiologic dis-
turbance leading to reduced perfusion and cellular hypoxia in sepsis
ii. Diabetes insipidus
is distributive shock. In this setting, a sepsis-induced cardiomyopathy

can develop, which reduces myocardial contractility, thus producing a The most easily identified new organ dysfunction from the history is 2041
cardiogenic component to what now would be described as a mixed the presence of a newly altered mental status or decrease in renal func-
type of shock. tion (oliguria). In some cases, the type of shock (and the specific disease
process) is apparent from the history. Patients with distributive shock
Undifferentiated Shock Upon initial presentation, many patients from sepsis may present with fever and a history revealing of a focal
have undifferentiated shock in which the shock type and specific dis-
site of infection. Anaphylactic distributive shock may be suggested by
ease process are not apparent. Using the history, physical examination,
the onset of hives, dyspnea, and new facial edema after exposure to
and initial diagnostic testing (including hemodynamic monitoring), the
common allergens. Cardiogenic shock may be identified by the onset
clinician attempts to classify a patient with one of the types of shock
of exertional chest discomfort. The patient with significant arrhythmia
outlined above so that proper therapy can be initiated to restore tissue
may have an initial complaint of palpitations with syncope or presyn-
perfusion and oxygen delivery.
cope. Hypovolemic shock may be identified in patients who present
The type of shock seen most commonly is dependent upon the clin-
with a history of trauma (blunt or penetrating) or GI bleed (hemateme-
ical area of practice. In the medical ICU, the largest number of patients
sis, melena, or bright red blood per rectum). A patient with hyperten-
have distributive shock related to sepsis. A cardiac ICU will have a
sion and tearing chest or back pain may be presenting with acute aortic
population weighted toward cardiogenic or obstructive types of shock.
dissection and obstructive type shock. Acute onset chest pain with dys-
The emergency department will see more of a mix of patients with
pnea in the setting of immobility and or underlying malignancy raises
trauma patients presenting with hypovolemic shock and septic patients

concern for obstructive shock due to pulmonary embolism.
having a distributive pathophysiology.
For most patients, the specific etiology will be less clear but the
■■STAGES OF SHOCK history can be helpful in raising the likelihood of a particular type of
Regardless of type, shock progresses through a continuum of three shock. As an example, a patient with a preexisting immune dysfunction
stages. These stages are compensated shock (preshock), shock (decom- or medication-induced neutropenia may present with hypoperfusion
pensated shock), and irreversible shock. During compensated shock, and new organ dysfunction, in which the clinician must have a high
the body utilizes a variety of physiologic responses to counteract suspicion for septic shock. Similarly, a patient with extensive cardiac
the initial insult and attempts to reestablish the adequate perfusion disease requires a higher suspicion for cardiogenic shock.
and oxygen delivery. At this point, there are no overt signs of organ
dysfunction. Laboratory evaluation may demonstrate mild organ dys- Physical Examination The physical examination should be
function (i.e., elevated creatinine or troponin) or a mild elevation of conducted with the aim of answering two questions. Is shock present
lactate. The specific compensatory response is determined by the initial (either in compensated stage prior to overt evidence of organ dys-
pathophysiologic defect. In early sepsis with reduction in SVR, there is function or decompensated indicated by the presence of new organ
a compensatory rise in HR (and CO). With early hemorrhagic volume dysfunction)? Secondly, what type of shock is present (distributive,
loss, there will be a compensatory increase in SVR. As the host com- cardiogenic, hypovolemic, or obstructive)?
pensatory responses are overwhelmed, the patient transitions into true The physical examination findings present during the compensated
shock with evidence organ dysfunction. Appropriate interventions to phase of shock tend to be nonspecific. These include an elevation of
restore perfusion and oxygen delivery during these initial two phases the HR (with the body’s attempt to increase CO) or tachypnea (to
of shock can reverse the organ dysfunction. If untreated the patient compensate for the developing metabolic acidosis). While nonspecific,
will progress to the third phase of irreversible shock. At this point, the clinician should recognize these findings early as they may herald
the organ dysfunction is permanent and often the patient progresses the development of end-organ dysfunction if perfusion and oxygen
to MSOF. delivery are not restored. Shock is most commonly seen in the setting
of circulatory failure. In most cases, this is manifest as hypotension (a
■■EVALUATION OF THE PATIENT WITH SHOCK mean arterial pressure [MAP] of <60 mmHg), but this finding is not
The evaluation of the patient with shock utilizes the history, physical always present. Many patients may have underlying conditions that
examination, and diagnostic testing toward two specific aims. The cause longstanding low blood pressure without any evidence of organ
first aim is confirmation of the presence of shock. Given the revers- dysfunction. Alternatively, patients with underlying hypertension may
ible nature of the organ dysfunction in early shock, it is important develop organ dysfunction at higher blood pressures.
that the clinician has a high clinical suspicion for this condition. The The physical examination can confirm the presence of shock prior to
possibility of shock should be considered all patients presenting with the return of laboratory testing. The central nervous system (CNS), kid-
new organ dysfunction. This early recognition of the presence of shock ney, and skin are the organ systems most easily assessed for evidence of
is an essential tenet of shock care (Table 296-3). A second aim of the organ dysfunction. These organ systems are considered the “windows”
initial assessment (history, physical examination, and diagnostic test- through which we can identify organ dysfunction. Decreased oxygen
ing) is to identify either a specific shock etiology or to determine the delivery to the brain is manifest as confusion and encephalopathy. In
type of shock present. We will discuss the role of the history, physical the early stage of shock, the body will redirect blood flow to the CNS
examination, and diagnostic testing toward these specific aims. While to maintain adequate perfusion. In the patient with shock and altered
the assessment of shock etiology is ongoing, the initiation of therapy mental status, all the usual compensatory mechanisms have been
should not be delayed until the final diagnosis is determined. Evalua- outstripped by the magnitude of shock pathophysiology. New enceph-
tion of shock etiology and initiation of therapy should be simultaneous. alopathy represents decompensated shock. To assess renal function
during the physical examination, one should evaluate the patient’s
History Obtaining a concise, focused history is essential. If the urine output since the time of presentation. If not already present, a
patient is unable to provide a history, ancillary information from any- urinary catheter should be placed for accurate hourly assessment of
one accompanying the patient should be obtained, and a brief chart urine output. In patients with normal baseline renal function, oliguria
review should be performed. As the history is being obtained, the clini- (<0.5 mL/kg per h) may indicate shock. Finally, decreased capillary
cian must be attentive to any details indicating new organ dysfunction. refill and cold and clammy skin are signs of hypoperfusion and shock.
Many components of the examination provide insight into hemody-
TABLE 296-3 Key Principles in the Treatment of Shock namics and assist in elucidating the type of shock present. Evaluation
1. Recognize shock early of jugular venous pressure (JVP) and peripheral edema can provide
2. Assess for type of shock present insight into right-sided cardiac pressures. Pulmonary auscultation can
3. Initiate therapy simultaneous with the evaluation into the etiology of shock identify signs of left-sided cardiac dysfunction. The physical exami-
4. Restoration of oxygen delivery is the aim of therapy
nation may be used to differentiate shock with high CO (distributive)
from that with low CO (cardiogenic shock, hypovolemic shock, and
5. Identify etiologies of shock which require additional lifesaving interventions
obstructive shock). Examination findings suggestive of high output

2042 shock (distributive) include warm peripheral extremities, brisk capil- circulating volume. Elevation of alkaline phosphatase may suggest
lary refill (<2 s), and bounding pulses. Alternatively, cool extremities, biliary obstruction and may thereby identify a source of infection in
delayed poor capillary refill, or weak pulses would indicate low CO patients with distributive shock. Elevation of cardiac enzymes can
forms of shock. Among those with evidence of low CO, the exami- indicate a primary cardiac problem with myocyte damage related to
nation can be used to distinguish between conditions with increased ischemia, myocarditis, or a pulmonary embolism. An elevation of the
intravascular filling pressure (cardiogenic shock) and intravascular white blood cell count may raise suspicion for an infective process, but
volume depletion (hypovolemic shock). The JVP may be elevated car- this is certainly not diagnostic; an accompanying left shift may improve
diogenic shock (with right-sided failure) and reduced (JVP <8 cm) in the sensitivity of this measure. While the extent of acidosis may be
hypovolemic shock. The presence of cardiogenic shock would be fur- determined with a venous blood gas (VBG), if there is accompanying
ther supported by an S3 gallop. One must remember, however, that it is hypoxemia an arterial blood gas should be obtained. For patients with
well established that patients with chronic heart failure do not present undifferentiated shock, there should always be a high index of suspicion
with the classical findings of acute heart failure. for possible infection. Urinalysis and urine sediment should be sent to
At times, the physical examination may identify the specific etiol- evaluate for pyuria. Blood cultures, urine cultures, and sputum cultures
ogy of shock. This is particularly helpful in the patient who cannot should be obtained. Radiographic evaluation should be directed to seek
provide a detailed history. The examination may demonstrate the site sources of infection suggested by the history and physical examination.
of an untreated infection (cellulitis, abscess, infected pressure injury, or Lactate measurement has a role in the diagnosis, risk stratification,
focal). The examination may reveal a brady- or tachyarrhythmia lead- and, potentially, the treatment of shock. Increased lactate (hyperlactemia)
ing to development of shock. Similarly, large ecchymosis may indicate and lactic acidosis (hyperlactemia and pH <7.35) are common in shock.
PART 8
a significant bleed related to trauma or spontaneous retroperitoneal Lactate is a product of anaerobic glucose metabolism. In glycolysis,
bleeding. The rectal examination may reveal GI hemorrhage. Pulsus the enzyme phosphofuctokinase metabolizes glucose to pyruvate.
paradox and elevated JVP may suggest the presence of cardiac tampon- Under aerobic conditions, the pyruvate is then converted (in the mito-
ade. Patients with a tension PTX may have a paucity of breath sounds chondria) to acetyl CoA and enters the Krebs cycle with resulting ATP
over the affected side, deviation of the trachea away from the affected generation through oxidative phosphorylation. In the setting of cellular
side, or subcutaneous emphysema. hypoxia, the Krebs (tricarboxylic acid) cycle cannot oxidize the pyru-
Combinations of easily assessed examination components have been vate, and thus, the pyruvate is converted to lactate by the enzyme lac-
combined to create a scoring system to identify high risk patient popula- tate dehydrogenase. Under normal conditions, lactate is produced from
tions. The shock index (SI) is defined as the HR/systolic blood pressure skeletal muscle, brain, skin, and intestine. In the setting of reduced oxy-
(SBP) with a normal SI being 0.5–0.7. An elevated SI (>0.9) has been gen delivery and cellular hypoxia, the amount of lactate produced from
proposed to be a more sensitive indicator of transfusion requirement these tissues increases (and other tissue can begin to produce lactate).
and of patients with critical bleeding among those with hypovolemic While most of the studies have been performed in patients with septic
(hemorrhagic) shock than either HR or BP alone. The SI may also shock, there is evidence that elevated lactate correlates with a worse
identify patients at risk for postintubation hypotension. This concept outcome. A recent systematic literature review evaluating the role of
of use of a clinical score to identify at-risk patients has been extended lactate measurement in a variety of critically ill populations supported
to patients with distributive shock from sepsis. The quick Sequential the value of serial lactate measurements in the evaluation of critically
Organ Failure Assessment (qSOFA) score is a rapid assessment scale ill patients and their response to therapy.
that assigns a point for SBP <100, respiratory rate >22, or altered men-
ECG The electrocardiogram (ECG) is an essential part of the evalu-
tal status (Glasgow Coma Scale <15). A qSOFA ≥2 (with a concern for
ation of the patient with shock. There may be a bradycardia or tachy-
infection) is associated with a significantly greater risk of death or pro-
cardic arrhythmia causing a reduction in CO. ST segment elevation
longed ICU stay. The Third International Consensus Definition of Sep-
myocardial infarction may be identified. The presence of the S1 Q3
sis has recommended the use of the qSOFA to identify the most acutely
T3 pattern would raise concerns for pulmonary embolism. Reduced
ill subset of patients with sepsis (longer length of stay, increased need
voltage in the presence of electrical alternans raises the possibility of
for ICU admission, and higher in-hospital mortality).
pericardial tamponade.
Diagnostic Testing Laboratory evaluation should be initiated Echocardiography Echocardiography is increasingly used as an
promptly in all patients with suspected shock. The laboratory evalu- essential tool to help categorize shock, and it provides an assessment
ation is directed toward the dual aim of assessing the extent of end- that is both rapid and noninvasive. Familiarity with basic echocardio-
organ dysfunction and of gaining insight into the possible etiology of graphic techniques and interpretation is now expected in the critical
shock. Table 296-4 outlines the recommended initial laboratory evalu- care setting. Accordingly, competency standards have been proposed
ation of the patient with undifferentiated shock. for critical care providers in both basic and advanced echocardio-
graphic techniques. The bedside echocardiogam performed by the ICU
BLOOD TESTS Evaluation of blood urea nitrogen (BUN), creatinine, and team does not replace a formal examination performed by the echoc-
transaminases provide an assessment of the extent of end-organ dys- ardiography service.
function related to shock. Urine electrolytes with subsequent calculation The basic echocardiographic assessment for the shock patient
of the fractional excretion of sodium (FENa) or fractional excretion of is transthoracic echocardiography (TTE) utilizing both the two-
urea (FEUrea) may indicate states of hypovolemia or decreased effective dimensional (2D) and M mode. Standardized, focused echocardiogra-
phy protocols such as the RACE protocol (rapid assessment for cardiac
TABLE 296-4 Initial Laboratory Evaluation of Undifferentiated Shock echocardiography) have been introduced to facilitate the assessment of
1. Lactate cardiac function. It focuses the examination on LV function, RV func-
2. Renal function tests tion, and pericardium. It also can assess volume, but the use of echocar-
diography for volume assessment will be discussed in the section below.
3. Liver function tests
The 2D mode can evaluate LV size, wall thickness, and ventricular
4. Cardiac enzymes
function. Ventricular size and thickness can suggest longer standing
5. Complete blood count (with differential) cardiac processes. Evaluation of LV function through estimation of
6. PT, PTT, and INR left ventricular ejection fraction (LVEF), and can identify shock with
7. Urinalysis and urine sediment globally reduced LV function or regional wall motion abnormalities.
8. Arterial blood gas Similarly, the assessment of RV function also examines RV size and
9. ECG wall thickness (to identify conditions such as elevated pulmonary pres-
Abbreviations: INR, International normalized ratio; PT, prothrombin time; PTT, sures or suggest pulmonary embolism), and also evaluate the patient
partial thromboplastin time. for pericardial tamponade. Two-dimensional echocardiography can

also be used to assess valve function, including acute processes, such as monitoring is not required, but in all of these studies patients in the 2043
mitral valve rupture. Assessment of valvular function is often a process “usual care” arms of the study received early initial volume resuscita-
that requires a higher skilled practitioner. The performance of the bed- tion. For patients with suspected septic shock, a minimum of 30 mL/kg
side echocardiogram by the critical care practitioner does not replace is recommended by the Surviving Sepsis Campaign. While the need for
formal assessment by a cardiologist. volume resuscitation is most apparent for patients with distributive or
hypovolemic shock, even patients with cardiogenic shock may benefit
■■INITIAL TREATMENT OF SHOCK by cautious volume replacement. In these patients, there should be a
Since shock can progress rapidly to an irreversible stage, a key princi- careful assessment of volume status prior to volume administration.
ple in shock management is to initiate treatment for circulatory shock In general, volume replacement therapy should be given as a bolus
simultaneous with efforts to elucidate shock etiology (Table 296-3). with a predefined endpoint to assess the effect of the volume resuscita-
If the initial history, physical examination, and laboratory evaluation tion. Most commonly, the volume resuscitation will begin with crystal-
have identified the shock type or the specific etiology, then therapy loid. In patients with hypovolemic shock due to ongoing hemorrhage,
is directed to reverse the underlying physiologic abnormality causing volume replacement with packed red blood cells is warranted. In cases
the hypoperfusion and reduced oxygen delivery. Details of the optimal of massive transfusion, platelets and fresh frozen plasma should be
care for the specific disease processes leading to shock may be found in provided to offset the dilution of these components during volume
other chapters of this text. As many patients will present with undiffer- replacement. Since hemoglobin is a key determinant of CaCO2 red cell

entiated shock, in this section we will discuss treatment directed at the administration may be a part of volume replacement even without
patient with undifferentiated shock. At the conclusion of this section, hemorrhage if hemoglobin content is <7 g/dL in order to optimize
we will highlight etiologies of shock that require initiation of lifesaving oxygen delivery.
specific therapy. Assessment of intravascular volume status (and the adequacy of
The development of shock is a medical emergency, and optimal ther- volume resuscitation) begins with the physical examination (described
apy involves the involvement of a multidisciplinary team to allow the above). The passive leg raise (PLR) test can predict responsiveness
evaluation and initiation of therapy to begin simultaneously. Patients to additional intravenous fluid (IVF) by providing the patient with
must be treated in a setting where adequate resources are available an endogenous volume bolus. While the patient is resting in a semi-
to support frequent reassessments and invasive monitoring. Most recumbent position at a 45-degree angle, the bed is placed in tren-
patients with shock should be cared for in an ICU setting. delenburg such that the patient’s head becomes horizontal and the legs
A key early consideration is to ensure adequate intravenous access. are extended at a 45-degree angle. There is then an immediate (within
Placement of a peripheral venous catheter (16G or 18G) will provide 1 min) assessment of changes in CO (or pulse pressure variation as a
initial access for the aggressive volume resuscitation that is required surrogate). It is important to emphasize that one does not merely look
for patients with distributive or hypovolemic shock. If there is con- for changes in blood pressure; if the shock patient is mechanically
cern for distributive shock with sepsis, this IV access will also permit ventilated there is the option of looking at changes in SV variation (or
prompt antibiotic administration. For patients with ongoing hypoten- pulse pressure variation) during the respiratory cycle to assess volume
sion despite adequate volume resuscitation, placement of a central responsiveness. A >12% SV variation suggests a volume-responsive
venous catheter (CVC) is indicated to provide therapy with vasopres- state. This measurement requires that the patient be in a volume cycle
sors and inotropes. The CVC will provide a mechanism for hemody- mode of ventilation, without breath-to-breath variations in intratho-
namic monitoring (CVP) as well as a means to obtain central venous racic pressure and without arrhythmias. A final caveat to the use of
oxygen saturations (ScvO2). The ScvO2 is a surrogate of mixed venous these parameters to assess volume status is that these studies are
oxygen saturation, and, thus, can provide insight into the adequacy performed on patients being ventilated with tidal volumes larger than
of oxygen delivery. Central venous access using a sheath will provide currently used to minimize ventilator-induced lung injury.
an access point for placement of a Swan Ganz catheter if more detailed There is also increased use of echocardiography to assist in determi-
assessment of hemodynamic measurements are required (PCWP, CO, nation of intravascular fluid status, with a variety of static and dynamic
and SVR). If the patient presents critically ill or in the midst of cardio- variables that the trained operator can assess. The most commonly used
pulmonary arrest, the quickest method of obtaining central access will parameters to assess adequacy of volume resuscitation are inferior vena
be through the use of an intraosseous device. Placement of an arterial cava (IVC) diameter and IVC collapse. Alternatively, serial assessments
line allows for intravascular measurement of blood pressure and of LV function can be performed while volume is being administered.
continuous determination of MAP. In addition, it can provide insight Placement of a pulmonary artery catheter (PAC) is another tool for
into the adequacy of volume resuscitation through the measurement assessment of volume status. This more invasive measure involves
of systolic or pulse pressure variation. The arterial line will provide placement of the PAC into the central venous circulation and through
access for determination of arterial oxygen tension, which is helpful the right heart. Ports in the PAC (Swan Ganz catheter) allow for direct
since peripheral oximetry measurements (SpO2) can be unreliable in measurement of CVP, pulmonary artery (PA), and PCWPs. The PCWP is
states of tissue hypoperfusion. The arterial line facilitates repeated used as a surrogate for LA pressure. While studies have not identified a
measures of acid base status or lactate to assess the impact of treatment. mortality or length-of-stay benefit with routine use of PA catheterization,
All patients with shock should have a urinary catheter placed to permit there are cases where it may be beneficial. Patients with mixed shock
hourly assessment of renal function as another potential indication of (distributive and cardiogenic) or those with ongoing shock of unclear
the adequacy of resuscitation etiology are examples of situations in which it should be considered.
The need for continued volume replacement must be frequently
Volume Resuscitation Initial volume resuscitation has the aim reassessed. As the patient continues to receive treatment for shock, the
of restoring tissue perfusion and is crucial to optimal shock therapy. initial proper strategy regarding volume management may change in
Assessment of current intravascular volume status and determination light of development of processes that independently require a differ-
of the optimal amount of volume resuscitation are challenging. The ent volume management strategy. For patients who initially present
physiologic goal of volume resuscitation is to move the patient to the with shock but then develop failure related to acute respiratory dis-
nonpreload-dependent portion of the Starling curve. Most patients tress syndrome (ARDS) or renal failure, it may be reasonable to begin
with any of the four shock types will benefit from an increase in intra- volume removal.
vascular volume. For patients with distributive shock, the need for
early aggressive volume replacement is well established. In the past, Vasopressor and Inotropic Support If intravascular volume
the use of early goal-directed therapy (EGDT) in septic shock targeted status has been optimized with volume resuscitation but hypotension
specific measures of CVP, MAP, and SvO2 to guide volume resus- and inadequate tissue perfusion persist, then vasopressor and inotropic
citation (and initiation of vasopressors and inotropes). More recent support should be initiated. The use of vasopressors and inotropes
studies have demonstrated that targeted resuscitation using invasive must be tailored to the primary physiologic disturbance. The clinician

2044 must understand the receptor selectivity of various agents and that for stress dose steroids. Cardiogenic shock patients with arrhythmia
some agents the selectivity may be dose-dependent. In patients with may require treatment as outlined in advanced cardiac life support
distributive shock, the aim is to increase the SVR. Norepinephrine is algorithms or placement of an artificial pacemaker. In cases of acute
the first choice vasopressor: with potent α1 and β1 adrenergic effects. ischemic events, consideration must be given to revascularization
The α1 causes vasoconstriction while β1 has positive inotropic and and temporary mechanical supportive measures. In the case of valve
chronotropic effects. At high doses, epinephrine has a similar profile dysfunction, emergency surgery may be considered. Patients with
(at lower doses the β effects predominate), but is associated with tach- hypovolemic shock due to hemorrhage may require surgical interven-
yarrhythmia, myocardial ischemia, decreased splanchnic blood flow, tion in the case of trauma or endoscopic or interventional radiology
pulmonary hypertension, and acidosis. In distributive shock, vaso- procedures in the case of a GI source of blood loss. Among patients
pressin deficiency may be present. Vasopressin acts on the vasopressin with obstructive shock, a tension PTX would necessitate immediate
receptor to reverse vasodilation and redistribute flow to the splanchnic decompression. Proximal pulmonary embolism requires evaluation for
circulation. In a randomized trial in patients with septic shock, the thrombolytic therapy or surgical removal of the clot. Dissection of the
addition of low-dose vasopressin did not reduce all-cause 28-day ascending aorta may require surgical intervention.
mortality compared to norepinephrine. Vasopressin is safe and has a
role as a second agent for hypotension in septic shock. Dopamine does ■■FURTHER READING
not have a role as a first line agent in distributive shock. A random- Mebazaa A et al: Acute heart failure and cardiogenic shock: A multidis-
ized control study in patients with all cause circulatory shock did not ciplinary practical guidance. Intensive Care Med 42:147, 2016.
show a survival benefit, but did reveal an increase in adverse events Monnet X et al: Passive leg raising for predicting fluid responsiveness:
PART 8
(arrhythmia). In this study, the subgroup of patients with cardiogenic A systematic review and meta-analysis. Intensive Care Med 42:1935,
shock had increased mortality. For patients with cardiogenic shock, 2016.
dobutamine is the first line agent; it is a synthetic catecholamine with Pro CI et al: A randomized trial of protocol-based care for early septic
primarily β-mediated effects and minimal α adrenergic effects. The β1 shock. N Engl J Med 370:1683, 2014.
effect is manifest in increased inotropy and the β2 effect leads to vaso- Rhodes A et al: Surviving sepsis campaign: International guidelines
dilation with decreased afterload; it can be used with norepinephrine in for management of sepsis and septic shock: 2016. Intensive Care Med
patients with mixed distributive and cardiogenic shock. 43:304, 2017.
Vincent JL, De Backer D: Circulatory shock. N Engl J Med 369:1726,
■■OXYGENATION AND VENTILATION SUPPORT 2013.
In addition to the cellular hypoxia caused by the circulatory failure, Vincent JL et al: The value of blood lactate kinetics in critically ill
patients with shock may present with hypoxemia. For patients with patients: A systematic review. Crit Care 20:257, 2016.
distributive shock, this may be related to a primary pulmonary pro-
cess (pneumonia in a patient with septic shock). For patients with
cardiogenic or obstructive shock, the hypoxemia may be related to LV
297 Sepsis and Septic Shock

dysfunction and elevations of PCWP. For patients with all .types . of
shock, there can be development of ARDS and subsequent V/Q mis-
match and shunt. Supplemental oxygen should be initiated and titrated
to maintain SpO2 of 92–95%. This may require intubation and initiation Christopher W. Seymour, Derek C. Angus
of mechanical ventilation. If the patient requires intubation and initia-
tion of mechanical ventilation, this should be provided promptly so as
to minimize the duration of tissue hypoxia. Patients with shock may ■■INTRODUCTION AND DEFINITIONS
have high minute ventilatory needs to compensate for metabolic aci- Sepsis is a common and deadly disease. More than two millennia ago,
dosis. As shock progresses, they may not be able to maintain adequate Hippocrates wrote that sepsis was characterized by rotting flesh and
respiratory compensation, which may be a second indication to initiate festering wounds. Several centuries later, Galen described sepsis as
mechanical ventilator support. If mechanical support is initiated, it a laudable event required for wound healing. Once the germ theory
is important to provide ventilation with lung-protective strategies was proposed by Semmelweis, Pasteur, and others in the nineteenth
focused on low tidal volume ventilation and optimization of positive century, sepsis was recast as a systemic infection referred to as “blood
end-expiratory pressure to minimize ventilator-induced lung injury. In poisoning” and was thought to be due to pathogen invasion and
addition, there should be daily sedation cessation to assess underlying spread in the bloodstream of the host. However, germ theory did
neurologic function and minimize time on mechanical ventilation. not fully explain sepsis: many septic patients died despite successful
There are currently little data to support the use of noninvasive venti- removal of the inciting pathogen. In 1992, Bone and colleagues pro-
lation in the setting of shock. posed that the host, not the germ, was responsible for the pathogenesis
Antibiotic Administration Sepsis and septic shock are the most of sepsis. Specifically, they defined sepsis as a systemic inflammatory
response to infection. Yet sepsis arose in response to many different
common cause of shock. For patients presenting with undifferentiated
pathogens, and septicemia was neither a necessary condition nor a
shock, if the diagnosis of septic shock is being entertained then broad
helpful term. Thus, these investigators instead proposed the term severe
spectrum antibiotics should be administered after obtaining appropri-
sepsis to describe cases where sepsis was complicated by acute organ
ate cultures. For patients with sepsis, every hour delay in antibiotic
dysfunction and the term septic shock for a subset of sepsis cases that
administration is associated with an increase in mortality. While it is
were complicated by hypotension despite adequate fluid resuscitation
ideal to initiate antibiotics after appropriate cultures, the inability to
along with perfusion abnormalities.
obtain cultures should not delay the start of treatment. When sepsis is
In the past 20 years, research has revealed that many patients develop
excluded as a cause of shock, an important aspect of antibiotic steward-
acute organ dysfunction in response to infection but without a mea-
ship is to stop all antibiotics.
surable inflammatory excess (i.e., without the systemic inflammatory
Specific Causes of Shock Requiring Tailored Intervention response syndrome [SIRS]). In fact, both pro- and anti-inflammatory
The initial evaluation (history, physical examination, and diagnostic responses are present along with significant changes in other path-
testing) may have identified an etiology of shock that requires urgent ways. To clarify terminology and reflect the current understanding of
lifesaving intervention in addition to the initial treatment steps out- the pathobiology of sepsis, the Sepsis Definitions Task Force in 2016
lined above. Patients with distributive shock secondary to anaphylaxis proposed the Third International Consensus Definitions specifying that
require removal of the inciting allergen, administration of epinephrine, sepsis is a dysregulated host response to infection that leads to acute
and vascular support with intravenous fluid resuscitation and vaso- organ dysfunction. This definition distinguishes sepsis from uncompli-
pressors. Adrenal insufficiency requires replacement with intravenous cated infection that does not lead to organ dysfunction, a poor course,

TABLE 297-1 Definitions and Criteria for Sepsis and Septic Shock 2045
COMMON CLINICAL CRITERIA IN 1991/2003

CONDITION DEFINITION FEATURES (“SEPSIS-1”/”SEPSIS-2”) CRITERIA IN 2016 (“SEPSIS-3”)
Sepsis A life-threatening organ Include signs of infection, Suspected (or documented) infection Suspected (or documented)
dysfunction caused by a with organ dysfunction, plus plus ≥2 systemic inflammatory infection and an acute increase
dysregulated host response to altered mentation; tachypnea; response syndrome (SIRS) criteriaa in ≥2 sepsis-related organ failure
infection hypotension; hepatic, renal, or assessment (SOFA) pointsb
hematologic dysfunction
Septic shock A subset of sepsis in Signs of infection, plus altered Suspected (or documented) infection Suspected (or documented)
which underlying circulatory mentation, oliguria, cool plus persistent arterial hypotension infection plus vasopressor therapy
and cellular/metabolic peripheries, hyperlactemia (systolic arterial pressure, <90 mmHg; needed to maintain mean arterial
abnormalities lead to mean arterial pressure, <60 mmHg; or pressure at ≥65 mmHg and serum
substantially increased change in systolic by >40 mmHg from lactate >2.0 mmol/L despite
mortality risk baseline adequate fluid resuscitation
a
SIRS criteria include 1 point for each of the following (score range, 0–4): fever >38°C (>100.4°F) or <36°C (<96.8°F); tachypnea with >20 breaths per min; tachycardia
with heart rate >90 beats per min; leukocytosis with white blood cell count >12,000/μL; leukopenia (<4000/μL) or >10% bands. bSOFA score is a 24-point measure of
organ dysfunction that uses six organ systems (renal, cardiovascular, pulmonary, hepatic, neurologic, hematologic), where 0–4 points are assigned per organ system.
CHAPTER 297 Sepsis and Septic Shock

or death. In light of the wide variation in the ways that septic shock is provision of supportive therapy, in which case epidemiologic studies
identified in research, clinical, or surveillance settings, the Third Inter- count the “treated,” rather than the actual, incidence. In the United
national Consensus Definitions further specified that septic shock be States, recent cohort studies using administrative data suggest that
defined as a subset of sepsis cases in which underlying circulatory and upwards of 2 million cases of sepsis occur annually. Shock is present in
cellular/metabolic abnormalities are profound enough to substantially ~30% of cases, resulting in an estimated 230,000 cases in a recent sys-
increase mortality risk. tematic review. An analysis of data (both clinical and administrative)
To aid clinicians in identifying sepsis and septic shock at the from 300 hospitals in the United Healthcare Consortium estimated
bedside, new “Sepsis-3” clinical criteria for sepsis include (1) a sus- that septic shock occurred in 19 per 1000 hospitalized encounters. The
pected infection and (2) acute organ dysfunction, defined as an increase incidences of sepsis and septic shock are also reported to be increasing
by two or more points from baseline (if known) on the sequential (or (according to ICD9-CM diagnosis and procedure codes), with a rise of
sepsis-related) organ failure assessment (SOFA) score (Table 297-1). almost 50% in the past decade. However, the stability of objective clin-
Criteria for septic shock include sepsis plus the need for vasopressor ical markers (e.g., provision of organ support, detection of bacteremia)
therapy to elevate mean arterial pressure to ≥65 mmHg with a serum over this period in a two-center validation study suggests that new
lactate concentration >2.0 mmol/L despite adequate fluid resuscitation. ICD-9 coding rules, confusion over semantics (e.g., septicemia versus
severe sepsis), rising capacity to provide intensive care, and increased
■■ETIOLOGY case-finding confound the interpretation of serial trends. Studies from
Sepsis can arise from both community-acquired and hospital-acquired other high-income countries report rates of sepsis in the ICU similar to
infections. Of these infections, pneumonia is the most common source, those in the United States.
accounting for about half of cases; next most common are intraabdom- While the data demonstrate that sepsis is a significant
inal and genitourinary infections. Blood cultures are typically positive public-health burden in high-income countries, its impact on
in only one-third of cases, while many cases are culture negative at all the populations of low- and middle-income countries is prob-
sites. Staphylococcus aureus and Streptococcus pneumoniae are the most ably even more substantial because of the increased incidence of infec-
common gram-positive isolates, while Escherichia coli, Klebsiella species, tious diseases and the high prevalence of HIV in some parts of the
and Pseudomonas aeruginosa are the most common gram-negative iso- developing world. Although there are fewer high-quality studies on
lates. In recent years, gram-positive infections have been reported more sepsis in these countries, the available data support sepsis as a major
often than gram-negative infections, yet a 75-country point-prevalence public-health problem. For example, a study of one cohort in rural
study of 14,000 patients on intensive care units (ICUs) found that 62% Uganda found an incidence of laboratory-confirmed sepsis tenfold that
of positive isolates were gram-negative bacteria, 47% were gram- of current global sepsis estimates; as only a minority of patients with
positive bacteria, and 19% were fungi. sepsis develop bacteremia, the incidence of sepsis in the cohort was
The many risk factors for sepsis are related to both the predisposition probably even higher. Case–fatality rates in low- and middle-income
to develop an infection and, once infection develops, the likelihood countries are also higher than those in high-income countries, as exem-
of developing acute organ dysfunction. Common risk factors for plified by two observational cohorts in Brazil with mortality rates >40%.
increased risk of infection include chronic diseases (e.g., HIV infection,
chronic obstructive pulmonary disease, cancers) and immunosuppres- ■■PATHOGENESIS
sion. Risk factors for progression from infection to organ dysfunction For many years, the clinical features of sepsis were considered the
are less well understood but may include underlying health status, result of an excessive inflammatory host response (SIRS). More
preexisting organ function, and timeliness of treatment. Age, sex, and recently, it has become apparent that infection triggers a much more
race/ethnicity all influence the incidence of sepsis, which is highest complex, variable, and prolonged host response than was previously
at the extremes of age, higher in males than in females, and higher in thought. The specific response of each patient depends on the pathogen
blacks than in whites. The differences in risk of sepsis by race are not (load and virulence) and the host (genetic composition and comor-
fully explained by socioeconomic factors or access to care, raising the bidity), with different responses at local and systemic levels. The host
possibility that other factors, such as genetic differences in suscepti- response evolves over time with the patient’s clinical course. Generally,
bility to infection or in the expression of proteins critical to the host proinflammatory reactions (directed at eliminating pathogens) are
response, may play a role. responsible for “collateral” tissue damage in sepsis, whereas anti-
inflammatory responses are implicated in the enhanced susceptibility
■■EPIDEMIOLOGY to secondary infections that occurs later in the course. These mecha-
The incidences of sepsis and septic shock depend on how acute organ nisms can be characterized as an interplay between two “fitness costs”:
dysfunction and infection are defined as well as on which data sources direct damage to organs by the pathogen and damage to organs stem-
are studied. Disparate estimates come from administrative data, pro- ming from the host’s immune response. The host’s ability to resist as
spective cohorts with manual case identification, and large electronic well as tolerate both direct and immunopathologic damage will deter-
health-record databases. Organ dysfunction is often defined by the mine whether uncomplicated infection becomes sepsis.

2046
Electron transport chain activity
CELL
Increased ATP
O2 diffusion Lactate/H+
distance
Activated Mitochondrial
leukocyte Tissue edema dysfunction DO2 Tissue
oxygenation
INTERSTITIUM
Endothelial
leak/dysfunction Barrier function
Cytokines DO2
Inflammation Thrombus/
Platelets
DAMPs
MICROCIRCULATION
PART 8
Antithrombin
Tissue Tissue factor
Protein C
Inflammatory damage pathway inhibitor
Activated Lactate/H+
mediators Tissue factor Altered
protein C Hypotension
Fibrinolysis Hypovolemia microvascular
PAMPs Vasodilation flow

TLR,
NLR, or
CLR
Adhesion
Transmigration
Innate immune Pathogens Activated endothelium

cells ICAM, VCAM-1 expression
FIGURE 297-1 Select mechanisms implicated in the pathogenesis of sepsis-induced organ and cellular dysfunction. The host response to sepsis involves multiple
mechanisms that lead to decreased oxygen delivery (DO2) at the tissue level. The duration, extent, and direction of these interactions are modified by the organ under
threat, host factors (e.g., age, genetic characteristics, medications), and pathogen factors (e.g., microbial load and virulence). The inflammatory response is typically
initiated by an interaction between pathogen-associated molecular patterns (PAMPs) expressed by pathogens and pattern recognition receptors expressed by innate
immune cells on the cell surface (Toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene
1–like receptors and nucleotide-binding oligomerization domain–like receptors [NLRs]). The resulting tissue damage and necrotic cell death lead to release of damage-
associated molecular patterns (DAMPs) such as uric acid, high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. These molecules
promote the activation of leukocytes, leading to greater endothelial dysfunction, expression of intercellular adhesion molecule (ICAM) and vascular cell adhesion
molecule 1 (VCAM-1) on the activated endothelium, coagulation activation, and complement activation. This cascade is compounded by macrovascular changes such
as vasodilation and hypotension, which are exacerbated by greater endothelial leak tissue edema, and relative intravascular hypovolemia. Subsequent alterations
in cellular bioenergetics lead to greater glycolysis (e.g., lactate production), mitochondrial injury, release of reactive oxygen species, and greater organ dysfunction.
Initiation of Inflammation Over the past decade, our knowl- intravascular coagulation. Abnormalities in coagulation are thought
edge of pathogen recognition has increased tremendously. Pathogens to isolate invading microorganisms and/or to prevent the spread of
activate immune cells by an interaction with pattern recognition infection and inflammation to other tissues and organs. Excess fibrin
receptors (Fig. 297-1), of which four main classes are prominent: Toll- deposition is driven by coagulation via tissue factor, a transmembrane
like receptors (TLRs), RIG-I-like receptors, C-type lectin receptors, and glycoprotein expressed by various cell types; by impaired anticoagu-
NOD-like receptors; the activity of the last group occurs partially in lant mechanisms, including the protein C system and antithrombin;
protein complexes called inflammasomes. The recognition of structures and by compromised fibrin removal due to depression of the fibrino-
conserved across microbial species—so-called pathogen-associated lytic system. Coagulation (and other) proteases further enhance inflam-
molecular patterns (PAMPs)—by all these receptors results in upreg- mation via protease-activated receptors. In infections with endothelial
ulation of inflammatory gene transcription and initiation of innate predominance (e.g., meningococcemia), these mechanisms can be com-
immunity. A common PAMP is the lipid A moiety of lipopolysaccha- mon and deadly.
ride (LPS or endotoxin), which attaches to the LPS-binding protein on
the surface of monocytes, macrophages, and neutrophils. LPS is trans-
Organ Dysfunction Although the mechanisms that underlie
organ failure in sepsis are only partially known, impaired tissue oxy-
ferred to and signals via TLR4 to produce and release cytokines such
genation plays a key role. Several factors contribute to reduced oxygen
as tumor necrosis factor that grow the signal and alert other cells and
delivery in sepsis and septic shock, including hypotension, reduced
tissues. Up to 10 TLRs have been identified in humans.
red-cell deformability, and microvascular thrombosis. Inflammation
At the same time, these receptors also sense endogenous molecules
can cause dysfunction of the vascular endothelium, accompanied by
released from injured cells—so-called damage-associated molecular
cell death and loss of barrier integrity, giving rise to subcutaneous and
patterns (DAMPs), such as high-mobility group protein B1, S100 pro-
body-cavity edema. An excessive and uncontrolled release of nitric
teins, and extracellular RNA, DNA, and histones. The release of DAMPs
oxide causes vasomotor collapse, opening of arteriovenous shunts,
during sterile injuries such as those incurred during trauma gives rise to
and pathologic shunting of oxygenated blood from susceptible tissues.
the concept that the pathogenesis of multiple-organ failure may be sim-
In addition, mitochondrial damage due to oxidative stress and other
ilar in sepsis and noninfectious critical illness. In addition to activating
mechanisms impairs cellular oxygen utilization. The slowing of oxi-
the proinflammatory cytokines, the inflammatory responses implicated
dative metabolism, in parallel with impaired oxygen delivery, reduces
in the pathogenesis of sepsis also activate the complement system,
cellular O2 extraction. Yet energy (i.e., ATP) is still needed to support
platelet-activating factor, arachidonic acid metabolites, and nitric oxide.
basal, vital cellular function, which derives from glycolysis and fer-
Coagulation Abnormalities Sepsis is commonly associated mentation and thus yields H+ and lactate. With severe or prolonged
with coagulation disorders and frequently leads to disseminated insult, ATP levels fall beneath a critical threshold, bioenergetic failure

ensues, toxic reactive oxygen species are released, and apoptosis leads 2047
emergency. The general manifestations of shock include arterial
to irreversible cell death and organ failure. The actual morphologic hypotension with evidence of tissue hypoperfusion (e.g., oliguria,
changes in sepsis-induced organ failure are also complex. Generally, altered mental status, poor peripheral perfusion, or hyperlactemia).
organs such as the lung undergo extensive microscopic changes, while
other organs may undergo rather few histologic changes. In fact, some
organs (e.g., the kidney) may lack significant structural damage while ■■CLINICAL MANIFESTATIONS
still having significant tubular-cell changes that impair function. The specific clinical manifestations of sepsis are quite variable, depend-
ing on the initial site of infection, the offending pathogen, the pattern
Anti-Inflammatory Mechanisms The immune system harbors of acute organ dysfunction, the underlying health of the patient, and
humoral, cellular, and neural mechanisms that may exacerbate the the delay before initiation of treatment. The signs of both infection and
potentially harmful effects of the proinflammatory response. Phago- organ dysfunction may be subtle. Guidelines provide a long list of
cytes can switch to an anti-inflammatory phenotype that promotes potential warning signs of incipient sepsis (Table 297-1). Once sepsis
tissue repair, while regulatory T cells and myeloid-derived suppressor has been established and the inciting infection is assumed to be under
cells further reduce inflammation. The so-called neuroinflammatory control, the temperature and white blood cell (WBC) count often return
reflex may also contribute: sensory input is relayed through the affer- to normal. However, organ dysfunction typically persists.
ent vagus nerve to the brainstem, from which the efferent vagus nerve
activates the splenic nerve in the celiac plexus, with consequent norepi- Cardiorespiratory Failure Two of the most commonly affected

nephrine release in the spleen and acetylcholine secretion by a subset of organ systems in sepsis are the respiratory and cardiovascular systems.
CD4+ T cells. The acetylcholine release targets α7 cholinergic receptors Respiratory compromise classically manifests as acute respiratory distress
on macrophages, reducing proinflammatory cytokine release. Disrup- syndrome (ARDS), defined as hypoxemia and bilateral infiltrates of non-
tion of this neural-based system by vagotomy renders animals more cardiac origin that arise within 7 days of the suspected infection. ARDS
vulnerable to endotoxin shock, while stimulation of the efferent vagus can be classified by Berlin criteria as mild (PaO2/FiO2, 201–300 mmHg),
nerve or α7 cholinergic receptors attenuates systemic inflammation in moderate (101–200 mmHg), or severe (≤100 mmHg). A common com-
experimental sepsis. peting diagnosis is hydrostatic edema secondary to cardiac failure or
volume overload. Although traditionally identified by elevated pulmo-
Immune Suppression Patients who survive early sepsis but nary capillary wedge measurements from a pulmonary artery catheter
remain dependent on intensive care occasionally demonstrate evidence (>18 mmHg), cardiac failure can be objectively evaluated on the basis
of a suppressed immune system. These patients may have ongoing of clinical judgment or focused echocardiography.
infectious foci despite antimicrobial therapy or may experience the Cardiovascular compromise typically presents as hypotension. The
reactivation of latent viruses. Multiple investigations have documented cause can be frank hypovolemia, maldistribution of blood flow and
reduced responsiveness of blood leukocytes to pathogens in patients intravascular volume due to diffuse capillary leakage, reduced sys-
with sepsis; these findings were recently corroborated by post-mortem temic vascular resistance, or depressed myocardial function. After ade-
studies revealing strong functional impairments of splenocytes har- quate volume expansion, hypotension frequently persists, requiring
vested from ICU patients who died of sepsis. Immune suppression was the use of vasopressors. In early shock, when volume status is reduced,
evident in the lungs as well as the spleen; in both organs, the expression systemic vascular resistance may be quite high with low cardiac out-
of ligands for T cell–inhibitory receptors on parenchymal cells was put; after volume repletion, however, this picture may rapidly change
increased. Enhanced apoptotic cell death, especially of B cells, CD4+ to low systemic vascular resistance and high cardiac output.
T cells, and follicular dendritic cells, has been implicated in sepsis-
associated immune suppression and death. In a cohort of >1000 ICU Kidney Injury Acute kidney injury (AKI) is documented in >50%
admissions for sepsis, secondary infections developed in 14% of of septic patients, increasing the risk of in-hospital death by six- to
patients, and the associated genomic response at the time of infection eightfold. AKI manifests as oliguria, azotemia, and rising serum crea-
was consistent with immune suppression, including impaired glycolysis tinine levels and frequently requires dialysis. The mechanisms of sepsis-
and cellular gluconeogenesis. The most common secondary infections induced AKI are incompletely understood. AKI may occur in up to 25%
included catheter-related bloodstream infections, ventilator-associated of patients in the absence of overt hypotension. Current mechanistic
infections, and abdominal infections. What is not yet understood is the work suggests that a combination of diffuse microcirculatory blood-
optimal way to identify those sepsis patients who have hyperinflamed flow abnormalities, inflammation, and cellular bioenergetic responses
rather than immunosuppressed phenotypes. Similarly, it is unknown to injury contribute to sepsis-induced AKI beyond just organ ischemia.
whether the dysfunctional immune system is driving organ dysfunc- Neurologic Complications Typical central nervous system dys-
tion and secondary infections or whether the immune system itself is function presents as coma or delirium. Imaging studies typically show
just another dysfunctional organ. no focal lesions, and electroencephalographic findings are usually
consistent with nonfocal encephalopathy. Sepsis-associated delirium is
APPROACH TO THE PATIENT considered a diffuse cerebral dysfunction caused by the inflammatory
Sepsis and Septic Shock response to infection without evidence of a primary central nervous
system infection. Consensus guidelines recommend delirium screening
At the bedside, a clinician begins by asking, “Is this patient septic?” with valid and reliable tools such as the Confusion Assessment Method
Consensus criteria for sepsis and septic shock agree on core diagnostic for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delir-
elements, including suspected or documented infection accompa- ium Screening Checklist (ICDSC). Critical-illness polyneuropathy and
nied by acute, life-threatening organ dysfunction. If infection is myopathy are also common, especially in patients with a prolonged
documented, the clinician must determine the inciting cause and course. For survivors of sepsis, neurologic complications can be severe.
the severity of organ dysfunction, usually by asking: “What just In a national (U.S.) representative prospective cohort of >1000 elderly
happened?” Severe infection can be evident, but it is often quite patients with severe sepsis, moderate to severe cognitive impairment
difficult to recognize. Many infection-specific biomarkers and increased by 10.6 percentage points among patients who survived
molecular diagnostics are under study to help discriminate sterile severe sepsis (odds ratio, 3.34; 95% confidence interval [CI], 1.53–7.25)
inflammation from infection, but these tools are not commonly used. over that among survivors of nonsepsis hospitalizations. Many of these
The clinician’s acumen is still crucial to the diagnosis of infection. limitations persisted for up to 8 years.
Next, the primary physiologic manifestations of organ dysfunction
can be assessed quickly at the bedside with a six-organ framework,
Additional Manifestations Many other abnormalities occur in
sepsis, including ileus, elevated aminotransferase levels, altered glyce-
yielding the SOFA score. Particular focus should then be placed
mic control, thrombocytopenia and disseminated intravascular coag-
on the presence or absence of shock, which constitutes a clinical
ulation, adrenal dysfunction, and sick euthyroid syndrome. Adrenal

2048 dysfunction in sepsis is widely studied and is Variable Threshold Units
thought to be related more to reversible dys- Heart rate >90 BPM
function of the hypothalamic–pituitary axis or
tissue glucocorticoid resistance than to direct Respiratory rate >20 BPM
damage to the adrenal gland. The diagnosis Temperature <36 C
is difficult to establish. Recent clinical prac- SIRS
White blood cell count >12 k/uL
tice guidelines do not recommend use of the variables
adrenocorticotropic hormone stimulation test Temperature >38 C
or determination of the plasma cortisol level White blood cell count <4 k/uL
to detect relative glucocorticoid insufficiency.
Bands >10 %
■■DIAGNOSIS
Systolic blood pressure ≤100 mmHg
Laboratory and Physiologic Findings
Serum creatinine ≥1.2 mmHg
A variety of laboratory and physiologic changes
are found in patients with suspected infection PaO2/FiO2 ratio ≤300
who are at risk for sepsis. In a 12-hospital cohort Platelets ≤150 k/uL
of electronic health records related to >70,000 SOFA
PART 8
encounters (Fig. 297-2), only tachycardia (heart variables Glasgow coma scale <15
rate, >90 beats per min) was present in >50% of Bilirubin ≥1.2 mg/dL
encounters; the most common accompanying
Mechanical ventilation Present/absent
abnormalities were tachypnea (respiratory rate,
>20 breaths per min), hypotension (systolic Vasopressors Present/absent

blood pressure, ≤100 mmHg), and hypoxia Vasopressors More than one
(SaO2, ≤90%). Leukocytosis (WBC count,
>12,000/μL) was present in fewer than one- FIGURE 297-2 Distribution of SIRS and SOFA variables among infected patients at risk for sepsis, as
documented in the electronic health record. Dark green bars represent the proportion of such patients
third of patients and leukopenia (WBC count, with abnormal findings; light green bars, the proportion with normal findings; and white bars, the proportion
<4000/μL) in fewer than 5%. Notably, many with missing data. (Adapted from CW Seymour et al: Assessment of clinical criteria for sepsis: For the Third
features that may identify acute organ dys- International Consensus Definitions for Sepsis and Septic Shock [Sepsis-3]. JAMA 315:762, 2016.)
function, such as platelet count, total bilirubin,
or serum lactate level, are measured in only a
small minority of at-risk encounters. If measured, metabolic acidosis similar to that of more complicated measures of organ dysfunction.
with anion gap may be detected, as respiratory muscle fatigue occurs The qSOFA score is undergoing broader evaluation in other cohorts, in
in sepsis-associated respiratory failure. Other, less common findings low-and middle-income settings, and in algorithms linked to clinical
include serum hypoalbuminemia, troponin elevation, hypoglycemia, decision-making. Recent work has also shown that, although SIRS
and hypofibrinogenemia. criteria may be fulfilled in sepsis, they sometimes are not and do not
meaningfully contribute to the identification of patients with suspected
Diagnostic Criteria There is no specific test for sepsis, nor is there infection who are at greater risk of a poor course, ICU admission, or
a gold-standard method for determining whether a patient is septic. In death—outcomes more common among patients with sepsis than
fact, the definition of sepsis can be written as a logic statement: among those without.
As stated above, recent definitions have specified that septic shock
sepsis = f (threat to life | organ dysfunction | dysregulated host response | infection),
is a subset of sepsis in which circulatory and cellular/metabolic abnor-
where sepsis is the dependent variable, which in turn is a function of malities are profound enough to substantially increase mortality risk,
four independent variables linked in a causal pathway, with—from left but the application of this definition as a criterion for enrollment of
to right—one conditional upon the other. There may be uncertainty patients varies significantly in clinical trials, observational studies, and
about whether each variable exists, whether it can be measured, and quality improvement work. For clarity, criteria are proposed for septic
whether the causal and conditional relationships hold. If we assume shock that include (1) sepsis plus (2) the need for vasopressor therapy
that organ dysfunction exists and can be measured, then attributing the to elevate mean arterial pressure to ≥65 mmHg, with (3) a serum lactate
marginal degradation in function to a dysregulated host response is not concentration >2.0 mmol/L after adequate fluid resuscitation.
simple and requires the ability to determine preexisting dysfunction, The new definitions and diagnostic criteria were externally vali-
other noninfectious contributions to organ dysfunction, and—ideally— dated in >1 million encounters stored in electronic health records. Nev-
the mechanism by which the host response to an infection causes organ ertheless, given the uncertainty around the diagnosis of sepsis, Sepsis-3
dysfunction. is undergoing both validation in prospective studies and incorporation
In order to sort through these complex details, clinicians need simple into clinical practice and quality improvement initiatives.
bedside criteria to operationalize the logic statement (Fig. 297-3). With Arterial lactate is a long-studied marker of tissue hypoperfusion,
this mandate, the Sepsis Definitions Task Force recommended that, once and hyperlactemia and delayed lactate clearance are associated with
infection is suspected, clinicians consider whether it has caused organ a greater incidence of organ failure and death in sepsis. In a study of
dysfunction by determining a SOFA score. The SOFA score ranges from >1200 patients with suspected infection, 262 (24%) of 1081 patients
0 to 24 points, with up to 4 points accrued across six organ systems. The exhibited an elevated lactate concentration (≥2.5 mmol/L) even in
SOFA score is widely studied in the ICU among patients with infection, the setting of normal systolic blood pressure (>90 mmHg) and were
sepsis, and shock. With ≥2 new SOFA points, the infected patient is con- at elevated risk of 28-day in-hospital mortality. However, lactic aci-
sidered septic and may be at ≥10% risk of in-hospital death. dosis may occur in the presence of alcohol intoxication, liver disease,
Because the SOFA score requires multiple laboratory tests and may diabetes mellitus, administration of total parenteral nutrition, or
be costly to measure repeatedly, the quick SOFA (qSOFA) score was pro- antiretroviral treatment, among other conditions. Furthermore, in
posed as a clinical prompt to identify patients at high risk of sepsis outside sepsis, an elevated lactate concentration may simply be the manifes-
the ICU, whether on the medical ward or in the emergency department. tation of impaired clearance. These factors may confound the use of
The qSOFA score ranges from 0 to 3 points, with 1 point each for systolic lactate as a stand-alone biomarker for the diagnosis of sepsis; thus it
hypotension (≤100 mmHg), tachypnea (≥22 breaths/min), or altered should be used in the context of other markers of infection and organ
mentation. A qSOFA score of ≥2 points has a predictive value for sepsis dysfunction.

Health Health 2049
Uncomplicated Uncomplicated
infection Organ infection
Organ
dysfunction
dysfunction
Sepsis Sepsis

FIGURE 297-3 Schematic of the importance of accurate, easy-to-use criteria for sepsis and its components, infection and organ dysfunction. In the ideal case (left),
criteria clearly distinguish sepsis patients from other patients with uncomplicated infection or organ dysfunction. The reality (right), however, is that existing criteria
fail to make clear distinctions, leaving a significant proportion of patients in areas of uncertainty. (Adapted from DC Angus et al: A framework for the development and
interpretation of different sepsis definitions and clinical criteria. Crit Care Med 44:e113, 2016.)
uncontrolled infection. Early resuscitation requires a structured

TREATMENT
approach including the administration of IV fluids and vasopres-
Sepsis and Septic Shock sors, with oxygen therapy and mechanical ventilation to support
injured organs. The exact components required to optimize resus-
EARLY TREATMENT OF SEPSIS AND SEPTIC SHOCK citation, such as choice and amount of fluid, appropriate type and
Recommendations for sepsis care begin with prompt diagnosis. Rec- intensity of hemodynamic monitoring, and role of adjunctive vaso-
ognition of septic shock by a clinician constitutes an emergency in active agents, all remain controversial, even after the completion and
which immediate treatment can be life-saving. Up-to-date guidelines reporting of recent large randomized trials.
for treatment are derived from international clinical practice guide- Evidence from an older study suggests that protocol-based, early
lines provided by the Surviving Sepsis Campaign. This consortium of goal-directed therapy (EGDT) may confer a greater survival advan-
critical care, infectious disease, and emergency medicine professional tage than clinical assessments of organ perfusion and management
societies has issued three iterations of clinical guidelines for the without a protocol. EGDT included an aggressive resuscitation pro-
management of patients with sepsis and septic shock (Table 297-2). tocol with specific hemodynamic thresholds for fluid administration,
The initial management of infection requires several steps: form- blood transfusion, and use of ionotropes. Given the many controver-
ing a probable diagnosis, obtaining samples for culture, initiating sial features of this older single-center trial, the recent ProCESS trial
empirical antimicrobial therapy, and achieving source control. More compared protocol-based standard care with protocol-based EGDT
than 30% of patients with severe sepsis require source control, mainly and usual care in >31 emergency departments in the United States.
for abdominal, urinary, and soft-tissue infections. The mortality rate Among 1341 patients, the 60-day in-hospital mortality rate for pro-
is lower among patients with source control than among those with- tocol-based standard care (18.2%) was similar to that for usual care
out, although the timing of intervention is debated. For empirical (18.9%) and protocol-based EGDT (21%). The ARISE trial confirmed
antibiotic therapy (Table 297-3), the appropriate choice depends on this finding, showing that, among 1600 patients with early septic
the suspected site of infection, the location of infection onset (i.e., shock at 51 centers in Australia and New Zealand, 90-day mortality
the community, a nursing home, or a hospital), the patient’s medical was similar for EGDT and usual care. Finally, the ProMISe trial,
history, and local microbial susceptibility patterns. In a single-center which enrolled 1260 patients in 56 hospitals in England, found
study of >2000 patients with bacteremia, the number of patients that EGDT offered no mortality benefit in early septic shock but
who needed to receive appropriate antimicrobial therapy in order to did increase treatment intensity and cost. Multiple subsequent
prevent one patient death was 4.0 (95% CI, 3.7–4.3). meta-analyses of the ProCESS, ARISE, and ProMISe trials confirmed
Antibiotic delays may be deadly. For every 1-h delay among patients that EGDT offers no mortality benefit while increasing health care
with sepsis, a 3–7% increase in the odds of in-hospital death is reported. utilization and ICU admission in well-resourced countries. Modified
Although meta-analyses report conflicting results, international clini- versions of EGDT were also tested in lower-resourced settings, with
cal practice guidelines recommend the administration of appropriate no change in outcome. Thus EGDT is no longer recommended as
broad-spectrum antibiotics within 1 h of recognition of severe sepsis the primary strategy for early resuscitation in septic shock. None-
or septic shock. Empirical antifungal therapy should be administered theless, some form of resuscitation is considered essential, and a
only to septic patients at high risk for invasive candidiasis. standardized approach, akin to the use of “trauma teams,” has been
The treatment elements listed above form the basis for two advocated to ensure prompt care. The patient should be moved to an
“bundles” of care: an initial management bundle to be completed appropriate setting, such as the ICU, for ongoing care.
within 3 h of presentation and a management bundle to be completed
SUBSEQUENT TREATMENT OF SEPSIS AND SEPTIC SHOCK
within 6 h. The initial management bundle includes (1) early admin-
istration of appropriate broad-spectrum antibiotics, (2) collection of After initial resuscitation, attention is focused on monitoring and
blood for culture before antibiotic administration, and (3) measure- support of organ function, avoidance of complications, and de-
ment of serum lactate levels. The management bundle includes escalation of care when possible.
(1) an intravenous fluid bolus, (2) treatment with vasopressors for Monitoring Hemodynamic monitoring devices may clarify the
persistent hypotension or shock, and (3) re-measurement of serum primary physiologic manifestations in sepsis and septic shock. The
lactate levels. Implementation of these two bundles has been associ- clinical usefulness of these monitoring devices can be attributable
ated with improved outcome in large multinational studies. to the device itself, the algorithm linked to the device, or the static/
Other elements of the initial management bundle are cardiore- dynamic target of the algorithm. Decades ago, the standard care of
spiratory resuscitation and mitigation of the immediate threats of shock patients included invasive devices like the pulmonary artery

2050 TABLE 297-2 Elements of Care in Sepsis and Septic Shock: Recommendations Adapted from International Consensus Guidelines
Resuscitation
Sepsis and septic shock constitute an emergency, and treatment should begin right away.
Resuscitation with IV crystalloid fluid (30 mL/kg) should begin within the first 3 h.
Saline or balanced crystalloids are suggested for resuscitation.
If the clinical examination does not clearly identify the diagnosis, hemodynamic assessments (e.g., with focused cardiac ultrasound) can be considered.
In patients with elevated serum lactate levels, resuscitation should be guided towards normalizing these levels when possible.
In patients with septic shock requiring vasopressors, the recommended target mean arterial pressure is 65 mmHg.
Hydroxyethyl starches and gelatins are not recommended.
Norepinephrine is recommended as the first-choice vasopressor.
Vasopressin should be used with the intent of reducing the norepinephrine dose.
The use of dopamine should be avoided except in specific situations—e.g., in those patients at highest risk of tachyarrhythmias or relative bradycardia.
Dobutamine use is suggested when patients show persistent evidence of hypoperfusion despite adequate fluid loading and use of vasopressors.
Red blood cell transfusion is recommended only when the hemoglobin concentration decreases to <7.0 g/dL in the absence of acute myocardial infarction, severe
hypoxemia, or acute hemorrhage.
Infection Control
PART 8
So long as no substantial delay is incurred, appropriate samples for microbiologic cultures should be obtained before antimicrobial therapy is started.
IV antibiotics should be initiated as soon as possible (within 1 h); specifically, empirical broad-spectrum therapy should be used to cover all likely pathogens.
Antibiotic therapy should be narrowed once pathogens are identified and their sensitivities determined and/or once clinical improvement is evident.
If needed, source control should be undertaken as soon as is medically and logistically possible.
Daily assessment for de-esclation of antimicrobial therapy should be conducted.

Respiratory Support
A target tidal volume of 6 mL/kg of predicted body weight (compared with 12 mL/kg in adult patients) is recommended in sepsis-induced ARDS.
A higher PEEP rather than a lower PEEP is used in moderate to severe sepsis-induced ARDS.
In severe ARDS (PaO2/FIO2, <150 mmHg), prone positioning is recommended, and recruitment maneuvers and/or neuromuscular blocking agents for ≤48 h are
suggested.
A conservative fluid strategy should be used in sepsis-induced ARDS if there is no evidence of tissue hypoperfusion.
Routine use of a pulmonary artery catheter is not recommended.
Spontaneous breathing trials should be used in mechanically ventilated patients who are ready for weaning.
General Supportive Care
Patients requiring a vasopressor should have an arterial catheter placed as soon as is practical.
Hydrocortisone is not suggested in septic shock if adequate fluids and vasopressor therapy can restore hemodynamic stability.
Continuous or intermittent sedation should be minimized in mechanically ventilated sepsis patients, with titration targets used whenever possible.
A protocol-based approach to blood glucose management should be used in ICU patients with sepsis, with insulin dosing initiated when two consecutive blood
glucose levels are >180 mg/dL.
Continuous or intermittent renal replacement therapy should be used in patients with sepsis and acute kidney injury.
Pharmacologic prophylaxis (unfractionated heparin or low-molecular-weight heparin) against venous thromboembolism should be used in the absence of
contraindications.
Stress ulcer prophylaxis should be given to patients with risk factors for gastrointestinal bleeding.
The goals of care and prognosis should be discussed with patients and their families.
Abbreviations: ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end-expiratory pressure.
Source: Adapted from A Rhodes et al: Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45:486,
2017.
catheter (PAC), also known as the continuous ScvO2 catheter. The may require administration of IV fluids or vasopressors, blood trans-
PAC can estimate cardiac output and measure mixed venous oxygen fusions, or ventilatory support.
saturation, among other parameters, to refine the etiology of shock Many crystalloids can be used in septic shock, including 0.9% nor-
and potentially influence patient outcomes. Recently, a Cochrane mal saline, Ringer’s lactate, Hartmann’s solution, and Plasma-Lyte.
review of 2923 general-ICU patients (among whom the proportion of Because crystalloid solutions vary in tonicity and inorganic/organic
patients in shock was not reported) found no difference in mortality anions, few of these preparations closely resemble plasma. Normal
with or without PAC management, and the PAC therefore is no lon- saline is widely used in the United States. Colloid solutions (e.g.,
ger recommended for routine use. Instead, a variety of noninvasive albumin, dextran, gelatins, or hydroxyethyl starch) are the most
monitoring tools, such as arterial pulse contour analysis (PCA) or widely used fluids in critically ill patients, with variability across
focused echocardiography, can provide continuous estimates of ICUs and countries. A clinician’s choice among colloids is influenced
parameters such as cardiac output, beat-to-beat stroke volume, and by availability, cost, and the desire to minimize interstitial edema.
pulse pressure variation. These tools, along with passive leg-raise Many think that a greater intravascular volume is gained by use of
maneuvers or inferior vena cava collapsibility on ultrasound, can colloids in shock, but the effects of colloids are modified by molec-
help determine a patient’s volume responsiveness but require that a ular weight and concentration as well as by vascular endothelial
variety of clinical conditions be met (e.g., patient on mechanical venti- changes during inflammation. A network meta-analysis using direct
lation, sinus rhythm); in addition, more evidence from larger random- and indirect comparisons in sepsis found evidence of higher mortal-
ized trials on the impact of these tools in daily management is needed. ity with starch than with crystalloids (relative risk [RR], 1.13; 95% CI,
0.99–1.30 [high confidence]) and no difference between albumin (RR,
Support Of Organ Function The primary goal of organ support is 0.83; 95% CI, 0.65, 1.04 [moderate confidence]) or gelatin (RR, 1.24;
to improve delivery of oxygen to the tissues as quickly as possible. 95%CI, 0.61, 2.55 [very low confidence]) and crystalloids. In general,
Depending on the underlying physiologic disturbance, this step crystalloids are recommended on the basis of strong evidence as

TABLE 297-3 Initial Antimicrobial Therapy for Severe Sepsis with No (pH <7.20) are common indications for mechanical ventilatory 2051
Obvious Source in Adults with Normal Renal Function support. Endotracheal intubation protects the airway, and positive-
CLINICAL CONDITION ANTIMICROBIAL REGIMENSa pressure breathing allows oxygen delivery to metabolically active
Septic shock The many acceptable regimens include (1)
organs in favor of inspiratory muscles of breathing and the dia-
(immunocompetent piperacillin-tazobactam (3.375–4.5 g q6h), (2) phragm. An experiment in dogs showed that the relative proportion
adult) cefepime (2 g q12h), or (3) meropenem (1 g q8h) of cardiac output delivered to respiratory muscles in endotoxic shock
or imipenem-cilastatin (0.5 g q6h). If the patient is decreased by fourfold with spontaneous ventilation over that with
allergic to β-lactam antibiotics, use (1) aztreonam mechanical ventilation. During intubation, patients in shock should
(2 g q8h) or (2) ciprofloxacin (400 mg q12h) or be closely monitored for vasodilatory effects of sedating medica-
levofloxacin (750 mg q24h). Add vancomycin
(loading dose of 25–30 mg/kg, then 15–20 mg/kg
tions or compromised cardiac output due to increased intrathoracic
q8–12h) to each of the above regimens. pressure, both of which may cause hemodynamic collapse. With
Neutropenia Regimens include (1) cefepime (2 g q8h), (2) hemodynamic instability, noninvasive mask ventilation may be less
(<500 neutrophils/μL) meropenem (1 g q8h) or imipenem-cilastatin suitable in patients experiencing sepsis-associated acute respiratory
(0.5 g q6h) or doripenem (500 mg q8h), or failure.
(3) piperacillin-tazobactam (3.375 g q4h). Add
vancomycin (as above) if the patient has a suspected Adjuncts One of the great disappointments in sepsis management
central line–associated bloodstream infection, severe over the past 30 years has been the failure to convert advances in

mucositis, skin/soft tissue infection, or hypotension. our understanding of the underlying biology into new therapies.
Add tobramycin (5–7 mg/kg q24h) plus vancomycin Researchers have tested both highly specific agents and those with
(as above) plus caspofungin (one dose of 70 mg, more pleotropic effects. The specific agents can be divided into those
then 50 mg q24h) if the patient has severe sepsis/
designed to interrupt the initial cytokine cascade (e.g., anti-LPS or
septic shock.
anti-proinflammatory cytokine strategies) and those that interfere
Splenectomy Use ceftriaxone (2 g q24h, or—in meningitis—2 g
q12h). If the local prevalence of cephalosporin-
with dysregulated coagulation (e.g., antithrombin or activated
resistant pneumococci is high, add vancomycin protein C). Recombinant activated protein C (aPC) was one of the
(as above). If the patient is allergic to β-lactam first agents approved by the U.S. Food and Drug Administration
antibiotics, use levofloxacin (750 mg q24h) or and was the most widely used. A large, randomized, double-blind,
moxifloxacin (400 mg q24h) plus vancomycin (as placebo-controlled, multicenter trial of aPC in severe sepsis (the
above). PROWESS trial) was reported in 2001; the data suggested an abso-
All agents are administered by the intravenous route.
a
lute risk reduction of up to 6% among aPC-treated patients with
Source: Adapted in part from DN Gilbert et al: The Sanford Guide to Antimicrobial severe sepsis. However, subsequent phase 3 trials failed to confirm
Therapy, 47th ed, 2017; and from RS Munford: Sepsis and septic shock, in DL this effect, and the drug was withdrawn from the market. It is no
Kasper et al (eds). Harrison’s Principles of Internal Medicine, 19th ed. New York,
McGraw-Hill, 2015, p 1757. longer recommended in the care of sepsis or septic shock.
Many adjunctive treatments in sepsis and septic shock target
changes in the innate immune response and coagulation cascade.
first-line fluids for sepsis resuscitation, with specific caveats; their Specific adjuncts like glucocorticoids in septic shock have continued
use is guided by resolution of hypotension, oliguria, altered men- to be widely used. A large negative clinical trial and a conflicting
tation, and hyperlactemia. Only weak evidence supports the use systematic review in 2009 extended the debate about whether
of balanced crystalloids, and guidelines recommend against using glucocorticoids lower 28-day mortality or improve shock reversal.
hydroxyethyl starches for intravascular volume replacement. Most meta-analyses report no change in mortality but an increase in
When circulating fluid volume is adequate, vasopressors are rec- shock reversal with glucocorticoid treatment. The recent HYPRESS
ommended to maintain perfusion of vital organs. Vasopressors such trial found no difference between patients with severe sepsis who
as norepinephrine, epinephrine, dopamine, and phenylephrine differ were treated with glucocorticoids and control patients in terms of
in terms of half-life, β- and α-adrenergic stimulation, and dosing reg- the development of shock or the mortality rate. These data and oth-
imens. Recent evidence comes from the SOAP II trial, a double-blind ers led to a suggestion in international clinical practice guidelines
randomized clinical trial at eight centers comparing norepinephrine against using IV hydrocortisone to treat septic shock if adequate
with dopamine in 1679 undifferentiated ICU patients with shock, fluid resuscitation and vasopressor therapy are able to restore hemo-
of whom 63% were septic. Although no difference was observed in dynamic stability. If not, the guidelines suggest the administration of
28-day mortality or in predefined septic-shock subgroup, arrhythmias IV hydrocortisone at a dose of 200 mg per day (weak recommenda-
were significantly greater with dopamine. These findings were con- tion, low quality of evidence).
firmed in a subsequent meta-analysis. As a result, expert opinion and Among other adjuncts, IV immunoglobulin may be associated
consensus guidelines recommend norepinephrine as the first-choice with potential benefit, but significant questions remain and such
vasopressor in septic shock. Levels of the endogenous hormone vaso- treatment is not part of routine practice. Despite a large number
pressin may be low in septic shock, and the administration of vaso- of observational studies suggesting that statin use mitigates the
pressin can reduce the norepinephrine dose. Consensus guidelines incidence or outcome of sepsis and severe infection, there are no
suggest adding vasopressin (up to 0.03 U/min) in patients without confirmatory randomized controlled trials, and statins are not an
a contraindication to norepinephrine, with the intent of raising mean element in routine sepsis care.
arterial pressure or decreasing the norepinephrine dose. There may De-Escalation of Care Once patients with sepsis and septic shock
be select indications for use of alternative vasopressors—e.g., when are stabilized, it is important to consider which therapies are no
tachyarrhythmias from dopamine or norepinephrine, limb ischemia longer required and how care can be minimized. The de-escalation
from vasopressin, or other adverse effects dictate. of initial broad-spectrum therapy, which observational evidence
The transfusion of red blood cells to high thresholds (>10 g/dL) indicates is safe, may reduce the emergence of resistant organisms
had been suggested as part of EGDT in septic shock. However, the as well as potential drug toxicity and costs. The added value of com-
recent Scandinavian TRISS trial in 1005 septic shock patients demon- bination antimicrobial therapy over that of adequate single-agent
strated that a lower threshold (7 g/dL) resulted in 90-day mortality antibiotic therapy in severe sepsis has not been established. Current
rates similar to those with a higher threshold (9 g/dL) and reduced guidelines recommend combination antimicrobial therapy only
transfusions by almost 50%. for neutropenic sepsis and sepsis caused by Pseudomonas. Large
Significant hypoxemia (PaO2, <60 mmHg; or SaO2, <90%), trials are under way in the United States to determine how serum
hypoventilation (rising PaCO2), increased work of breathing, and biomarkers like procalcitonin can assist clinicians in minimizing
inadequate or unsustainable compensation for metabolic acidosis antibiotic exposure, while European trials are indicating that this

2052 biomarker may lead to a reduction in the duration of treatment Group on Sepsis-Related Problems of the European Society of Inten-
and in daily defined doses in critically ill patients with a presumed sive Care Medicine. Intensive Care Med 22:707, 1996.
bacterial infection. Yealy DM et al: A randomized trial of protocol-based care for early
septic shock. N Engl J Med 370:1683, 2014.
■■PROGNOSIS
Before modern intensive care, sepsis and septic shock were highly
lethal, with infection leading to compromise of vital organs. Even
298 Cardiogenic Shock and

with intensive care, nosocomial mortality rates for septic shock often
exceeded 80% as recently as 30 years ago. Now, the U.S. Burden of
Disease Collaborators report that the primary risk factor for sepsis Pulmonary Edema
and septic shock—i.e., infection—is the fifth leading cause of years
of productive life lost because of premature death. More than half David H. Ingbar, Holger Thiele
of sepsis cases require ICU admission, representing 10% of all ICU
admissions. However, with advances in training, surveillance, moni-
toring, and prompt initiation of supportive care for organ dysfunction, Cardiogenic shock (CS) and pulmonary edema are life-threatening
the mortality rate from sepsis and septic shock is now closer to 20% high acuity conditions that require treatment as medical emergencies,
in many series. Although some data suggest that mortality trends are usually in an intensive care unit (ICU) or cardiac intensive care unit
PART 8
even lower, attention has been focused on the trajectory of recovery (CICU). The most common joint etiology is severe left ventricular
among survivors. Patients who survive to hospital discharge after (LV) dysfunction from myocardial infarction (MI) that leads to pul-
sepsis remain at increased risk of death in the following months and monary congestion and/or systemic hypoperfusion (Fig. 298-1). The
years. Those who survive often suffer from impaired physical or pathophysiology of pulmonary edema and shock are discussed in
neurocognitive dysfunction, mood disorders, and low quality of life.
Chaps. 33 and 296, respectively.

In many studies, it is difficult to determine the causal role of sepsis.
However, an analysis of the Health and Retirement Study—a large CARDIOGENIC SHOCK
longitudinal cohort study of aging Americans—suggested that severe CS is a low cardiac output state resulting in life-threatening end-organ
sepsis significantly accelerated physical and neurocognitive decline. hypoperfusion and hypoxia. The clinical presentation is typically char-
Among survivors, the rate of hospital readmission within 90 days after acterized by persistent hypotension (<90 mmHg systolic blood pressure
sepsis exceeds 40%. [BP]) unresponsive to volume replacement and is accompanied by clini-
cal features of peripheral hypoperfusion, such as elevated arterial lactate
■■PREVENTION
(>2 mmol/L). Objective hemodynamic parameters such as cardiac index
In light of the persistently high mortality risk in sepsis and septic
or pulmonary capillary wedge pressure can help confirm the diagnosis,
shock, prevention may be the best approach to reducing avoidable
but are not mandatory. The in-hospital mortality rates range from 40 to
deaths, but preventing sepsis is a challenge. The aging of the popula-
60%, depending on shock severity and the associated underlying cause.
tion, the overuse of inappropriate antibiotics, the rising incidence of
Acute MI with LV dysfunction remains the most frequent cause of CS
resistant microorganisms, and the use of indwelling devices and cathe-
with other causes listed in Table 298-1. Circulatory failure based on
ters contribute to a steady burden of sepsis cases. The number of cases
cardiac dysfunction may be caused by primary myocardial failure, most
could be reduced by avoiding unnecessary antibiotic use, limiting use
commonly secondary to acute MI (Chap. 269), and less frequently by car-
of indwelling devices and catheters, minimizing immune suppression
diomyopathy or myocarditis (Chap. 254), cardiac tamponade (Chap. 265),
when it is not needed, and increasing adherence to infection control
arrhythmias (Chap. 249), or critical valvular heart disease (Chap. 256).
programs at hospitals and clinics. To facilitate earlier treatment, such
pragmatic work could be complemented by research into the earliest Incidence The incidence of CS complicating acute MI has decreased
pathophysiology of infection, even when symptoms of sepsis are to 5–10%, largely due to increasing use of early mechanical reperfusion
nascent. In parallel, the field of implementation science could inform therapy for acute MI. Shock is more common with ST-elevation MI
how best to increase adoption of infection control in high-risk settings (STEMI) than with non-STEMI (Chap. 269).
and could guide appropriate care. LV failure accounts for ~80% of cases of CS complicating acute MI.
Acute severe mitral regurgitation (MR), ventricular septal rupture
■■FURTHER READING (VSR), predominant right ventricular (RV) failure, and free wall rup-
Angus DC et al: Epidemiology of severe sepsis in the United States: ture or tamponade account for the remainder. A recently recognized
Analysis of incidence, outcome, and associated costs of care. Crit Care uncommon cause of transient CS is the Takotsubo syndrome.
Med 29:1303, 2001.
Boomer JS et al: Immunosuppression in patients who die of sepsis and Pathophysiology The understanding of the complex pathophysi-
multiple organ failure. JAMA 306:2594, 2011. ology of CS has evolved over the past decades. In general, a profound
De Backer D et al: Comparison of dopamine and norepinephrine in the depression of myocardial contractility results in a deleterious spiral of
treatment of shock. N Engl J Med 362:779, 2010. reduced cardiac output, low blood pressure, and ongoing myocardial
Fleischmann C et al: Assessment of global incidence and mortality ischemia, followed by further contractility reduction (Fig. 298-1). This
of hospital-treated sepsis. Current estimates and limitations. Am J vicious cycle usually leads to death if not interrupted. CS can result in
Respir Crit Care Med 193:259, 2016. both acute and subacute derangements to the entire circulatory sys-
Medzhitov R et al: Disease tolerance as a defense strategy. Science tem. Hypoperfusion of vital organs and extremities remains a clinical
335:936, 2012. hallmark. Although ineffective stroke volume is the inciting event,
Rhodes A et al: Surviving Sepsis Campaign: International guidelines for inadequate circulatory compensation also may contribute to shock. Ini-
management of sepsis and septic shock: 2016. Crit Care Med 45:486, tial peripheral vasoconstriction may improve coronary and peripheral
2017. perfusion at the cost of increased afterload. However, over the course
Rochwerg B et al: Fluid resuscitation in sepsis: A systematic review of CS systemic inflammation response triggered by acute cardiac injury
and network meta-analysis. Ann Intern Med 161:347, 2014. often induces pathologic vasodilatation. Inflammatory cytokines,
Seymour CW et al: Assessment of clinical criteria for sepsis: For the endothelial and inducible nitric oxide synthase may augment NO pro-
Third International Consensus Definitions for Sepsis and Septic duction, accompanied by peroxynitrite, which has a negative inotropic
Shock (Sepsis-3). JAMA 315:762, 2016. effect and is cardiotoxic. Lactic acidosis and hypoxemia contribute to
Vincent JL et al: The SOFA (sepsis-related organ failure assessment) the vicious circle, as severe acidosis reduces the efficacy of endogenous
score to describe organ dysfunction/failure. On behalf of the Working and exogenous catecholamines. During ICU support bleeding and/or

2053
Acute Myocardial Infarction
Left ventricular dysfunction

systolic diastolic
Ventilation
LVEDP ↑
Lung edema ↑
Fluids + + SIRS Cardiac output ↓
inotropes/ Stroke volume ↓
Vasopressors
Mechanical
+ Hypotension
support Hypoxia
device eNOS
iNOS Peripheral perfusion ↓
Bleeding/
Transfusion Coronary
CHAPTER 298 Cardiogenic Shock and Pulmonary Edema

perfusion ↓
Ischemia
+
Reperfusion:
PCI/CABG
NO ↑ Vasoconstriction
Peroxynitrite ↑ fluid retention
Interleukins ↑ Progressive
TNF-α ↑ left ventricular
dysfunction
SVR ↓
Pro-inflammation
Catecholamin sensitivity ↓
Contractility ↓ Death
FIGURE 298-1 Pathophysiology of cardiogenic shock and potential treatment targets. The pathophysiological concept of the expanded cardiogenic shock spiral and
treatment targets. CABG, coronary artery bypass grafting; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; LVEDP, left ventricular end
diastolic pressure; NO, nitric oxide; PCI, percutaneous coronary intervention; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular resistance;
TNF, tumor necrosis factor. (Reproduced and adapted, with permission, from H Thiele et al: Shock in acute myocardial infarction: The Cape Horn for trials? Eur Heart J
31: 1828, 2010.)
transfusions may trigger inflammation and are usually associated with may be present. Typically there is a weak apical pulse and soft S1, and
higher mortality (Fig. 298-1). an S3 gallop may be audible. Acute, severe MR and VSR usually are
associated with characteristic systolic murmurs (Chap. 269). Crackles
Patient Profile In patients with MI, older age, prior MI, diabetes are audible in most patients with LV failure. Oliguria/anuria is com-
mellitus, anterior MI location, and multivessel coronary artery dis- mon. Often CS patients require early mechanical ventilation (~80%)
ease with extensive coronary artery stenoses are associated with an for management of acute hypoxemia, increased work of breathing,
increased risk of CS. Shock associated with a first inferior MI should and hemodynamic instability; catecholamines often are required to
prompt a search for a mechanical cause or RV involvement. CS may maintain adequate blood pressure.
rarely occur in the absence of significant stenosis, as seen in Takotsubo
syndrome or fulminant myocarditis. LABORATORY FINDINGS The white blood cell count and C-reactive
protein typically are elevated. Renal function often is progressively
Timing Shock is present on admission in approximately one- impaired. Newer renal function markers such as Cystatin C or Neu-
quarter of MI patients who develop CS; one-quarter develop it rapidly trophil gelatinase-associated lipocalin (NGAL) do not add prognostic
thereafter, within 6 h of MI onset, and another quarter develop shock information over creatinine. Hepatic transaminases are elevated due
later on the first day. Later onset of CS may be due to reinfarction, to liver hypoperfusion in ~20% of patients and may be very high. The
marked infarct expansion, or mechanical complications. arterial lactate level is usually elevated to >2 mmol/L. ABGs usually
Diagnosis For these unstable patients, supportive therapy must demonstrate hypoxemia and anion gap metabolic acidosis. Glucose
be initiated simultaneously with diagnostic evaluation (Fig. 298-2). A levels at admission are often elevated, a strong independent predictor
focused history and physical examination should be performed along for mortality. Cardiac markers, creatine kinase and its MB fraction, and
with an electrocardiogram (ECG), chest X-ray, arterial blood gas (ABG) troponins I and T are typically markedly elevated in acute MI.
analysis, lactate measurement, and blood specimens to the laboratory. ELECTROCARDIOGRAM In acute MI with CS, Q waves and/or ST eleva-
Initial echocardiography is an invaluable tool to elucidate the underly- tion in multiple leads or left bundle branch block are usually present.
ing cause of CS. Approximately one-half of MIs with CS are anterior infarctions. Global
CLINICAL FINDINGS Most patients initially are dyspneic, appear pale, ischemia due to severe left main stenosis usually is accompanied by
apprehensive, and diaphoretic, and mental status may be altered. The aVR lead ST segment elevation and ST depressions in multiple leads.
pulse is typically weak and rapid or occasionally severe bradycardia CHEST ROENTGENOGRAM The chest x-ray typically shows pulmonary
due to high-grade heart block may be present. BP is typically reduced vascular congestion and often pulmonary edema, but may be normal
(<90 mmHg; or catecholamines required to maintain blood pressure in up to a third of patients. The heart size is usually normal when CS
>90 mmHg), but occasionally BP may be maintained by very high results from a first MI, but may be enlarged when it occurs in a patient
systemic vascular resistance. Tachypnea and jugular venous distention with a previous MI.

2054 ADVANCED HEMODYNAMIC MONITORING Recently new central venous
TABLE 298-1 Etiologies of Cardiogenic Shock (CS)a and Cardiogenic
Pulmonary Edema catheter systems linked to computer-based algorithms provide con-
Etiologies of Cardiogenic Shock or Pulmonary Edema tinuous monitoring of a variety of derived hemodynamic parameters,
including cardiac output, stroke volume, stroke volume variation, and
Acute myocardial infarction/ischemia
systemic vascular resistance. When combined with a femoral arterial
Left ventricular failure catheter, calculated extravascular lung water and pulmonary permea-
Ventricular septal rupture bility index can be monitored. The information allows for more ratio-
Papillary muscle/chordal rupture–severe mitral regurgitation nal therapy and assessment, but has not yet shown improved clinical
Ventricular free wall rupture outcomes in patients with shock or pulmonary edema (Table 298-3).
Other conditions complicating large myocardial infarctions
CARDIAC CATHETERIZATION AND CORONARY ANGIOGRAPHY The defini-
Excess negative inotropic or vasodilator medications tion of the coronary anatomy provides useful information and is imme-
Post-cardiac arrest diately indicated in all patients with CS complicating MI for further
Post-cardiotomy reperfusion treatment. Furthermore, cardiac catheterization should
Refractory sustained supra or ventricular tachyarrhythmias also be considered for resuscitated cardiac arrest survivors without
Refractory sustained bradyarrhythmias ST-segment elevation because ~70% of these patients have relevant
Acute fulminant myocarditis coronary artery disease.
End-stage cardiomyopathy
PART 8
Takotsubo syndrome/Apical ballooning syndrome TREATMENT

Hypertrophic cardiomyopathy with severe outflow obstruction
Aortic dissection with aortic insufficiency or tamponade Acute Myocardial Infarction
Severe valvular heart disease
GENERAL MEASURES
Critical aortic or mitral stenosis

In addition to the usual treatment of acute MI (Chap. 269), initial
Acute severe aortic regurgitation or mitral regurgitation
therapy is aimed at maintaining adequate systemic and coronary
Toxic/metabolic perfusion by raising the blood pressure with vasopressors and
β-blocker or calcium channel antagonist overdose adjusting volume status to a level that ensures optimum LV filling
Hypertensive crisis pressure (Fig. 298-2). There is some interpatient variability, but
Post-cardiac arrest stunning generally adequate perfusion occurs with a mean arterial BP of
Myocardial depression in setting of septic shock or SIRS 60–65 mmHg or a systolic BP ~90 mmHg. Hypoxemia and acidosis
Myocardial contusion need to be corrected; up to 90% of patients require ventilatory sup-
Other Etiologies of Cardiogenic Shockb port, decreasing the stress from increased work of breathing (see
“Pulmonary Edema,” below) (Fig. 298-2). Moderate glucose control
Right ventricular failure due to:
(≤180 mg/dL or 10.0 mmol/L) should be a goal and hypoglycemia
Acute myocardial infarction must be avoided. Negative ionotropic agents should be discontin-
Acute or decompensated chronic cor pulmonale ued. Bradyarrhythmias may require transvenous pacing. Recurrent
Pericardial tamponade ventricular tachycardia or rapid atrial fibrillation may require imme-
Toxic/metabolic diate treatment (Chap. 241).
Severe acidosis, severe hypoxemia
REPERFUSION-REVASCULARIZATION
a
The etiologies of CS are listed. Most of these can cause pulmonary edema Rapid revascularization of the infarct-related artery is the only
instead of shock or pulmonary edema with CS. bThese cause CS but not
pulmonary edema. evidence-based treatment strategy for mortality reduction in CS
and forms the mainstay therapeutic intervention for CS due to
MI (Fig. 298-2). In the SHOCK Trial 132 lives were saved per 1000
ECHOCARDIOGRAM An echocardiogram (Chap. 236) should be patients treated with early revascularization with percutaneous
obtained promptly in patients with suspected/confirmed CS to help coronary intervention (PCI) or coronary artery bypass graft (CABG)
define its etiology. Echocardiography is able to delineate the extent compared with initial medical therapy. Outcome benefit correlates
of infarction/myocardium in jeopardy and the presence of mechan- strongly with the time between symptom onset and reperfusion. In
ical complications such as VSR, MR, or cardiac tamponade. Further- general, PCI with drug-eluting stents of the infarct-related artery
more, valvular obstruction or insufficiency, dynamic LV outflow tract is the preferred reperfusion strategy. Approximately 80% of CS
obstruction, proximal aortic dissection with aortic regurgitation or patients present with multivessel coronary artery disease. The recent
tamponade may be seen, or indirect evidence for pulmonary embolism CULPRIT-SHOCK randomized trial showed that culprit lesion only
may be obtained (Chap. 273) (Table 298-2). PCI with possible staged revascularization led to a reduction in
30-day mortality or renal replacement therapy in comparison to
PULMONARY ARTERY CATHETERIZATION The use of pulmonary artery immediate multivessel PCI. This reduction in the primary study
catheter (PAC) hemodynamic monitoring is declining because clini- endpoint was mainly driven by a 30-day mortality reduction. Cur-
cal trials have shown no mortality benefit. However, hemodynamic rently, vascular access for diagnostic angiography and PIC via the
data provided by a PAC can confirm the presence and severity of CS, radial artery is preferred when feasible over femoral arterial access
involvement of the right ventricle, left-to-right shunting, pulmonary due to its greater safety. CABG is currently performed in only 5% of
artery pressures and trans-pulmonary gradient, and the pulmonary cases mainly if coronary anatomy is not amenable to PCI.
and systemic vascular resistance. It can help in recognition of acute
MR, decreased left atrial filling pressure, and secondary occult sepsis VASOPRESSORS AND INOTROPES
and to exclude left-to-right shunts. Equalization of diastolic pressures Inotropic agents are theoretically appealing in CS treatment. How-
suggests cardiac tamponade, but echocardiogram is more definitive. ever, current evidence is scarce. Vasoactive medications are often
The detailed hemodynamic profile can be used to individualize and used in the management of patients with CS and all have important
monitor therapy and to provide prognostic information, such as disadvantages, including increase in myocardial O2 consumption,
cardiac index and cardiac power, can be obtained. The use of a PAC is afterload, lethal arrhythmias, and possible myocardial cell death.
currently recommended by the American Heart Association for poten- As a consequence, catecholamines should be used in the lowest
tial utilization in cases of diagnostic or CS management uncertainty possible doses for the shortest possible time. Despite their frequent
or in patients with severe CS who are unresponsive to initial therapy. use, little clinical outcome data proves their benefit or is available

2055
Cardiogenic shock (ECG, laboratory markers)
Non myocardial infarction Myocardial infarction
Echocardiography
Invasive angiography + revascularization (IB)
Consider invasive angiography (+ revascularization)
echocardiography (IC) or left ventricular angiogram
treatment of underlying cause
Myocardial dysfunction Mechanical complication
IABP (IIa/C)

No IABP (III) Ventricular septal Mitral
Free wall rupture
defect regurgitation
Surgical (IC)/Inter- Mitral repair/ Surgical closure

ventional closure (IIb/C) replacement (IC) (IC)
Inotropes/Vasopressors (IIa/C + IIb/B) Inotropes/Vasopressors (IIa/C + IIb/B)

Fluids Fluids
Ventilation (avoid hyperoxemia) Ventilation (avoid hyperoxemia)
Renal replacement therapy? Renal replacement therapy?
Hyperglycemic control Hyperglycemic control
No stabilization Stabilization
Temporary percutaneous MC S (IIb/C) Weaning

Recovery cardiac function No recovery cardiac function
Weaning Assessment neurology +

endorgan function
Severe neurological deficit Normal neurological function
Age, comorbidities?
Weaning Long-term surgical
MCS
Bridge-to Destination Bridge-to

recovery therapy transplant
FIGURE 298-2 Emergency management of patients with cardiogenic shock. Treatment algorithm for patients with CS. The class of recommendation and level of evidence
according to European Society of Cardiology guidelines is provided (see Further Reading citations Authors/Task Force members, S Windecker et al: Eur Heart J 35:2541,
2014, and P Ponikowski et al: Eur Heart J 37:2129, 2016). ECG, electrocardiogram; IABP, intraaortic balloon pump; MCS, mechanical circulatory support.
to guide the initial selection of vasoactive therapies in patients with doses (2.5 μg/kg per min), but moderate chronotropic activity at
CS. No vasopressor has been demonstrated to change outcome in higher doses. Its vasodilating activity often precludes its use when
large clinical trials. Norepinephrine is reasonable as the first line a vasoconstrictor effect is required. Levosimendan may also be
vasopressor based on randomized trials compared to dopamine. appealing despite a lack of randomized data, but was not beneficial
Norepinephrine was associated with fewer adverse events, includ- for organ dysfunction in sepsis.
ing arrhythmias, compared to dopamine in a randomized trial
of patients with several etiologies of circulatory shock and with MECHANICAL CIRCULATORY SUPPORT
improved survival in a pre-specified subgroup of CS patients. Nor- The most commonly used mechanical circulatory support (MCS)
epinephrine dosing is usually begun at 2 to 4 μg/min and titrated device has been the intraaortic balloon pump (IABP), which is
upward based on blood pressure. inserted into the aorta via the femoral artery and provides passive
Dopamine’s hemodynamic effects vary depending upon dose and hemodynamic support. However, routine IABP use in conjunction
there is interpatient variability in responses. Low doses stimulate with early revascularization (predominantly with PCI) did not reduce
renal dopaminergic receptors and with increasing dosage there is either 30-day or 12-month mortality in the IABP-SHOCK II trial. IABP
stimulation of first β-adrenergic receptors and then a adrenergic also had no benefit on secondary endpoints (arterial lactate, catecho-
receptors. Dopamine should be avoided as first-line therapy for MI lamine doses, renal function, or intensive care severity of illness unit
with CS based on hemodynamic and proarrhythmogenic effects. scores). IABP is no longer recommended for CS with LV failure.
Dobutamine is a synthetic sympathomimetic amine with positive Active MCS devices to support the left, right, or both ventricles
inotropic action and minimal positive chronotropic activity at low can be placed percutaneously or surgically. Temporary percutaneous

2056 TABLE 298-2 Utility of the Echocardiogram in Cardiogenic Shock or MCS can be used as bridge to recovery, to surgically implanted
Pulmonary Edema devices, to heart transplantation, or as a temporizing measure when
CLINICAL QUESTION INFORMATION the neurologic status is uncertain. Percutaneous MCS including the
Ventricular Function Predominantly left, right or biventricular
TandemHeart, Impella devices, and also venoarterial extracorporeal
involvement membrane oxygenation (VA-ECMO) have been used in patients
Etiology Acute Myocardial Infarction not responding to standard treatment (catecholamines, fluids, and
• Extent of infarction/myocardium in jeopardy
IABP) and also as a first-line treatment. Active percutaneous MCS
results in better hemodynamic support compared to IABP. How-
• Status of the non-culprit infarct zone
ever, the appropriate role of MCS is uncertain as a positive impact
• Presence of mechanical complications
on clinical outcomes or mortality has not yet been demonstrated in
Acute/Chronic Valvular Insufficiency/ trials or metaanalyses.
Obstruction/Stenosis (Native/Prosthetic)
Surgically implanted devices can support the circulation as
• Etiology: endocarditis; degenerative valve bridging therapy for cardiac transplant candidates or as destination
disease
therapy (Chap. 255). Assist devices should be used selectively in
• Location and hemodynamic consequences
suitable patients based on decisions by a multidisciplinary team
Dynamic Left Ventricular Tract Obstruction with expertise in the selection, implantation, and management of
Takotsubo Syndrome MCS devices.
Cardiac Tamponade
PART 8
• Circumferential versus localized effusion Prognosis The expected death rates for patients with MI com-
• Route of pericardiocentesis if indicated plicated by CS range widely based on age, severity of hemodynamic
Acute Pulmonary Embolism abnormalities, severity of clinical hypoperfusion (arterial lactate, renal
• Right ventricular function function), and performance of early revascularization. The recently
• Pulmonary artery pressure introduced IABP-SHOCK II score predicts prognosis based on six read-
• Presence of clot in transition/Patent foramen ily available variables: age >73 years; prior stroke; glucose at admission
ovale >10.6 mmol/L (191 mg/dL); creatinine at admission >132.6 μmol/L
Acute Aortic Syndrome (1.5 mg/dL); thrombolysis in myocardial infarction flow grade after
• Nature and extent of dissection PCI <3; and arterial blood lactate at admission >5 mmol/L. It also may
• Degree of aortic insufficiency
help guide treatment strategies.
• Presence of pericardial effusion ■■SHOCK SECONDARY TO RIGHT VENTRICULAR
Hemodynamics Volume assessment by inferior vena cava INFARCTION
diameter and inspiratory collapse Persistent CS due to predominant RV failure accounts for only 5% of CS
Estimated pulmonary artery systolic pressure complicating MI. It often results from proximal right coronary artery
Estimated left atrial pressure occlusion. The salient features are relatively high right atrial pressures,
Therapeutic guidance Guide vasoactive support RV dilation and dysfunction, and only mildly or moderately depressed
Monitor response to therapy LV function. High right-sided pressures may be absent without volume
Mechanical circulatory support decisions loading. However, CS often has overlap combinations of both RV and
Catheter position and guidance LV ischemia, given a shared septum and the effect of ventricular inter-
Pulmonary Pleural effusion dependence on RV function. Management of isolated RV CS includes
Lung edema fluid administration to optimize right atrial pressure (10–15 mmHg);
avoidance of excess fluids, which shift the interventricular septum into
Pneumothorax
the LV; catecholamines; early reestablishment of infarct-artery flow;
Pulmonary infiltration
and MCS.
TABLE 298-3 Hemodynamic Patternsa

RA, mmHg RVS, mmHg RVD, mmHg PAS, mmHg PAD, mmHg PCW, mmHg CI, (L/min)/m2 SVR, (dyn · s)/cm5
Normal values <6 <25 0–12 <25 0–12 <6–12 ≥2.5 (800–1600)
MI without pulmonary – – – – – ~13 (5–18) ~2.7 (2.2–4.3) –
edemab
Pulmonary edema ↔↑ ↔↑ ↔↑ ↑ ↑ ↑ ↔↓ ↑
Cardiogenic shock
LV failure ↔↑ ↔↑ ↔↑ ↔↑ ↑ ↑ ↓ ↔↑
RV failurec ↑ ↓↔↑d ↑ ↓↔↑d ↔↓↑d ↓↔↑d ↓ ↑
Cardiac tamponade ↑ ↔↑ ↑ ↔↑ ↔↑ ↔↑ ↓ ↑
Acute mitral regurgitation ↔↑ ↑ ↔↑ ↑ ↑ ↑ ↔↓ ↔↑
Ventricular septal rupture ↑ ↔↑ ↑ ↔↑ ↔↑ ↔↑ ↑PBF ↓SBF ↔↑
Hypovolemic shock ↓ ↔↓ ↔↓ ↓ ↓ ↓ ↓ ↑
Septic shock ↓ ↔↓ ↔↓ ↓ ↓ ↓ ↑ ↓
a
There is significant patient-to-patient variation. Pressure may be normalized if cardiac output is low. bForrester et al classified nonreperfused MI patients into four
hemodynamic subsets. (From JS Forrester et al: N Engl J Med 295:1356, 1976.) PCW pressure and CI in clinically stable subset 1 patients are shown. Values in
parentheses represent range. c”Isolated” or predominant RV failure. dPCW and pulmonary artery pressures may rise in RV failure after volume loading due to RV dilation
and right-to-left shift of the interventricular septum, resulting in impaired LV filling. When biventricular failure is present, the patterns are similar to those shown for LV
failure.
Abbreviations: CI, cardiac index; MI, myocardial infarction; P/SBF, pulmonary/systemic blood flow; PAS/D, pulmonary artery systolic/diastolic; PCW, pulmonary capillary
wedge; RA, right atrium; RVS/D, right ventricular systolic/diastolic; SVR, systemic vascular resistance.
Source: Table prepared with the assistance of Krishnan Ramanathan, MD.

■■MITRAL REGURGITATION The use of a Swan-Ganz catheter permits measurement of pulmonary 2057
(See also Chap. 269) Acute severe MR due to papillary muscle dys- capillary wedge pressure (PCWP) and helps differentiate high-pressure
function and/or rupture may complicate MI and result in CS and/ (cardiogenic) from normal-pressure (non-cardiogenic) causes of pul-
or pulmonary edema. This complication most often occurs on the first monary edema. PAC is indicated when the etiology of the pulmonary
day, with a second peak several days later. The diagnosis is confirmed edema is uncertain, when edema is refractory to therapy, or when it
by echocardiography (Table 298-2). Afterload reduction with IABP and, is accompanied by hypotension. Data derived from use of a catheter
if tolerated, vasodilators to reduce pulmonary edema, is recommended often alter the treatment plan, but no impact on mortality rates has
as a bridge to surgery or interventional treatment. Mitral valve repair been demonstrated.
or reconstruction is the definitive therapy and should be performed
early in the course in suitable candidates. Other options include per-
cutaneous edge-to-edge repair which has been successful in small case TREATMENT
series.
Pulmonary Edema
■■VENTRICULAR SEPTAL RUPTURE The treatment of pulmonary edema depends on the specific etiology.
(See also Chap. 269) VSR complicating MI is a relatively rare event As an acute, life-threatening condition, a number of measures must
associated with very high mortality if CS is present (>80%). The inci- be applied immediately to support the circulation, gas exchange,
dence of infarct-related VSR without reperfusion was 1–2% but has

and lung mechanics. Simultaneously, conditions that frequently
decreased to 0.2% in the era of reperfusion. VSR occurs a median of complicate pulmonary edema, such as infection, acidemia, anemia,
24 h after infarction, but may occur up to 2 weeks later. Echocardiogra- and acute kidney dysfunction, must be corrected.
phy demonstrates shunting of blood from the left to the right ventricle
and may visualize the opening in the interventricular septum. Current SUPPORT OF OXYGENATION AND VENTILATION
guidelines recommend immediate surgical VSR closure, irrespective of Patients with acute cardiogenic pulmonary edema generally have
the patient’s hemodynamic status, to avoid further hemodynamic dete- an identifiable cause of acute LV failure—such as arrhythmia,
rioration. IABP support as bridge to surgery is recommended. Given ischemia/infarction, or myocardial decompensation (Chap. 252)—
high mortality, suboptimal surgical results and many patients not being that may be rapidly treated, with improvement in gas exchange. In
eligible for surgery, interventional percutaneous VSR umbrella device contrast, non-cardiogenic edema usually resolves much less quickly,
closure has been developed. Results of interventional VSR closure and most patients require mechanical ventilation.
suggest a similar outcome as surgery. How to close the VSR should be Oxygen Therapy Support of oxygenation is essential to ensure
based on a heart team decision. adequate O2 delivery to peripheral tissues, including the heart.
■■FREE WALL RUPTURE Generally the goal is O2 saturation of ≥92%, but very high saturation
Myocardial rupture is a dramatic complication of MI that is most (>98%) may be detrimental.
likely to occur during the first week after the onset of symptoms. The Positive-Pressure Ventilation Pulmonary edema increases the
clinical presentation typically is a sudden loss of pulse, blood pres- work of breathing and the O2 requirements of this work, imposing
sure, and consciousness but sinus rhythm on ECG (pulseless electrical a significant physiologic stress on the heart. When oxygenation
activity) due to cardiac tamponade (Chap. 265). Free wall rupture may or ventilation is not adequate in spite of supplemental O2, posi-
also result in CS due to subacute tamponade when the pericardium tive-pressure ventilation by face or nasal mask or by endotracheal
temporarily seals the rupture sites. Definitive surgical repair is required. intubation should be initiated. Noninvasive ventilation (Chap. 295)
can rest the respiratory muscles, improve oxygenation and cardiac
■■ACUTE FULMINANT MYOCARDITIS function, and reduce the need for intubation. In refractory cases,
(See also Chap. 254) Myocarditis can mimic acute MI with ST abnor- mechanical ventilation can relieve the work of breathing more com-
malities or bundle branch block on the ECG and marked elevation of pletely than can noninvasive ventilation. Mechanical ventilation
cardiac markers. Acute myocarditis causes CS in a small proportion of with positive end-expiratory pressure can have multiple beneficial
cases. These patients are typically younger than those with CS due to effects on pulmonary edema, as it: (1) decreases both preload and
acute MI and often do not have typical ischemic chest pain. Echocar- afterload, thereby improving cardiac function; (2) redistributes lung
diography usually shows global LV dysfunction. Initial management is water from the intraalveolar to the extraalveolar space, where the
the same as for CS complicating acute MI but does not involve revas- fluid interferes less with gas exchange; and (3) increases lung vol-
cularization. Endomyocardial biopsy is recommended to determine the ume to avoid atelectasis.
diagnosis and need for immunosuppressives for entities such as giant
Renal Replacement Therapy For pulmonary edema patients with
cell myocarditis. Refractory CS can be managed with MCS.
refractory volume overload, metabolic acidosis (pH <7.15–7.25),
■■PULMONARY EDEMA hypoxemia, and/or persistent hyperkalemia, renal replacement
The etiologies and pathophysiology of pulmonary edema are therapy should be considered. For patients who are hypotensive or
discussed in Chap. 33. requiring ionotropic support, continuous renal replacement therapy
usually is better tolerated than intermittent hemodialysis.
Diagnosis Acute pulmonary edema usually presents with the REDUCTION OF PRELOAD
rapid onset of dyspnea at rest, tachypnea, tachycardia, and severe
hypoxemia. Crackles and wheezing due to alveolar flooding and air- In most forms of pulmonary edema, the quantity of extravascular
way compression from peribronchial cuffing may be audible. Release lung water is determined by a combination of the pulmonary cap-
of endogenous catecholamines often causes hypertension. illary pressures (PCWP), the pulmonary vascular permeability, and
It is often difficult to distinguish between cardiogenic and non- the intravascular volume status.
cardiogenic causes of acute pulmonary edema. Echocardiography may Diuretics The “loop diuretics” furosemide, bumetanide, and
identify systolic and diastolic ventricular dysfunction and valvular torasemide are effective in most forms of pulmonary edema, even in
lesions. Electrocardiographic ST elevation and evolving Q waves are the presence of hypoalbuminemia, hyponatremia, or hypochloremia.
usually diagnostic of acute MI and should prompt immediate insti- Furosemide is also a venodilator that rapidly reduces preload before
tution of MI protocols and coronary artery revascularization therapy any diuresis occurs, and is the diuretic of choice. The initial dose of
(Chap. 269). Brain natriuretic peptide levels, when substantially furosemide should be ≤0.5 mg/kg, but a higher dose (1 mg/kg) is
elevated, support heart failure as the etiology of acute dyspnea with required in patients with renal insufficiency, chronic diuretic use,
pulmonary edema (Chap. 252). or hypervolemia or after failure of a lower dose. Combinations of

2058 diuretics and/or continuous infusion are helpful to achieve the Stimulation of Alveolar Fluid Clearance A variety of drugs and
desired degree of diuresis in selected patients. cellular therapies can stimulate alveolar epithelial ion transport
Nitrates Nitroglycerin and isosorbide dinitrate act predominantly and upregulate the clearance of alveolar solute and water, but this
as venodilators but have coronary vasodilating properties as well. strategy has not been proven beneficial in clinical trials thus far.
Their onset is rapid and they are effectively administered by a vari- SPECIAL CONSIDERATIONS
ety of routes. Sublingual nitroglycerin (0.4 mg × 3 every 5 min) is
Risk of Iatrogenic Cardiogenic Shock In the treatment of pulmonary
first-line therapy for acute cardiogenic pulmonary edema. If pulmo-
edema, vasodilators lower blood pressure, and their use, partic-
nary edema persists in the absence of hypotension, sublingual may
ularly in combination, may lead to hypotension, coronary artery
be followed by IV nitroglycerin, commencing at 5–10 μg/min. IV
hypoperfusion, and shock (Fig. 298-1). In general, patients with a
nitroprusside (0.1–5 μg/kg per min) is a potent venous and arterial
hypertensive response to pulmonary edema tolerate and benefit from
vasodilator. It is useful for patients with pulmonary edema and
these medications. In normotensive patients, low doses of single
hypertension, but is not recommended in states of reduced coronary
agents should be instituted sequentially, as needed.
artery perfusion. It requires close monitoring and titration using an
arterial catheter for continuous blood pressure measurement. Acute Coronary Syndromes (See also Chap. 269) Acute STEMI
complicated by pulmonary edema is associated with in-hospital
Morphine Given in 2- to 4-mg IV boluses, morphine is a transient
mortality rates of 20–40%. After immediate stabilization, coronary
venodilator that reduces preload while relieving dyspnea and
artery blood flow must be reestablished rapidly. Early primary PCI
anxiety. These effects can diminish stress, catecholamine levels,
PART 8
is the method of choice; alternatively, a fibrinolytic agent should be

tachycardia, and ventricular afterload in patients with pulmonary
administered. Early coronary angiography and revascularization by
edema and systemic hypertension. However, some registry trials
PCI or CABG also are indicated for patients with non-ST elevation
showed increased mortality by use of morphine.
acute coronary syndrome.
Angiotensin-Converting Enzyme (ACE) Inhibitors ACE inhibitors
Extracorporeal Membrane Oxygenation (ECMO) For patients with
reduce both afterload and preload and are recommended for hyper-
tensive patients. A low dose of a short-acting agent may be initiated acute, severe non-cardiogenic edema with a potential rapidly
and followed by increasing oral doses. In acute MI with heart fail- reversible cause, ECMO may be considered in highly selected
ure, ACE inhibitors reduce short- and long-term mortality rates. The patients as a temporizing supportive measure to achieve adequate
optimal starting point of ACE inhibitors has not been tested so far. gas exchange with current survival to discharge rates of 50–60%.
Usually venovenous ECMO is used in this setting. ECMO can
Other Preload-Reducing Agents IV recombinant brain natriuretic function as a bridge to transplantation or other interventions.
peptide (nesiritide) is a potent vasodilator with diuretic properties
and is effective in the treatment of cardiogenic pulmonary edema. It Unusual Types of Edema Specific etiologies of pulmonary edema
should be reserved for refractory patients and is not recommended may require particular therapy. Re-expansion pulmonary edema
in the setting of ischemia or MI. can develop after removal of long-standing pleural space air or
fluid. These patients may develop hypotension or oliguria with
Physical Methods In nonhypotensive patients, venous return can pulmonary edema resulting from rapid fluid shifts into the lung.
be reduced by use of the sitting position with the legs dangling Diuretics and preload reduction are contraindicated, and intravas-
along the side of the bed. cular volume repletion often is needed while supporting oxygena-
Inotropic and Inodilator Drugs The sympathomimetic amines tion and gas exchange.
dopamine and dobutamine (see above) are potent inotropic agents. High-altitude pulmonary edema often can be prevented by use
The bipyridine phosphodiesterase-3 inhibitors (inodilators), such of dexamethasone, calcium channel–blocking drugs, or long-acting
as milrinone (50 μg/kg followed by 0.25–0.75 μg/kg per min), inhaled β2-adrenergic agonists. Treatment includes descent from
stimulate myocardial contractility while promoting peripheral and altitude, bed rest, oxygen, and, if feasible, inhaled nitric oxide; nifed-
pulmonary vasodilation. Inodilators may be helpful in selected ipine may also be effective.
patients with cardiogenic pulmonary edema and severe LV dys- For pulmonary edema resulting from upper airway obstruction,
function, but there is little published clinical data. recognition of the obstructing cause is key, because treatment then is
Digitalis Glycosides Once a mainstay of treatment because of to relieve or bypass the obstruction.
their positive inotropic action (Chap. 252), digitalis glycosides are
rarely used at present. However, they may be useful for control of ■■FURTHER READING
ventricular rate in patients with rapid ventricular response to atrial Authors/Task Force members, Windecker S et al: 2014 ESC/EACTS
fibrillation or flutter and LV dysfunction with pulmonary edema, Guidelines on myocardial revascularization: The Task Force on
because they do not have the negative inotropic effects of other Myocardial Revascularization of the European Society of Cardiology
drugs that inhibit atrioventricular nodal conduction. (ESC) and the European Association for Cardio-Thoracic Surgery
Intraaortic Balloon Counterpulsation IABP (Chap. 255) may be (EACTS). Eur Heart J. 35:2541, 2014.
helpful in rare instances of acute MR from infective endocarditis, Hochman JS: Cardiogenic shock complicating acute myocardial infarc-
but is not typically used for pulmonary edema with CS. tion: Expanding the paradigm. Circulation 107:2998, 2003.
Hochman JS et al: Early revascularization in acute myocardial infarc-
Treatment of Tachyarrhythmias and Atrioventricular tion complicated by cardiogenic shock. SHOCK Investigators. Should
Resynchronization (See also Chap. 247) Sinus tachycardia or we emergently revascularize occluded coronaries for cardiogenic
atrial fibrillation can result from elevated left atrial pressure and shock? N Engl J Med 341:625, 1999.
sympathetic stimulation. Tachycardia itself can limit LV filling time Ouweneel DM et al: Impella CP versus intra-aortic balloon pump sup-
and raise left atrial pressure further. Although relief of pulmonary port in acute myocardial infarction complicated by cardiogenic shock.
congestion will slow the sinus rate or ventricular response in atrial The IMPRESS in Severe Shock trial. J Am Coll Card 69:278, 2017.
fibrillation, a primary tachyarrhythmia may require cardioversion. Ponikowski P et al: 2016 ESC Guidelines for the diagnosis and
In patients with reduced LV function and without atrial contrac- treatment of acute and chronic heart failure. The Task Force for the
tion or with lack of synchronized atrioventricular contraction, diagnosis and treatment of acute and chronic heart failure of the
placement of an atrioventricular sequential pacemaker should be European Society of Cardiology (ESC) Developed with the special
considered (Chap. 239). contribution of the Heart Failure Association (HFA) of the ESC. Eur
Reduction in Pulmonary Vascular Permeability At present, no Heart J 37:2129, 2016.
clinical therapies have been demonstrated as clinically effective to Thiele H et al: Intraaortic balloon support for myocardial infarction
reduce the “leakiness” of the pulmonary capillaries. with cardiogenic shock. N Engl J Med 367:1287, 2012.

Thiele H et al: Management of cardiogenic shock. Eur Heart J 36:1223, a cardiovascular cause for the arrest is often presumed based upon the 2059
2015. absence of evidence for a traumatic or other non-cardiac cause at the
Thiele H et al: Percutaneous short-term active mechanical support time of the arrest. If the patient does not survive an SCA, the death is
devices in cardiogenic shock: A systematic review and collaborative classified as a sudden cardiac death (SCD). Deaths that occur during
meta-analysis of randomized trials. Eur Heart J 2017; epub ahead of hospitalization or within 30 days after resuscitated cardiac arrest are
print: doi.org/10.1093/eurheartj/ehx1363. usually counted as SCDs in epidemiologic studies.
Thiele H et al: PCI strategies in patients with acute myocardial infarc- SCD also includes a broader category of unexplained rapid deaths
tion and cardiogenic shock. N Engl J Med 2017; epub: DOI: 10.1056/ thought to be due to cardiac causes where resuscitation was not
NEJMoa1710261. attempted. In epidemiologic studies, SCD is usually defined as an
van Diepen S et al: Contemporary management of cardiogenic shock: unexpected death without obvious extra-cardiac cause that occurs in
A scientific statement. Circulation 136:e232, 2017. association with a witnessed rapid collapse or within 1 h of the onset
of symptoms. This definition is based on the presumption that rapid
deaths are often due to an arrhythmia, an assumption that cannot
always be validated. Approximately half of all SCDs are not witnessed,
and in the United States, few deaths undergo autopsies, and non-
299 Cardiovascular
cardiac conditions that evolve rapidly such as acute cerebral hemor-
Collapse,
CHAPTER 299 Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac Death
rhage, aortic rupture, and pulmonary embolism cannot be excluded
Cardiac Arrest, and Sudden without an autopsy. Therefore, definitive information necessary to
establish the cause of death is usually not available. In unwitnessed
Cardiac Death cases, the definition is often further expanded to include unexpected
deaths where the subject was documented to be well when last
Christine M. Albert, William G. Stevenson observed within the preceding 24 h. This expanded definition further
decreases the certainty that the death was due to an arrhythmia or
cardiac causes. The majority of countries, including the United States,
do not have national surveillance systems or reporting requirements
OVERVIEW AND DEFINITIONS for SCD; thus the true incidence and frequency of SCD and its different
(SEE TABLE 299-1) mechanisms can only be estimated.
Cardiovascular collapse is severe hypotension from acute dysfunction
of the heart or peripheral vasculature causing hypotension with result- EPIDEMIOLOGY
ing cerebral hypoperfusion and loss of consciousness that can be the
result of a cardiac arrhythmia, severe myocardial or valvular dysfunc- ■■DEMOGRAPHICS
tion, loss of vascular tone, and/or acute disruption of venous return. SCA and SCD are major public health problems that account for 15%
When an effective circulation is restored spontaneously, patients of all deaths and comprise 50% of all cardiac deaths. In the United
present with syncope (see Chap. 18). If spontaneous resolution does States alone, there are an estimated 350,000 EMS-attended out-of-
not occur, then cardiac arrest occurs, ultimately resulting in death if hospital cardiac arrests and 210,000 SCDs in the adult population. The
resuscitation attempts are unsuccessful or not initiated. Underlying estimated societal burden of premature death due to SCD is 2 million
etiologies for cardiovascular collapse include benign conditions such years of potential life lost for men and 1.3 million years of potential
as vasovagal syncope, but also life-threatening conditions, including: life lost for women, which is greater than most other leading causes of
ventricular tachyarrhythmias, severe bradycardia, severely depressed death. Although cardiac pathology, particularly coronary heart disease
myocardial contractility, as with massive acute myocardial infarction (CHD), underlies the majority of SCD, up to two-thirds of all SCD occur
(MI) or pulmonary embolus, and other catastrophic events interfering as the first clinical expression of previously undiagnosed heart disease.
with cardiac function such as myocardial rupture with cardiac tampon- SCD rates have declined but not as steeply as rates for CHD in general.
ade or papillary muscle rupture with torrential mitral regurgitation. Age, gender, race, and geographic region all influence the incidence
Sudden cardiac arrest (SCA) refers to an abrupt loss of cardiac of SCD. Rates of out-of-hospital cardiac arrest are lower in Asia (52.5
function resulting in complete cardiovascular collapse due either to an per 100,000 person-years) than Europe (86.4 per 100,000 person-years),
acute life-threatening cardiac arrhythmia or abrupt loss of myocardial North America (98.1 per 100,000 person-years), or Australia (111.9 per
pump function that requires emergency medical intervention for res- 100,000 person-years); and also vary within geographic regions of the
toration of effective circulation. Most SCAs occur outside the hospital, United States. SCD is rare in individuals of younger than 35 years of
and fewer than 10% of these victims survive to be discharged from the age (1–3 per 100,000 per year), and increases markedly with age as the
hospital despite undergoing attempted resuscitation by emergency incidence of coronary artery disease (CAD), heart failure (HF), and
medical services (EMS). For those that die prior to hospital admission, other predisposing conditions also increase. Although absolute SCD
TABLE 299-1 Distinction between Cardiovascular Collapse, Cardiac Arrest, and Death
TERM DEFINITION QUALIFIERS MECHANISMS
Cardiovascular collapse Sudden loss of effective circulation due to Broad term that includes cardiac arrest and Same as “Cardiac Arrest,” plus
cardiac and/or peripheral vascular factors transient events that characteristically revert vasodepressor syncope or other
that may reverse spontaneously (e.g., spontaneously presenting as syncope. causes of transient loss of blood flow.
neurocardiogenic syncope, vasovagal syncope)
or require interventions (e.g., cardiac arrest).
Cardiac arrest Abrupt cessation of cardiac function resulting Rare spontaneous reversions; likelihood of Ventricular fibrillation, ventricular
in loss of effective circulation which may successful intervention relates to mechanism tachycardia, asystole, bradycardia,
be reversible by prompt emergency medical of arrest, clinical setting, availability of pulseless electrical activity, noncardiac
intervention, but will lead to death in its emergency medical services, and prompt mechanical factors (e.g., pulmonary
absence. return of circulation. embolism).
Sudden cardiac death Sudden unexpected death attributed to cardiac In unwitnessed cases, the definition is often Same as Cardiac Arrest.
arrest, which if witnessed occurs within one hour expanded to include unexpected deaths
of symptom onset. where the subject was documented to be
well within the preceding 24 h.
Source: Modified from RJ Myerburg, A Castellanos: Cardiovascular collapse, cardiac arrest, and sudden cardiac death, in Harrison’s Principles of Internal Medicine,
19th ed, DL Kasper et al (eds). New York, McGraw-Hill Education, 2015, pp 1764–1771, Table 327-1.

2060 rates increase with age, the proportion of deaths that are due to SCD appear to be particularly important markers of SCD risk in blacks, in
decreases markedly as other causes of death increase. whom the prevalence of these conditions is greater. Smoking markedly
Women have a lower incidence of SCD and SCA than men, and elevates risk, and smoking cessation lowers risk particularly among
women are more likely to present with pulseless electrical activity individuals who have not yet developed overt CHD. Serum cholesterol
(PEA) and to have their SCD occur at home as compared to men. appears to be more strongly related to SCD at younger ages, and the
Possibly related to these factors, the SCD rate has not declined as much benefits of cholesterol lowering on SCD incidence have not been firmly
for younger women compared to men in recent years. Black as opposed established. There also appears to be a genetic component to SCD
to white Americans have higher rates of SCD, are more likely to have risk that is distinct from that associated with other manifestations
unwitnessed arrests, to be found with PEA, and have worse rates of of atherosclerosis. A history of SCD among a first-degree relative is
survival. Socioeconomic disparities, with resuscitation being less likely associated with an increased risk for SCD, and with the occurrence of
in low income neighborhoods, is likely a contributing factor, but does ventricular fibrillation (VF) during acute MI, but is not associated with
not appear to account for the entirety of the elevated SCD rate in blacks. an increased risk for acute MI. These data suggest that genetic factors
Alternatively, individuals of Hispanic ethnicity appear to have lower may predispose to fatal ventricular arrhythmia in the setting of ische-
rates of SCD, despite having a higher prevalence of cardiac risk factors. mia, rather than to CHD in general.
It also appears that the incidence of SCD may be relatively low among Obstructive sleep apnea and seizure disorders are also associated
Asian populations as well, both within the United States and globally. with increased SCD risk, and the underlying mechanism is not clear,
These gender and racial differences in SCD/SCA incidence and sur- but may be due to hypoxia and/or suffocation-induced cardiac arrest.
vival are poorly understood and warrant further research. Atrial fibrillation also appears to be associated with an increased risk of
PART 8
SCD, which is partly, but not entirely, accounted for by its association
■■RISK FACTORS (SEE FIG. 299-1) with underlying heart disease. Patients with chronic kidney disease are
The presence of overt structural heart disease and/or a certain types also at higher SCD risk with annualized SCD rates approaching 5.5%
of inherited arrhythmia syndromes markedly elevates SCD risk (see in patients undergoing dialysis. Electrolyte shifts and LVH, which are
Chaps. 249 and 250). Preexisting CHD and HF are the most preva- common in this population, have been suggested to play a role. There
lent predisposing cardiac conditions and are associated with four- to are also potential dietary influences on SCD risk. Individuals with
tenfold increases in SCD risk. Correspondingly, SCD shares many higher intakes of polyunsaturated fatty acids, particularly n-3 fatty
of the same risk factors with CHD and HF, including: hypertension, acids, and other components of a Mediterranean-style diet have lower
diabetes, hypercholesterolemia, obesity, and smoking. Diabetes is a SCD risks in observational studies, possibly due to antiarrhythmic
particularly strong risk factor for SCD even in patients with established effects of dietary components. Low levels of alcohol intake may be
CHD. Hypertension and resultant left ventricular hypertrophy (LVH) beneficial, but heavy intake (>3 drinks/day) appears to elevate risk.
Idiopathic
Valvular heart disease
VF/Others Coronary heart disease ~ 40–70%
1–5%
White Men: 70%
Women and Black Men 40–50%
Inherited arrhythmia Asians< 40%
syndrome
(LQTS, BrS, CPVT, ERS, etc.)
1–2% in Western countries Myocardial Substrates:
10% in Asia Myocardial scar
Sudden Cardiac Death Hypertrophy
Causes Fibrosis
Myocardial stretch
Cardiomyopathies
Electrical heterogeneity
(NIDCM, HCM, ARVC, etc.)
Ion channel functional modification
10–15% in Western countries
Abnormal calcium handing
30–35% in Asia
Triggers
Population‐Based Risk Factors Heart failure/Stretch
Male sex Family history of SCD (genetics) Ischemia
Black race Diet low in N‐3 PUFA Myocardial inflammation
Diabetes Atrial fibrillation Vigorous exertion
Current smoking Obstructive sleep apnea Electrolyte abnormality
Hypertension Heavy alcohol intake Environmental stress
Chronic kidney disease Low magnesium levels Psychological stress/Depression
ECG features (QT, QRS prolongation, early repolarization, LVH)
CPVT, LQTS Coronary Heart Disease

0 HCM, ARVC 35 Valvular Heart Disease
Age of SCD onset NIDCM

BrS, ERS
B
FIGURE 299-1 A. Proportionate causes, substrates, risk factors, and triggers of sudden cardiac death (SCD); and B. variation of causes by age of onset. (Modified from
M Hayashi et al: The spectrum of epidemiology underlying sudden cardiac death. Circ Res 116:1887, 2015.)

■■PRECIPITATING FACTORS Despite the limitations of these data, it is generally accepted that SCD 2061
SCD/SCA occurs with higher frequency at certain times, locations, and is most commonly associated with underlying CAD, although the
in association with certain activities and exposures. There are circadian proportion due to CAD varies markedly by age, race, and sex. It is
variations in the incidence of SCD and cardiac arrest, with peaks in estimated that ~70–75% of SCDs in white men are due to CAD, as com-
incidence in the morning hours and again in the later afternoon. There pared to only 40–50% in women and blacks. The proportion of SCDs
is also seasonal variability in SCD rates, which may be related to tem- with underlying CAD may be even lower in Asian ethnicities. Recent
perature and light exposure. Rates are highest during winter in the data suggest that the proportion of SCDs with CAD may be declining
northern hemisphere and summer in the southern hemisphere. SCD in some parts of Europe (Fig. 299-2A) and the United States, and, at the
rates also acutely peak during disasters such as earthquakes and terror- same time, increasing in parts of Japan and other parts of Asia. Beyond
ist attacks. SCA arrests are more likely to occur in certain locations as CAD, non-ischemic cardiomyopathies (hypertrophic, dilated, and
well, with notable clustering around train stations, airports, and other infiltrative) are the second most frequent cause of SCD in the United
public places where there is significant population transit. SCD rates States and European countries. Other less common causes include val-
tend to be higher in urban areas and individuals that live near major vular heart disease, myocarditis, myocardial hypertrophy (often from
roadways are at elevated SCD risk. There is also a well-recognized hypertension), and rare primary electrical heart diseases such as the
acute elevation in SCD risk that occurs during or shortly after bouts long QT and Brugada syndrome. On average, 5–10% of SCA victims
of vigorous exertion, and men appear to be more susceptible. Habitual do not have a significant cardiac abnormality at the time of autopsy or
exercise and training lowers this acute risk, but does not appear to after extensive premortem cardiac evaluation, and this also varies by
eliminate it entirely. Exertion-associated SCDs are particularly tragic gender and race. Before 35 years of age, atherosclerotic CAD accounts
and highly publicized when they occur in highly trained athletes; for a much smaller proportion of deaths, with hypertrophic cardiomyo-
however, the majority of such deaths actually occur in the general pathy (HCM), coronary artery anomalies, myocarditis, arrhythmogenic
“non-athlete” population. The common thread amongst these precipi- right ventricular cardiomyopathy, and primary ion channelopathies
tating factors is likely heightened autonomic tone, which can promote accounting for a significant number of these deaths.
ischemia and has direct proarrhythmia and electrophysiologic actions
that lower the threshold for VF. ■■CARDIAC RHYTHMS AND SUDDEN DEATH
The initial rhythm found when EMS arrive at the scene of an out-of-
CAUSES OF SUDDEN CARDIAC DEATH hospital cardiac arrest is an important indication of the potential cause
of the arrest and of the prognosis. In the early days of EMS systems,
■■UNDERLYING HEART DISEASE (FIG. 299-1) over half of victims were found in VF, giving rise to the hypothesis
Our understanding regarding the diseases which contribute to SCD that ischmic VF or ventricular tachycardia (VT) degenerating to VF
is derived primarily from autopsy series and cardiac evaluations in was the most common event. The proportion of cardiac arrests found
cardiac arrest survivors, which are highly variable in level of detail. in VF has decreased markedly since the 1970s, to only 20–25%, and
Proportion of Treated Cardiac Arrest

Temporal Changes in Causes of Sudden with Ventricular Fibrillation as Initial
Cardiac Death on Autopsy Rhythm
100% 70%
60%
74% 73% 60%
80% 66%
50% 47%
60% 40%
Ischemic 40%
34% Non-Ischemic
40% 26% 27% 30% 25%
20% 20%
10%
0%
1998–2002 2003–2007 2008–2012 0%
A B 1979–1980 1989–1990 1999–2000 2006–2007
35%
Overall VT or VF Asystole or PEA Proportion of Acute MI Patients with Low
30% LVEF (<30–35%)
20%
Survival to Discharge
25% 17%
20% 15%
15%
10% 8.3%
10%
5%
5% 5%
2.5%
0%
2005–06 2007 2008 2009 2010 2011 2012 0%
Jordaens EHJ 2001 Avezum AJC 2008 Bauer EHJ 2009 Voller H Europace
C D 2011
FIGURE 299-2 Changing epidemiology of sudden cardiac death/arrest. A. The proportion of sudden cardiac deaths attributable to coronary artery disease among
individuals without a history of heart disease in Finland over time. Postmortem examinations are mandatory in Finland, which has the highest autopsy rate in
Western World (J Junttila et al: Circ Arrhythm Electrophysiol 2016). B. Proportion of treated cardiac arrest with ventricular fibrillation as first recorded rhythm in Seattle,
Washington, U.S. over time. (Data from L Cobb et al: JAMA 288:3008, 2002, and G Nichol et al: JAMA 300:1423, 2008.) C. Rates of overall survival and survival from
shockable and nonshockable rhythms to hospital discharge among 70,027 out-of-hospital cardiac arrests across the United States from 2005 to 2012 (Cardiac Arrest
to Enhance Survival Registry). (From P Chan et al: Circulation 1876:1882, 2014.) D. Proportion of myocardial infarction patients with left ventricular ejection fractions
<30–35% in myocardial infarction registries over time.

2062 PEA or asystole are now the most common scenarios (Fig. 299-2B). ion channel alterations that prolong action potential duration, impair
However, the vast majority of cardiac arrests are not monitored at the cellular calcium handling, and diminished cellular coupling. These
time of collapse, and since arrhythmias are inherently unstable once processes occur in a wide variety of diseases associated with depressed
hemodynamic collapse occurs, the rhythm at the time of EMS arrival ventricular function and/or hypertrophy, including CAD, valvular
may not reflect the rhythm that initially precipitated the SCA. VF heart disease, myocarditis, and non-ischemic cardiomyopathies.
and primary bradycardias can degenerate quickly into asystole. VF
as an initial rhythm still predominates in public locations or in other
Absence of Structural Heart Disease In the absence of struc-
tural heart disease, VF can be due to an inherited ion channel abnor-
situations when there is a short time between collapse and arrival of
mality, as in the long QT and Brugada syndromes (Chap. 250), rapid
EMS, suggesting that VF remains a common initial rhythm. However,
atrial fibrillation associated with the Wolff-Parkinson-White syndrome
there are also data to support an absolute decrease in VF incidence.
(Chap. 244), or drug toxicities, such as polymorphic VT due to drugs
Proposed explanations include decreases in underlying CHD inci-
that prolong the QT interval (Chap. 250). PEA can result from pul-
dence, increased used of beta blockers in CHD, and implantable cardio-
monary emboli, exsanguination, or the terminal phase of respiratory
verter defibrillators (ICD) in high-risk patients. There also appears to
arrest.
be an increase of PEA incidence over the past several years, suggesting
that the proportion of SCD due to abrupt hemodynamic collapse in
the absence of preceding fatal arrhythmia may be increasing. Proposed MANAGEMENT OF CARDIAC ARREST
explanations for these proportional changes in PEA versus VF include As the ability to predict SCA in the population is very limited, com-
the aging of the population and the increased prevalence of end-stage munity approaches to reduce death focus on the rapid identification
PART 8
cardiovascular disease and other severe comorbidities. These older, of victims and implementation of resuscitation measures by those
sicker patients may be more likely to have
arrests in the home and to have acute pre- TABLE 299-2 Causes of Cardiovascular Collapse and Sudden Cardiac Arrest
cipitants leading to PEA (i.e., respiratory, CAUSE PATHOPHYSIOLOGIC SUBSTRATE RHYTHM PRESENTATION
metabolic, vascular), and/or be less likely Cardiac Causes

to sustain VF up to the point of EMS arrival. Coronary artery disease Acute myocardial ischemia / Polymorphic VT/VF
Atherosclerotic, coronary spasm, Infarction, ventricular rupture, Bradyarrhythmia
■■DISEASE SPECIFIC congenital anomalies
tamponade
Pulseless electrical activity
MECHANISMS Ventricular scar from healed
Ventricular tachycardia
Coronary artery disease can cause SCD through infarction
a number of mechanisms (Table 299-2). Ventricular fibrillation
The most common cause is acute MI or Cardiomyopathies Ventricular scar Ventricular tachycardia
transient ischemia that leads to polymorphic Dilated, hypertrophic, ARVC, Ventricular hypertrophy Polymorphic VT/VF
VT and VF (see Chap. 250). Other primary infiltrative disease, valvular Pump failure Pulseless electrical activity
disease with LV failure
mechanisms include severe bradyarrhyth- Bradyarrhythmia
mias such as heart block with a slow escape Congenital heart disease Ventricular scar from surgical Ventricular tachycardia
rhythm, or PEA due to a massive MI or (tetralogy of Fallot, VSD, others) repair Bradyarrhythmias
associated myocardial rupture. Areas of ven- Hypertrophy Polymorphic VT/VF
tricular scar from prior infarcts increase the Aortic stenosis Obstruction to outflow Bradyarrhythmia
predisposition to reentrant VT, which often
Ventricular hypertrophy Pulseless electrical activity
degenerates to VF. Once patients have suf-
Bradyarrhythmia
fered a MI, their risk of SCD elevates up to
Polymorphic VT/VF
tenfold, with the highest absolute rates in
the first 30 days after MI. The mechanisms Mitral valve prolapse/Mitral Pump failure Ventricular tachycardia
regurgitation Ventricular scar Polymorphic VT/VF
underlying SCD vary at different time points
after MI, with non-arrhythmic causes such as Arrhythmia syndromes without Abnormal cellular electrophysiology Polymorphic VT/VF
myocardial rupture and/or extensive rein- structural heart disease:
farction predominating early, within the first Genetic:
1–2 months, and ischemic polymorphic VT Long QT
and/or scar-related ventricular arrhythmias Brugada
prevailing later. VT and sudden death can, CPVT
and often does, occur years after an initial Idiopathic VF, early repolarization
MI. Drug toxicities (acquired long QT,
others)
Cardiomyopathies and Other Forms Electrolyte abnormalities (severe
of Structural Heart Disease Scar- hypokalemia)
mediated reentrant VT can also occur in a Wolff-Parkinson-White Syndrome Accessory atrioventricular Preexcited AF/VF
host of nonischemic cardiomyopathies in connection
which replacement fibrosis and/or inflamma- Non-Cardiac Causes of Cardiovascular Collapse
tory ventricular infiltrates occur (Chap. 249).
Pulmonary embolism PEA
In congenital heart disease, surgical scars
created during corrective surgery, such as Stroke PEA, bradyarrhythmia
those performed to correct ventricular sep- Aortic dissection PEA, VF
tal defects in tetralogy of Fallot, can also Exsanguination PEA
serve as the substrate for ventricular re- Tension pneumothorax PEA
entry. Other common predisposing processes Sepsis PEA
such as LVH, ventricular stretch due to fluid Neurogenic PEA, bradyarrhythmia
overload, and cardiomyocyte dysfunction Drug overdose PEA, bradyarrhythmia
can result in electrical heterogeneity and
Abbreviations: AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; CPVT, catecholaminergic
other electrophysiologic changes that predis- polymorphic ventricular tachycardia; LV, left ventricle; PEA, pulseless electrical activity; VF, ventricular fibrillation;
pose to ventricular arrhythmias, including VSD, ventricular septal defect; VT, ventricular tachycardia.

who first encounter the victim, most likely the lay public, who ide- consideration given to placement of an advanced airway (endotracheal 2063
ally summon EMS and initiate basic life support measures with chest tube or supraglottic airway device). Epinephrine 1 mg every 3–5 min
compressions. The approach is codified in the “out-of-hospital chain of may be administered intravenously or intraosseously. If circulation is
survival” which includes (1) initial evaluation and recognition of the not restored or the patient is less than fully conscious despite return
SCA; (2) rapid initiation of cardiopulmonary resuscitation (CPR) with of circulation, confirmation that acidosis and hypoxia are adequately
an emphasis on chest compressions; (3) defibrillation as quickly as pos- addressed should be assessed with arterial blood gas analysis. If meta-
sible usually with an automatic external defibrillation applied by the bolic acidosis persists after successful defibrillation and with adequate
lay rescuer or EMT; (4) basic and advanced EMS; and (5) advanced life ventilation, 1 meq/kg NaHCO3 may be administered.
support and postcardiac arrest care. There have been major advances The cardiac rhythm guides resuscitation when monitoring is avail-
in each of these areas and survival rates to hospital discharge have able. VT is treated with external shocks synchronized to the QRS when
increased from about 6% in 2005 to 10% in 2012, but much more prog- VT is monomorphic, and asynchronous shocks for polymorphic VT or
ress is needed (Fig. 299-2C). VF. If VT/VF recurs after one or more shocks, amiodarone 300 mg can
The initial goal of resuscitation is to achieve the return of sponta- be administered as a bolus via intravenous or intraosseous route in the
neous circulation. Success is related to the time between collapse and hope that arrhythmia recurrence will be prevented after the next shock,
initiation of resuscitation, decreasing markedly after 5 min, and the followed by a 150 mg bolus if the arrhythmia recurs. If amiodarone
rhythm at the time of EMT arrival, being best for VT (25–30%), worse fails, lidocaine can be administered.
for VF and poor for PEA and asystole (<5%). Outcomes are also deter- Consideration of etiology should also guide therapy (Chaps. 249
mined by the clinical state and comorbidities of the victim prior to the and 250). Commonly encountered causes of recurrent VT/VF may be
arrest, being worse for those with severe disease, such as cardiogenic due to ongoing myocardial ischemia or infarction that would benefit
shock, prior to arrest. from emergent coronary angiography and revascularization, or QT
prolongation causing the polymorphic VT torsades des pointes that
■■INITIAL EVALUATION AND INITIATION OF CPR may respond to administration of magnesium. Hyperkalemia should
The rescuer should check for a response from the victim, shout for help, respond to administration of calcium, while other measures are imple-
and call or ask someone else to call their local emergency number (e.g., mented to reduce serum K.
911), ideally on a cell phone that can be placed on speaker mode at the PEA/asystole should be managed with CPR, ventilation, and
patient’s side such that the responding dispatcher can provide instruc- administration of epinephrine. Causes of PEA/asystole that require
tions and queries to the rescuer. Consideration of aspiration or airway specific therapy should be considered including airway obstruction,
obstruction is important and if suspected a Heimlich maneuver may hypoxia, hypovolemia, acidosis, hyperkalemia, hypothermia, toxins,
dislodge the obstructing body. A trained healthcare provider would cardiac tamponade, tension pneumothorax, pulmonary embolism, and
also check for a pulse (taking no longer than 10 s so as not to delay initi- MI. Naloxone should be administered if opiate overdose is suspected.
ation of chest compressions) and assess breathing. Gasping respirations
and brief seizure activity are common during SCA and may be misin- ■■POSTCARDIAC ARREST ACUTE MANAGEMENT
terpreted as breathing and responsiveness. Chest compressions should Following restoration of effective circulation, the possibility of acute
be initiated without delay and administered at a rate of 100–120/min MI should be immediately assessed. More than 90% of patients who
depressing the sternum by 5 cm (2 in.) and allowing full chest recoil have ST elevation consistent with acute MI will be found to have a
between compressions. Chest compressions generate forward cardiac culprit coronary stenosis/occlusion and likely benefit from emergent
output with sequential filling and emptying of the cardiac chambers, coronary angiography with percutaneous angioplasty and stenting.
with competent valves maintaining forward direction of flow. Interrup- Angiography should also be considered if an acute coronary syndrome
tion of chest compressions should be minimized to reduce end organ is suspected, even if ST segment elevation is absent, as more than
ischemia. Ventilation may be administered with two breaths for every half of selected patients undergoing angiography for this concern
30 compressions if a trained rescuer is present, but for lay rescuers with- are found to have a coronary lesion as a potential cause of the ACA.
out training, chest compressions alone (“hands only CPR”) are more Decisions regarding which patients without ST segment elevation
likely to be effectively applied and of similar benefit. If a second rescuer should undergo urgent angiography are complex and factors such as
is present, they should be sent to seek out an automatic external defi- hemodynamic or electrical instability, evidence of ongoing ischemia,
brillator (AED), which are now widely available in many public areas. comorbidities, and overall prognosis are taken into consideration.
Hemodynamic instability is often present following resuscitation
■■RHYTHM-BASED MANAGEMENT (FIG. 299-3) and further ischemic end organ damage is a major consideration.
The rapidity with which defibrillation/cardioversion is achieved is an Optimizing ventilation with consideration of acidosis, hypoxemia,
important predictor of outcome. A defibrillator, most often an AED, and electrolyte abnormalities is important. Maintaining systolic BP at
should be applied as soon as available. AEDs are easily used by lay res- >90 mmHg, mean BP >65 mmHg is desirable and may require admin-
cuers and trained first responders, such as police officers and trained istration of vasopressors and adjustment of volume status. Potentially
security guards. When the arrest is witnessed, the use of AEDs by lay treatable reversible causes including hyperkalemia, severe hypoka-
responders can improve cardiac arrest survival rates. Once patches are lemia, and drug toxicity with QT prolongation causing torsades des
applied to the chest, a brief pause in chest compressions is required pointes should be identified and treated (Chap. 250).
to allow the AED to record the rhythm. An AED will advise a shock After stable spontaneous circulation is achieved, brain injury due
if the recorded rhythm meets criteria for VF or VT. Chest compres- to ischemia and reperfusion is a major determinant of survival and
sions are continued while the defibrillator is being charged. As soon accounts for over two-thirds of deaths. The probability of successful
as a diagnosis of VF or VT is established, a biphasic waveform shock neurologic recovery decreases rapidly with time between collapse
of 150–200 J should be delivered. Chest compressions are resumed and restoration of circulation and is <30% at 5 min in the absence of
immediately and continue for 2 min until the next rhythm check. If bystander CPR. The time between collapse and restoration of circula-
VT/VF is still present, a second maximal energy shock is delivered. tion is generally imprecise and some patients have a period of hypoten-
This sequence is continued until personnel to administer advanced life sive VT prior to complete collapse, such that a reported long period
support are available, or return of spontaneous circulation is achieved. prior to arrival of rescuers does not always preclude a good recovery.
Electrocardiogram (ECG) rhythm strips produced by the AED should Therapeutic hypothermia (targeted temperature management) has
be retrieved, as the initial rhythm can be an important consideration in been shown to improve the likelihood of survival and neurologic recov-
determining the cause of the arrest and to guide further therapy and ery in patients who present with shockable (VT or VF) rhythms and
evaluation if resuscitation is successful. is recommended for all cardiac arrest patients who remain comatose,
When advanced cardiac life support is available, an intravenous or regardless of presenting rhythm, who have lack of purposeful response
intraosseous line is established for administration of medication and to verbal commands following return of spontaneous circulation.

2064
Ventricular Fibrillation or Pulseless Ventricular Tachycardia
Chest compressions at 100–120/min
Immediate defibrillation
and resume CPR for 2 min
No ROSC
2 min of chest compressions/ventilation and repeat shock

No ROSC
Continue chest compressions, I.V. or I.O. access, advanced airway

Epinephrine 1 mg q 3–5 min
Repeat shock
No ROSC
I.V. amiodarone 300 mg (may repeat 150 mg), continue CPR

Repeat shock
Specific therapies
PART 8
Polymorphic VT/VF Monomorphic Sinusoidal VT Asystole Pulseless electrical

Acute coronary syndrome: VT Hyperkalemia: activity
lidocaine, PCI Ca, NaHCO3.
lidocaine
Acquired long QT: Mg, Acute coronary
procainamide
transvenous pacing, syndrome

isoproterenol. Drug toxicity
Brugada syndrome, idiopathic VF:
isoporterenol, quinidine.
Bradyarrhythmia/Asystole Pulseless Electrical Activity
CPR, intubate, I.V. access
[Confirm asystole] [Assess pulse]
Identify and treat reversible causes
* Hypoxia * Hypovolemia * Pulmonary embolus

* Hyper- /hypokalemia * Hypoxia * Drug overdose
* Severe acidosis * Tamponade * Hyperkalemia
* Drug overdose * Pneumothorax * Severe acidosis
* Hypothermia * Hypothermia * Massive acute M.I.
Epinephrine — 1 mg I.V. {repeat 3–5 min}
For Bradycardia:
Atropine 1 mg I.V.
Pacing — external or pacing wire
B
FIGURE 299-3 Algorithm for approach to cardiac arrest due to VT or VF (shockable rhythm). A. Chest compressions with ventilation and defibrillation or cardioversion
should be initiated as soon as possible. Defibrillation should be repeated with minimal interruption of chest compressions. Once an intravenous or intraosseous
access is established, administration of epinephrine defibrillation and amiodarone and defibrillation are performed. Further therapy can be guided by possible causes
as suggested by the initial or recurrent cardiac rhythm as shown. i.v., intravenous; i.o., intraosseous; CPR, cardiopulmonary resuscitation; PCI, percutaneous coronary
intervention. B. Algorithm for approach to cardiac arrest due to bradyarrhythmias/asystole and pulseless electrical activity. Chest compressions with ventilation (and
intubation) should be initiated as soon as possible, and i.v. access should be obtained. Once an intravenous or intraosseous access is established, administration of
epinephrine is performed. At the same time, an investigation for potential reversible causes should be made and any such causes should be treated if present. For
bradycardic rhythms, atropine 1 mg IV and external subcutaneous or transvenous pacing are also performed. Defibrillation should be repeated with minimal interruption
of chest compressions. Once an intravenous or intraosseous access is established, administration of epinephrine is performed. Further therapy can be guided by
possible causes. CPR, cardiopulmonary resuscitation; I.O., intraosseous; I.V., intravenous.

A constant target temperature of 32–36°C for at least 24 h is recom- present and the recurrence rate is significant regardless of whether the 2065
mended. Shivering suppression with analgesics and sedatives may arrest occurred in association with elevated serum troponin. An ICD is
be needed. Induction of hypothermia should be started in-hospital, usually warranted even if revascularization is also needed.
as no benefit was shown for implementation before hospital arrival, Patients who have cardiac arrest due to a treatable reversible cause,
and administration of large volumes of cold saline for this purpose such as hyperkalemia, or drug toxicity with QT prolongation causing
increased the risk of pulmonary edema. Brain injury is often accompa- torsades des pointes (Chap. 250), that can be adequately addressed and
nied by seizures and status epilepticus that may have further deleteri- prevented by other means do not usually need an ICD. An ICD is usu-
ous effects, warranting periodic or continuous electroencephalography ally recommended for cardiac arrest due to VT or VF without a clearly
(EEG) monitoring and treatment. A number of other therapies hoped reversible cause, particularly when structural heart disease, such as
to improve postarrest outcomes have been assessed, but have not been hypertrophic or dilated cardiomyopathy, arrhythmogenic cardiomyop-
shown to be beneficial, including administration of corticosteroids, athy, cardiac sarcoidosis, or a cardiac syndrome associated with sudden
hemofiltration, and efforts to tightly control blood glucose. death, including Brugada syndrome, or LQTS are present (Chaps. 249
Hypothermia and sedation preclude reliable prognostication for and 250). In patients with structural heart disease, it is important to
neurologic recovery. Functional neurologic assessment for neurologic recognize that life-threatening arrhythmias can be an indication of ter-
recovery is generally deferred for at least 72 h after return to normo- minal, end-stage heart disease with minimal prospect for meaningful
thermia, typically 4–5 days after the cardiac arrest. Features that predict survival despite successful resuscitation, and ICDs will not alter the
poor outcome include absence of pupillary reflex to light, status myo- course of these patients and should not be implanted in this situation,
clonus, absence of EEG reactivity to external stimuli, and persistent unless there is a prospect for cardiac replacement therapy with future
burst suppression on EEG. cardiac transplantation or a ventricular assist device.
■■LONG-TERM MANAGEMENT AFTER SURVIVAL OF PREVENTION OF SCD

OUT-OF-HOSPITAL CARDIAC ARREST Although advances in CPR and postresuscitation care have improved
For patients who survive cardiac arrest and have neurologic recovery,
survival rates after cardiac arrest, 90% of patients will not survive to
the likely underlying cause of the arrest guides further treatment. For
be discharged from the hospital. Of those that do survive, a proportion
arrests not due to an obvious non-cardiac cause, a full evaluation for the
(~20%) are left with severe neurologic and/or physical disability. The
forms of structural heart disease outlined in Fig. 299-1 and Table 299-2
majority of cardiac arrests do not occur in public places where AEDs
should be performed including an assessment for underlying CAD and
and rapid defibrillation have the greatest impact. Patients who suffer
ischemia as well as echocardiography and/or cardiac MRI to look for
an arrest at home also have longer EMS response times and are much
evidence of prior MI, valvular disease, nonischemic cardiomyopathies less likely to be found in VF. Finally, 50% of cardiac arrests are not
and to provide an assessment of left ventricular ejection fraction (LVEF). witnessed precluding effective resuscitation efforts. Thus, preventive
If the initial evaluation is not definitive or is suggestive of an inflamma- efforts are critical to reducing mortality from cardiac arrest.
tory cardiomyopathy (i.e., sarcoidosis, myocarditis), a cardiac PET-scan
and/or endomyocardial biopsy may also be performed. Patients with- ■■SCD RISK STRATIFICATION
out obvious structural abnormalities should undergo an evaluation The presence of overt structural heart disease and/or primary electrical
for primary electrical disease (long-QT syndrome [LQTS], Brugada heart disease is associated with an increased risk of SCD that varies
syndrome, early repolarization syndrome, or WPW). In cases where with the severity and type of disease. For patients with structural
a heritable syndrome is suspected, further genetic evaluation should heart disease, depressed left ventricular function is the best validated
be considered. Diagnostic electrophysiology studies are warranted in marker for risk, and clinical HF elevates risk further. After MI, SCD risk
selected patients to assess inducible arrhythmias, or perform provoc- increases gradually as the LVEF decreases to 40% and then exponen-
ative testing, such as with epinephrine challenge for LQTS, or sodium tially thereafter. In addition to LVEF and CHF, other potential markers
channel blocker (e.g., procainamide) challenge for Brugada syndrome. of increased SCD risk in the setting of structural heart disease include
Patients with shockable rhythms at arrest (VF and VT) that are not unexplained syncope, sustained VT induced at electrophysiology
deemed to have been due to a transient reversible cause and have study (EP study), left ventricular scar size and heterogeneity on cardiac
reasonable life expectancy should undergo insertion of an ICD for magnetic resonance, markers of altered autonomic function and altered
secondary prevention of SCA/SCD. Most of these patients will be repolarization, and QRS prolongation. The majority of these tests, with
found to have CAD. Patients with a VF arrest that occurs within the the exception of the EP study in post-MI patients, broadly predict death
first 48 h of a documented acute MI generally do not require an ICD from cardiovascular causes and are not able to discriminate patients
since they have a similar risk of sudden death over the next 5 years as who will die suddenly from those who will die of other cardiac causes.
infarct survivors who did not have a cardiac arrest. However, patients For instance, patients with the greatest degree of systolic HF and/or
who have a large infarction with acutely depressed LV ejection frac- lowest LVEF, although at elevated risk for SCD, are more likely to die
tion (e.g., <35%) have an increased risk for future development of from HF. Although sustained VT at EP study does identify individuals
life-threatening ventricular arrhythmias related to reentry in the infarct at a higher risk of SCA versus non-SCA in certain subsets of patients,
scar (Chap. 247). The percentage of patients with such large infarcts the sensitivity of the test is generally inadequate when LV function is
has been declining due to improved treatment strategies for acute MI significantly reduced.
(Fig. 299-2D). Implantation of an ICD early after MI in these patients
does not, however, improve survival, in part because a significant num- ■■PREVENTIVE THERAPIES FOR SCD IN
ber of sudden deaths in the first three months are due to recurrent myo- HIGH-RISK POPULATIONS
cardial ischemia or myocardial rupture, rather than arrhythmias. For Therapy with beta-adrenergic blockers has been demonstrated to
patients with large infarcts a wearable defibrillator that will treat VT/ reduce SCD risk in a multitude of settings including after MI, among
VF if it occurs may be used, while left ventricular remodeling is taking patients with ischemic and nonischemic cardiomyopathy, and in LQTS.
place, followed by reevaluation of arrhythmia risk after the infarct is Angiotensin-converting enzyme inhibitors, aldosterone antagonists,
healed to determine if an ICD is warranted. Patients who experience and most recently angiotensin-receptor/neprilysin inhibitors have
VF in-hospital >48 h after MI or in the setting of myocardial ischemia been associated with reductions in SCD in subsets of patients with
without infarction may be at risk for recurrent VT/VF. These patients structural heart disease, primarily ischemic and non-ischemic cardio-
should be evaluated and optimally treated for ischemia. If there is evi- myopathy accompanied by HF. Coronary artery bypass grafting has
dence that clearly implicates ischemia immediately preceding the onset also been associated with reductions in SCD risk, and revascularization
of VF without evidence of a prior MI, coronary revascularization may in general may lower SCD risk through reduction in ischemic events
be adequate therapy. Others may warrant an ICD. When the cardiac and resultant improvements in left ventricular systolic function by
arrest is due sustained monomorphic VT, a prior infarct scar is often reducing areas of hibernating myocardium.

2066 For patients whose disease continues to confer substantial risk of sus- with a history of MI more than 40 days ago, primary prevention ICDs
tained VT or VF on optimal medical therapy, an ICD is recommended are indicated for those with Class II-III NYHA HF and LVEF <35%, and
(Table 299-3). The ICD indication in these patients is referred to as “pri- those who are NYHA functional Class I with LVEF <30%. Although,
mary prevention of sudden death.” The indications for primary preven- ICDs have not been found to be beneficial when implanted within
tion ICDs vary depending on the type of underlying structural heart 40 days of a MI, those with recent or old MI, nonsustained VT, LVEF
disease and its severity, and variable strength of evidence. In patients <40% and inducible sustained VT at EP study also warrant an ICD.
TABLE 299-3 Implantable Cardioverter Defibrillator (ICD) Indications

INDICATION CLASS OF RECOMMENDATION* LEVEL OF EVIDENCE**
Secondary Prevention
All disease states ICD therapy is indicated in patients who are survivors of cardiac arrest CLASS I A
VT or VF due to VF or hemodynamically unstable sustained VT after evaluation
to define the cause of the event and to exclude any completely
reversible causes.
ICD therapy is indicated in patients with structural heart disease CLASS I B
and spontaneous sustained VT, whether hemodynamically stable or
unstable.
PART 8
ICD implantation is reasonable for patients with sustained VT and CLASS IIa C
normal or near-normal ventricular function.
Syncope ICD therapy is indicated in patients with syncope of undetermined CLASS I B
origin with clinically relevant, hemodynamically significant sustained
VT or VF induced at electrophysiological study.

ICD therapy may be considered in patients with syncope and advanced CLASS IIb C
structural heart disease in whom invasive and noninvasive have failed
to determine a cause.
Primary Prevention
Ischemic ICD therapy is indicated in patients with LVEF ≤ 35% due to prior MI CLASS I B
cardiomyopathy who are at least 40 days post-MI and are rare in NYHA functional
Class II or III.
ICD therapy is indicated in patients with LV dysfunction due to prior CLASS I A
MI who are at least 40 days post-MI, have an LVEF ≤ 30%, and are in
NYHA functional Class I.
ICD therapy is indicated in patients with nonsustained VT due CLASS I B
to prior MI, LVEF ≤ 40%, and inducible VF or sustained VT at
electrophysiological study.
Non-ischemic ICD therapy is indicated in patients with nonischemic DCM who have CLASS I B
cardiomyopathy an LVEF ≤35% and who are in NYHA functional Class II or III.
ICD implantation is reasonable for patients with unexplained syncope, CLASS IIa C
significant LV dysfunction, and nonischemic DCM.
ICD therapy can be considered in patients with non-ischemic heart CLASS IIb C
disease and NYHA functional Class I.
Hypertrophic ICD implantation is reasonable for patients with HCM who have one or CLASS IIa C
cardiomyopathy more major risk factors for SCD.
Arrhythmogenic right ICD implantation is reasonable for the prevention of SCD in patients CLASS IIa C
ventricular dysplasia with ARVC who have one or more risk factors for SCD.
Brugada syndrome ICD implantation is reasonable for patients with Brugada syndrome CLASS IIa C
who have had syncope.
ICD implantation is reasonable for patients with Brugada syndrome CLASS IIa C
who have documented VT that has not resulted in cardiac arrest.
Long-QT syndrome ICD implantation is reasonable to reduce SCD in patients with long-QT CLASS IIa B
syndrome who are experiencing syncope and/or VT while receiving
beta blockers.
ICD may be considered as primary therapy in patients long-QT CLASS IIb B
syndrome who are deemed to be at very high risk, especially those
with a contraindication to beta-blocker therapy.
Catecholaminergic ICD implantation is reasonable for patients with catecholaminergic CLASS IIa C
polymorphic VT polymorphic VT who have syncope and/or documented sustained VT
(CPVT) while receiving beta blockers.
Familial ICD therapy may be considered in patients with a familial CLASS IIa C
cardiomyopathy cardiomyopathy associated with SCD.
LV noncompaction ICD therapy may be considered. CLASS IIa C
CLASS OF RECOMMENDATION* LEVEL OF EVIDENCE**
CLASS I CLASS IIa LEVEL A LEVEL B LEVEL C
Procedure/treatment Additional studies with Multiple populations evaluated. Limited populations evaluated. Very limited populations
SHOULD be performed/ focused objectives needed. Data derived from multiple Data derived from a evaluated.
administered IT IS REASONABLE to perform randomized clinical trials or single randomized trial or Only consensus opinion of
procedure/administer meta-analyses. nonrandomized studies. experts, case studies, or
treatment. standard of care.
Abbreviations: VF, ventricular fibrillation; VT, ventricular tachycardia.

TABLE 299-4 Implantable Cardioverter Defibrillator (ICD) Not there was no benefit with ICDs in these patents. High-risk patients with 2067
Indicated low LVEFs may be considered for a wearable defibrillator with later
Patients who do not have a reasonable expectation of survival with an reassessment of ventricular function and ICD placement.
acceptable functional status for at least one year, even if they meet ICD ICDs for primary prevention of sudden death are also recommended
implantation criteria. for patients with diseases other than CAD, that put them at risk for
Patients with incessant VT or VF. SCD. ICDs are recommended for those with nonischemic DCM who
Patients with significant psychiatric illnesses that may be aggravated by device have an LVEF ≤ 35% and who are in NYHA functional Class II or III
implantation or that may preclude systematic follow-up. and receiving medical therapy. Benefit is more likely in patients aged
Patients with drug-refractory New York Heart Association class IV congestive <60 years, as non-arrhythmia causes of death increase with age. For
heart failure who are not candidates for cardiac transplantation or cardiac patients with LVEF <35%, HF, and left bundle branch block (LBBB)
resynchronization therapy. with QRS duration >150 ms cardiac resynchronization therapy also
Syncope of undetermined cause in a patient without inducible ventricular offers protection against SCD, particularly in patients with nonische-
tachyarrhythmias and without structural heart disease. mic cardiomyopathy. Primary prevention ICDs are also recommended
VF or VT is amenable to surgical or catheter ablation in patients without other in select high-risk patients with HCM, arrhythmogenic right ventric-
disease predisposing to SCA (e.g., atrial arrhythmias associated with the ular dysplasia, cardiac sarcoidosis, and Brugada syndrome and some
Wolff-Parkinson-White syndrome, RV or LV outflow tract VT, idiopathic VT, or
fascicular VT in the absence of structural heart disease). patients with congenital LQTS with high-risk features or that have
failed therapy with beta-adrenergic blocking agents. There are circum-
Patients with ventricular tachyarrhythmias due to a completely reversible
disorder in the absence of structural heart disease (e.g., electrolyte stances where an ICD is not indicated even if there is a significant sud-
imbalance, drugs, or trauma). den death risk (Table 299-4). Most notably, patients who do not have a
reasonable expectation of survival with an acceptable functional status
Adapted from: AE Epstein, JP DiMarco, KA Ellenbogen, et al: 2012 ACCF/AHA/
HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for for at least 1 year, should not undergo ICD placement.
device-based therapy of cardiac rhythm abnormalities: A report of the American
College of Cardiology Foundation/American Heart Association Task Force on ■■THE CHALLENGE OF SCD PREVENTION (FIG. 299-4)
Practice Guidelines and the Heart Rhythm Society. Circulation 127:e283–352,
2013. The Greatest Number of Sudden Deaths Occur in “Low
Abbreviations: LV, left ventricular; RV, right ventricular; VF, ventricular fibrillation; Risk” Patients While patients with reduced left ventricular func-
VT, ventricular tachycardia.
tion and HF are at substantially elevated SCD risk, only ~20% of all
In general, these criteria are not applied to patients who are within SCDs occur in patients with poor left ventricular function. Most SCDs
90 days of myocardial revascularization, since some will experience occur in individuals with preserved ventricular function who would
improvement in ventricular function and older trial data suggested not qualify for a primary prevention ICD. Although SCD rates are
Proportion of Sudden Cardiac Death by Clinical Subgroups
Post‐MI, CHD,
Su CM, or HF with
sta LVEF>35%
ine
dV
T/V
F5
Patients %
treated Other
LVEF <30–35%
with ICDs 15%
80%
No known Heart
disease
50%
Absolute Risk of Sudden Cardiac Death by Clinical Subgroups

7.2%
SCD Rate Per Year (%)
6.0%
3% Year:
Threshold for
ICD 3.0%
Demonstrate
benefit
1.5% 1.5%
1.0%
0.8%
0.08%
Sustained Ischemic CM, Ischemic + Non‐Ischemic Heart Failure POST‐MI, Multiple General
VT/VF LVEF<30% Non‐Ischemic CM, LVEF with LVEF>35% Cardiac Population
Arrest (MADIT) CM, LVEF ≤35% NYHA Preserved Risk Factors
≤35%, NYHA HF Class II‐ Ejection
HF Class II‐III IV, NT‐ Fraction
(SCD‐HEFT) proBNP>200 (HFPEF)
(DANISH Trial)
B
FIGURE 299-4 A. Proportion of sudden cardiac deaths that occur in clinical subgroups of the population treated and not treated with ICDs. B. Absolute risk on sudden
cardiac death within clinical subgroups in comparison to the threshold of risk where ICDs demonstrated benefit.

2068 elevated compared to the general population, the absolute SCD risk in to develop guidelines for management of patients with ventricular
patients with CHD or HF who have an LVEF >35% is not high enough arrhythmias and the prevention of sudden cardiac death): Developed
to warrant consideration of ICD therapy. While the incidence of SCD is in collaboration with the European Heart Rhythm Association and
lower in patients with preserved LVEF, SCD accounts for a greater pro- the Heart Rhythm Society. Circulation 114:e385, 2006.
portion of cardiac deaths, and active efforts are being made to advance
SCD risk stratification in this segment of the population. However,
at the present time, SCD prevention primarily involves cardiac risk
factor modification and standard medical therapy for the underlying
condition. Section 3 Neurologic Critical Care
Preventing Sudden Death in the General Population Only
300
about half of men and a third of women who suffer SCA are recognized
to have heart disease prior to the event, and only half have warning Coma
symptoms prior to the event. SCD often occurs without warning as the
first manifestation of cardiac disease. In order to prevent these SCDs, S. Andrew Josephson, Allan H. Ropper,
preventive interventions would need to be employed broadly to the Stephen L. Hauser
general population. Although several risk scores have recently been
developed with the intent to stratify SCD risk in low-risk populations,
PART 8
the clinical utility to date is limited by the low absolute incidence of

Coma is among the most common neurologic emergencies encountered
SCD which is estimated to be only 50–90 per 100,000 in the general
general medicine and requires an organized approach. It accounts for
adult population. Therefore, current efforts aimed at preventing SCD
a substantial portion of admissions to emergency wards and occurs on
in general populations primarily focus on modification of the SCD
all hospital services.
risk factors outlined previously. Individuals who adhere to a low
There exists a continuum of states of reduced alertness, the most

risk, healthy lifestyle that includes avoidance of smoking, maintain-
severe form being coma, defined as a deep sleeplike state with eyes
ing a healthy body weight, participating in moderate exercise, and a
closed from which the patient cannot be aroused. Stupor refers to a
Mediterranean-type dietary pattern have markedly lower rates of SCD.
higher degree of arousability in which the patient can be transiently
A substantial number of SCDs are likely to be preventable thorough
awakened by vigorous stimuli, accompanied by motor behavior that
lifestyle modifications and treatment of risk factors.
leads to avoidance or withdrawal from uncomfortable or aggravating
Acknowledgment stimuli. Drowsiness simulates light sleep and is characterized by easy
The authors gratefully acknowledge the prior contributions of Agustin arousal and the persistence of alertness for brief periods. Stupor and
Castellanos and Robert J. Myerburg. drowsiness are usually accompanied by some degree of confusion
(Chap. 24). A precise narrative description of the level of arousal and
■■FURTHER READING of the type of responses evoked by various stimuli as observed at the
Al-Khatib SM et al: 2017 AHA/ACC/HRS Guideline for management bedside is preferable to use of ambiguous terms such as lethargy, semi-
of patients with ventricular arrhythmias and the prevention of sud- coma, or obtundation.
den cardiac death: A report of the American College of Cardiology/ Several conditions that render patients unresponsive and simulate
American Heart Association Task Force on Clinical Practice Guide- coma are considered separately because of their special significance.
lines and the Heart Rhythm Society. Heart Rhythm Oct 26. pii: S1547- The vegetative state signifies an awake-appearing but nonresponsive
5271(17)31250-X. doi: 10.1016/j.hrthm.2017.10.036. [Epub ahead of state often in a patient who has emerged from coma. In the vegetative
print], 2017. state, the eyelids may open periodically, giving the appearance of
Callaway CW et al: Part 8: Post-Cardiac Arrest Care: 2015 American wakefulness. Respiratory and autonomic functions are retained. Yawning,
Heart Association Guidelines Update for Cardiopulmonary Resus- coughing, swallowing, and limb and head movements persist, but
citation and Emergency Cardiovascular Care. Circulation 132:S465, there are few, if any, meaningful responses to the external and inter-
2015. nal environment. There are always accompanying signs that indicate
Deo R, Albert CM: Epidemiology and genetics of sudden cardiac extensive damage in both cerebral hemispheres, e.g., decerebrate or
death. Circulation 125:620, 2012. decorticate limb posturing and absent responses to visual stimuli (see
Fishman GI et al: Sudden cardiac death prediction and prevention below). In the closely related but less severe minimally conscious state,
report from a National Heart, Lung, and Blood Institute and Heart the patient displays rudimentary vocal or motor behaviors, often spon-
Rhythm Society workshop. Circulation 122:2335, 2010. taneous, but some in response to touch, visual stimuli, or command.
Hayashi M et al: The spectrum of epidemiology underlying sudden Cardiac arrest with cerebral hypoperfusion and head trauma are the
cardiac death. Circ Res 116:1887, 2015. most common causes of the vegetative and minimally conscious states
Link MS et al: Part 7: Adult advanced cardiovascular life support: 2015 (Chap. 301).
American Heart Association guidelines update for cardiopulmo- The prognosis for regaining mental faculties once the vegetative
nary resuscitation and emergency cardiovascular care. Circulation state has supervened for several months is very poor, and after a year,
132:S444, 2015. almost nil; hence the term persistent vegetative state. Most reports of
Myerburg RJ et al: Pulseless electric activity: Definition, causes, mech- dramatic recovery, when investigated carefully, are found to yield to
anisms, management, and research priorities for the next decade: the usual rules for prognosis, but there have been rare instances in
Report from a National Heart, Lung, and Blood Institute Workshop. which recovery has occurred to a severely disabled condition and, in
Circulation 128:2532, 2013. rare childhood cases, to an even better state. Patients in the minimally
Neumar RW et al: Part 1: Executive summary. 2015 American Heart conscious state carry a better prognosis for some recovery compared
Association guidelines update for cardiopulmonary resuscitation and to those in a persistent vegetative state, but even in these patients, dra-
emergency cardiovascular care. Circulation 132:S315, 2015. matic recovery after 12 months is unusual.
Stecker EC et al: Public health burden of sudden cardiac death in the The possibility of incorrectly attributing meaningful behavior to
united states. Circ Arrhythm Electrophysiol 7:212, 2014. patients in the vegetative and minimally conscious states creates
Zipes DP et al: ACC/AHA/ESC 2006 Guidelines for management of inordinate problems and anguish for families and physicians. On the
patients with ventricular arrhythmias and the prevention of sudden other hand, the question of whether these patients lack any capability
cardiac death: A report of the American College of Cardiology/ for cognition has been reopened by functional MRI studies that have
American Heart Association Task Force and the European Society of demonstrated, in a small proportion of usually posttraumatic cases,
Cardiology Committee for Practice Guidelines (writing committee meaningful cerebral activation in response to verbal and other stimuli

as discussed in more detail below. This finding suggests at a minimum 2069
that some of these patients could in the future be able to communicate
their needs using technological advances and that further research
could shed light on treatment approaches targeting areas of the brain
and their connections that seem to be preserved in individual patients.
C
Apart from the above conditions, several syndromes that affect
alertness are prone to be misinterpreted as stupor or coma. Clinicians
should be aware of these pitfalls when diagnosing coma at the bedside. B
Akinetic mutism refers to a partially or fully awake state in which the
patient is able to form impressions and think, as demonstrated by later
A
recounting of events, but remains virtually immobile and mute. The
condition results from damage in the regions of the medial thalamic
nuclei or the frontal lobes (particularly lesions situated deeply or on the
orbitofrontal surfaces) or from extreme hydrocephalus. The term abulia
describes a milder form of akinetic mutism characterized by mental
and physical slowness and diminished ability to initiate activity. It is D
CHAPTER 300 Coma

also usually the result of damage to the medial frontal lobes and their
connections (Chap. 26).
Catatonia is a hypomobile and mute syndrome that occurs usually
as part of a major psychosis, typically schizophrenia or major depres-
sion. Catatonic patients make few voluntary or responsive movements,
although they blink, swallow, and may not appear distressed. There FIGURE 300-1 Types of cerebral herniation: (A) uncal; (B) central; (C) transfalcial;
are nonetheless signs that the patient is responsive, although it may and (D) foraminal.
take a careful examination to demonstrate them. For example, eyelid
elevation is actively resisted, blinking occurs in response to a visual
threat, and the eyes move concomitantly with head rotation, all of of herniation (Fig. 300-1). They are in essence “false localizing” signs
which are inconsistent with the presence of a brain lesion causing because they derive from compression of brain structures at a distance
unresponsiveness. It is characteristic but not invariable in catatonia from the mass lesion that is the direct cause of coma.
for the limbs to retain the postures in which they have been placed by In the most common form of herniation, brain tissue is displaced
the examiner (“waxy flexibility,” or catalepsy). With recovery, patients from the supratentorial to the infratentorial compartment through
often have some memory of events that occurred during their catatonic the tentorial opening; this is referred to as transtentorial herniation.
stupor. Catatonia is superficially similar to akinetic mutism, but clinical Uncal transtentorial herniation refers specifically to impaction of the
evidence of cerebral damage such as hyperreflexia and hypertonicity anterior medial temporal gyrus (the uncus) into the tentorial opening
of the limbs is lacking. The special problem of coma in brain death is just anterior to and adjacent to the midbrain (Fig. 300-1A). The uncus
discussed below. compresses the third nerve as the nerve traverses the subarachnoid
The locked-in state describes an important type of pseudocoma in space, causing enlargement of the ipsilateral pupil as the first sign
which an awake patient has no means of producing speech or voli- (the fibers subserving parasympathetic pupillary function are located
tional limb movement but retains voluntary vertical eye movements peripherally in the nerve). The coma that follows is due to compression
and lid elevation, thus allowing the patient to signal with a clear mind. of the midbrain (and therefore the RAS) against the opposite tentorial
The pupils are normally reactive. The usual cause is an infarction (e.g., edge by the displaced parahippocampal gyrus (Fig. 300-2). Lateral
basilar artery thrombosis) or hemorrhage of the ventral pons that tran- displacement of the midbrain may compress the opposite cerebral
sects all descending motor (corticospinal and corticobulbar) pathways. peduncle against the tentorial edge, producing a Babinski sign and
Another awake but de-efferented state occurs as a result of total paraly- hemiparesis contralateral to the hemiparesis that resulted from the
sis of the musculature in severe cases of neuromuscular weakness such mass (the Kernohan-Woltman sign). Herniation may also compress the
as in Guillain-Barré syndrome (Chap. 439), critical illness neuropathy anterior and posterior cerebral arteries as they pass over the tentorial
(Chap. 301), and pharmacologic neuromuscular blockade.
■■THE ANATOMY AND PHYSIOLOGY OF COMA

Almost all instances of coma can be traced to either (1) widespread
abnormalities of the cerebral hemispheres or to (2) reduced activity of
a special thalamocortical alerting system termed the reticular activating
system (RAS) which is diffusely located in the brainstem. The proper
functioning of this system, its ascending projections to the cortex,
and the cortex itself are required to maintain alertness and coherence
of thought. In addition to structural damage of these two systems,
suppression of reticulocerebral function can occur by drugs, toxins, or
metabolic derangements such as hypoglycemia, anoxia, uremia, and
hepatic failure; these types of metabolic causes of coma are far more
common than structural injuries.
Coma Due to Cerebral Mass Lesions and Herniation

Syndromes In addition to the fixed restriction of the skull,
A B
the cranial cavity is separated into compartments by infoldings of the
dura. The two cerebral hemispheres are separated by the falx, and the FIGURE 300-2 Coronal (A) and axial (B) magnetic resonance images from a
anterior and posterior fossae by the tentorium. Herniation refers to stuporous patient with a left third nerve palsy as a result of a large left-sided
subdural hematoma (seen as a gray-white rim). The upper midbrain and lower
displacement of brain tissue by an overlying or adjacent mass into a thalamic regions are compressed and displaced horizontally away from the mass,
contiguous compartment that it normally does not occupy. Coma and and there is transtentorial herniation of the medial temporal lobe structures,
many of its associated signs can be attributed to these tissue shifts, including the uncus anteriorly. The lateral ventricle opposite to the hematoma has
and certain clinical features are characteristic of specific configurations become enlarged as a result of compression of the third ventricle.

2070 reflections, with resultant brain infarction. These distortions may also catecholamines, altered glutamate and GABA tone, increases in brain
entrap portions of the ventricular system, resulting in hydrocephalus. calcium, inflammation with disruption of the blood brain barrier, and
Central transtentorial herniation denotes a symmetric downward frequent coexisting vascular disease.
movement of the thalamic structures through the tentorial opening Coma and seizures are common accompaniments of large shifts in
with compression of the upper midbrain (Fig. 300-1B). Miotic pupils sodium and water balance in the brain. These changes in osmolarity
and drowsiness are the heralding signs, in contrast to a unilaterally arise from systemic medical disorders, including diabetic ketoacidosis,
enlarged pupil of the uncal syndrome. Both uncal and central transten- the nonketotic hyperosmolar state, and hyponatremia from any cause
torial herniations cause progressive compression of the brainstem and (e.g., water intoxication, excessive secretion of antidiuretic hormone,
RAS, with initial damage to the midbrain, then the pons, and finally or atrial natriuretic peptides). Sodium levels <125 mmol/L induce
the medulla. The result is an approximate sequence of neurologic signs confusion, and levels <119 mmol/L are typically associated with coma
that corresponds to each affected level, with respiratory centers in the and convulsions, especially when these levels are achieved quickly. In
brainstem often spared until late in the herniation syndrome. Other hyperosmolar coma, the serum osmolarity is generally >350 mosmol/L.
forms of herniation include transfalcial herniation (displacement of the Hypercapnia depresses the level of consciousness in proportion to
cingulate gyrus under the falx and across the midline, Fig. 300-1C) and the rise in carbon dioxide (CO2) in the blood. In all of these metabolic
foraminal herniation (downward forcing of the cerebellar tonsils into encephalopathies, the degree of neurologic change depends to a large
the foramen magnum, Fig. 300-1D), which causes early compression of extent on the rapidity with which the serum changes occur. The patho-
the medulla, respiratory arrest, and death. physiology of other metabolic encephalopathies such as those due
A direct relationship between the various configurations of transten- to hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypo-
PART 8
torial herniation and coma is not always found. Drowsiness and stupor thermia are incompletely understood but must reflect derangements of
can occur with moderate horizontal displacement of the diencephalon CNS biochemistry, membrane function, or neurotransmitters.
(thalamus), before transtentorial herniation is evident. This lateral shift Coma due to drugs and toxins are typically in large measure revers-
may be quantified on axial images of computed tomography (CT) ible and leave no residual damage provided there has not been cardi-
and magnetic resonance imaging (MRI) scans (Fig. 300-2). In cases orespiratory failure. Many drugs and toxins are capable of depressing
of acutely enlarging masses, horizontal displacement of the pineal nervous system function. Some produce coma by affecting both the
gland (often calcified in adults) of 3–5 mm is generally associated with RAS and the cerebral cortex. The combination of cortical and brainstem
drowsiness, 6–8 mm with stupor, and >9 mm with coma. Intrusion of signs, which occurs in certain drug overdoses, may lead to an incorrect
the medial temporal lobe into the tentorial opening is also apparent diagnosis of structural brainstem disease. Overdose of medications that
on MRI and CT scans as obliteration of the cisterna that surrounds the have atropinic actions produces signs such as dilated pupils, tachycar-
upper brainstem. dia, and dry skin; opiate overdose produces pinpoint pupils <1 mm
in diameter. Some drug intoxications, such as with barbiturates, can
Coma Due to Metabolic Disorders and Toxins (including mimic all of the signs of brain death, thus toxic etiologies must always
Drug-induced) Many systemic metabolic abnormalities cause be excluded prior to making a diagnosis of brain death.
coma by interrupting the delivery of energy substrates (e.g., oxygen,
glucose) or by altering neuronal excitability (drugs and alcohol, anes- Epileptic Coma Generalized electrical seizures are associated
thesia, and epilepsy). These are some of the most common causes of with coma, even in the absence of motor convulsions (nonconvulsive
coma in large case series. The metabolic abnormalities that produce status epilepticus). As a result, consideration of EEG monitoring is
coma may, in milder forms, induce an acute confusional state. Thus, essential in the workup of coma to exclude this treatable etiology. The
in metabolic encephalopathies, clouded consciousness and coma are self-limited coma that follows a seizure, the postictal state, may be due to
in a continuum. exhaustion of energy reserves or effects of locally toxic molecules that
Cerebral neurons are fully dependent on cerebral blood flow (CBF) are the by-product of seizures. The postictal state produces continuous,
and the delivery of oxygen and glucose. CBF is ~75 mL per 100 g/min generalized slowing of the background EEG activity similar to that of
in gray matter and 30 mL per 100 g/min in white matter (mean ~55 mL metabolic encephalopathies. It typically lasts for a few minutes, but in
per 100 g/min); oxygen consumption is 3.5 mL per 100 g/min, and some cases can be prolonged for hours or even rarely for days.
glucose utilization is 5 mg per 100 g/min. Brain stores of glucose are Coma Due to Widespread Damage to the Cerebral
able to provide energy for ~2 min after blood flow is interrupted, and Hemispheres This category, comprising a number of unrelated
oxygen stores last 8–10 s after the cessation of blood flow. Simultaneous disorders, results from extensive bilateral structural cerebral damage
hypoxia and ischemia exhaust glucose more rapidly. The electroen- that simulates a metabolic disorder. Hypoxia-ischemia is perhaps the
cephalogram (EEG) rhythm in these circumstances becomes diffusely best characterized and one in which it is not possible initially to dis-
slowed, typical of metabolic encephalopathies, and as substrate deliv- tinguish the acute reversible effects of oxygen deprivation of the brain
ery worsens, eventually brain electrical activity ceases. from the subsequent effects of anoxic neuronal damage. Similar cere-
Unlike hypoxia-ischemia, which causes neuronal destruction, most bral damage may be produced by disorders that occlude widespread
metabolic disorders such as hypoglycemia, hyponatremia, hyperos- small blood vessels throughout the brain; examples include cerebral
molarity, hypercapnia, hypercalcemia, and hepatic and renal failure malaria, thrombotic thrombocytopenic purpura, and hyperviscosity.
cause only minor neuropathologic changes. The reversible effects of Diffuse white matter damage from cranial trauma or inflammatory
these conditions on the brain are not fully understood but may result demyelinating diseases can cause a similar coma syndrome.
from impaired energy supplies, changes in ion fluxes across neuronal
membranes, and neurotransmitter abnormalities. In hepatic encephal-
opathy (HE), high ammonia concentrations lead to increased synthe- APPROACH TO THE PATIENT
sis of glutamine in astrocytes with osmotic swelling, mitochondrial
energy failure, production of reactive nitrogen and oxygen species, Coma
increases in the inhibitory neurotransmitter GABA, and synthesis of
A video examination of the comatose patient is shown in Chap. V4.
putative “false” neurotransmitters. Other factors, including coexisting
Acute respiratory and cardiovascular problems should be attended
inflammation and metabolic abnormalities, also contribute to the coma
to prior to neurologic assessment. In most instances, a complete
in some patients. Over time, development of a diffuse astrocytosis is
medical evaluation, except for vital signs, funduscopy, and exami-
typical of chronic HE. The mechanism of the encephalopathy of renal
nation for nuchal rigidity, may be deferred until the neurologic
failure is also multifactorial. Unlike ammonia, urea does not produce
evaluation has established the severity and nature of coma. The
central nervous system (CNS) toxicity, and contributors to uremic
approach to the patient with coma from cranial trauma is dis-
encephalopathy may include accumulation of neurotoxic substances
cussed in Chap. 435.
such as creatinine, guanidine, and related compounds, depletion of

2071
HISTORY serial examinations are useful. Tickling the nostrils with a cotton
The cause of coma may be immediately evident as in cases of wisp is a moderate stimulus to arousal—all but deeply stuporous
trauma, cardiac arrest, or observed drug ingestion. In the remainder, and comatose patients will move the head away and arouse to some
certain points are useful: (1) the circumstances and rapidity with degree. An even greater degree of responsiveness is present if the
which neurologic symptoms developed; (2) antecedent symptoms patient uses his hand to remove an offending stimulus. Pressure
(confusion, weakness, headache, fever, seizures, dizziness, double on the knuckles or bony prominences and pinprick stimulation are
vision, or vomiting); (3) the use of medications, drugs, or alcohol; humane forms of noxious stimuli; pinching the skin causes unsightly
and (4) chronic liver, kidney, lung, heart, or other medical disease. ecchymoses and is generally not necessary but may be useful in
Direct interrogation of family, observers, and ambulance technicians eliciting abduction withdrawal movements of the limbs. Posturing
on the scene, in person or by telephone, is an important part of the in response to noxious stimuli indicates severe damage to the corti-
evaluation when possible. cospinal system, whereas abduction-avoidance movement of a limb
is usually purposeful and denotes an intact corticospinal system.
GENERAL PHYSICAL EXAMINATION Posturing may also be unilateral and coexist with purposeful limb
Fever suggests a systemic infection, bacterial meningitis, encephali- movements, reflecting incomplete damage to the motor system.
tis, heat stroke, neuroleptic malignant syndrome, malignant hyper-
BRAINSTEM REFLEXES
thermia due to anesthetics, or anticholinergic drug intoxication.
Given that the nuclei of the cranial nerves and the RAS are both
CHAPTER 300 Coma

Only rarely is fever attributable to a lesion that has disturbed hypo-
thalamic temperature-regulating centers (“central fever”) and this located in the brainstem, assessment of brainstem function is essen-
diagnosis should only be considered after an exhaustive search for tial to localization of the lesion in coma (Fig. 300-3). Patients
other causes fails to reveal an explanation for fever. A slight eleva- with preserved brainstem reflexes typically have a bihemispheric
tion in temperature may follow vigorous convulsions. Hypothermia localization to coma, including toxic or drug intoxication, whereas
is observed with alcohol, barbiturate, sedative, or phenothiazine patients with abnormal brainstem reflexes either have an RAS local-
intoxication; hypoglycemia; peripheral circulatory failure; or ization to their coma or are suffering from a herniation syndrome
extreme hypothyroidism. Hypothermia itself causes coma when the impacting the brainstem remotely from a cerebral mass lesion. The
temperature is <31°C (87.8°F) regardless of the underlying etiology. most important brainstem reflexes that are examined are pupillary
Tachypnea may indicate systemic acidosis or pneumonia. Aberrant size and reaction to light, spontaneous and elicited eye movements,
respiratory patterns that reflect brainstem disorders are discussed corneal responses, and the respiratory pattern.
below. Marked hypertension suggests hypertensive encephalopa-
thy, cerebral hemorrhage, large cerebral infarction, or head injury.
Hypotension is characteristic of coma from alcohol or barbiturate Pupillary light reflex
intoxication, internal hemorrhage or myocardial infarction causing
poor delivery of blood to the brain, sepsis, profound hypothyroid-
ism, or Addisonian crisis. The funduscopic examination can detect
increased intracranial pressure (ICP) (papilledema), subarachnoid
hemorrhage (subhyaloid hemorrhages), and hypertensive enceph-
alopathy (exudates, hemorrhages, vessel-crossing changes, papille-
dema). Cutaneous petechiae suggest thrombotic thrombocytopenic
purpura, meningococcemia, or a bleeding diathesis associated with
an intracerebral hemorrhage. Cyanosis and reddish or anemic skin
coloration are other indications of an underlying systemic disease or
carbon monoxide as responsible for the coma.
NEUROLOGIC EXAMINATION III III
The patient should first be observed without intervention by the
M
examiner. Tossing about in the bed, reaching up toward the face, L Pons
V
crossing legs, yawning, swallowing, coughing, or moaning reflect F
a drowsy state that is close to normal awakeness. Lack of restless Vl
movements on one side or an outturned leg suggests hemiplegia. Vll
Vlll
Subtle, intermittent twitching movements of a foot, finger, or facial
muscle may be the only sign of seizures. Multifocal myoclonus Medulla
almost always indicates a metabolic disorder, particularly uremia, Corneal-blink Reflex conjugate
anoxia, drug intoxication, or rarely a prion disease (Chap. 430). In a reflex eye movements
drowsy and confused patient, bilateral asterixis is a sign of metabolic
encephalopathy or drug intoxication.
Decorticate rigidity and decerebrate rigidity, or “posturing,” Respiratory
describe stereotyped arm and leg movements occurring spontane- neurons
ously or elicited by sensory stimulation. Flexion of the elbows and
wrists and supination of the arm (decorticate posturing) suggests
bilateral damage rostral to the midbrain, whereas extension of the
elbows and wrists with pronation (decerebrate posturing) indicates
damage to motor tracts caudal to the midbrain. These localizations
have been adapted from animal work and cannot be applied with
precision to coma in humans. In fact, acute and widespread disorders FIGURE 300-3 Examination of brainstem reflexes in coma. Midbrain and third
of any type, regardless of location, frequently cause limb extension. nerve function are tested by pupillary reaction to light, pontine function by
spontaneous and reflex eye movements and corneal responses, and medullary
LEVEL OF AROUSAL function by respiratory and pharyngeal responses. Reflex conjugate, horizontal
A sequence of increasingly intense stimuli is first used to determine eye movements are dependent on the medial longitudinal fasciculus (MLF)
the threshold for arousal and the motor response of each side of the interconnecting the sixth and contralateral third nerve nuclei. Head rotation
(oculocephalic reflex) or caloric stimulation of the labyrinths (oculovestibular
body. The results of testing may vary from minute to minute, and
reflex) elicits contraversive eye movements (for details see text).

2072 Pupillary Signs Pupillary reactions are examined with a bright, dif- Thermal, or “caloric,” stimulation of the vestibular apparatus
fuse light. Reactive and round pupils of midsize (2.5–5 mm) essen- (oculovestibular response) provides a more intense stimulus for the
tially exclude upper midbrain damage, either primary or secondary oculocephalic reflex but provides essentially the same information.
to compression. A response to light may be difficult to appreciate in The test is performed by irrigating the external auditory canal with
pupils <2 mm in diameter, and bright room lighting mutes pupil- cold water in order to induce convection currents in the labyrinths.
lary reactivity. One enlarged and poorly reactive pupil (>6 mm) sig- After a brief latency, the result is tonic deviation of both eyes to the
nifies compression or stretching of the third nerve from the effects side of cold-water irrigation. In comatose patients, nystagmus in the
of a cerebral mass above. Enlargement of the pupil contralateral opposite direction may not occur. The acronym “COWS” has been
to a hemispheral mass may occur but is infrequent. An oval and used to remind generations of medical students of the direction
slightly eccentric pupil is a transitional sign that accompanies early of nystagmus—cold water opposite, warm water same—but since
midbrain–third nerve compression. The most extreme pupillary nystagmus is often absent in the opposite direction due to frontal
sign, bilaterally dilated and unreactive pupils, indicates severe lobe dysfunction in coma, this mnemonic does not often hold true.
midbrain damage, usually from compression by a supratentorial When touching the cornea with a wisp of cotton, a response
mass. Ingestion of drugs with anticholinergic activity, the use of consisting of brief bilateral lid closure is normally observed. The
mydriatic eye drops, nebulizer treatments, and direct ocular trauma corneal reflex depends on the integrity of pontine pathways between
are among the causes of misleading pupillary enlargement. the fifth (afferent) and both seventh (efferent) cranial nerves; in
Reactive and bilaterally small (1–2.5 mm) but not pinpoint pupils conjunction with reflex eye movements, it is a useful test of pontine
PART 8
are seen in metabolic encephalopathies or in deep bilateral hemi- function. CNS-depressant drugs diminish or eliminate the corneal
spheral lesions such as hydrocephalus or thalamic hemorrhage. Even responses soon after reflex eye movements are paralyzed but before
smaller reactive pupils (<1 mm) characterize narcotic or barbiturate the pupils become unreactive to light. The corneal response may be
overdoses but also occur with extensive pontine hemorrhage. The lost for a time on the side of an acute hemiplegia.
response to naloxone and the presence of reflex eye movements (see
Respiratory Patterns These are of less localizing value in compar-

below) assist in distinguishing between these. Unilateral miosis in ison to other brainstem signs. Shallow, slow, but regular breathing
coma has been attributed to dysfunction of sympathetic efferents orig- suggests metabolic or drug depression. Cheyne-Stokes respiration
inating in the posterior hypothalamus and descending in the tegmen- in its typical cyclic form, ending with a brief apneic period, signifies
tum of the brainstem to the cervical cord. It is an occasional finding bihemispheral damage or metabolic suppression and commonly
in patients with a large cerebral hemorrhage that affects the thalamus. accompanies light coma. Rapid, deep (Kussmaul) breathing usually
Ocular Movements The eyes are first observed by elevating the implies metabolic acidosis but may also occur with pontomesen-
lids and observing the resting position and spontaneous move- cephalic lesions. Agonal gasps are the result of lower brainstem
ments of the globes. Horizontal divergence of the eyes at rest is nor- (medullary) damage and are recognized as the terminal respiratory
mal in drowsiness. As coma deepens, the ocular axes may become pattern of severe brain damage. A number of other cyclic breathing
parallel again. variations have been described but are of lesser significance.
Spontaneous eye movements in coma often take the form of
conjugate horizontal roving. This finding alone exonerates extensive ■■LABORATORY STUDIES AND IMAGING
damage in the midbrain and pons and has the same significance The studies that are most useful in the diagnosis of coma are chemi-
as normal reflex eye movements (see below). Conjugate horizontal cal-toxicologic analysis of blood and urine, cranial CT or MRI, EEG,
ocular deviation to one side indicates damage to the frontal lobe and CSF examination. Arterial blood gas analysis is helpful in patients
on the same side or less commonly the pons on the opposite side. with lung disease and acid-base disorders. The metabolic aberrations
This phenomenon is summarized by the following maxim: The eyes commonly encountered in clinical practice are usually revealed by
look toward a hemispheral lesion and away from a brainstem lesion. Sei- measurement of electrolytes, glucose, calcium, magnesium, osmolarity,
zures involving the frontal lobe drive the eyes to the opposite side, and renal (blood urea nitrogen) and hepatic (NH3) function. Toxicologic
simulating a pontine destructive lesion. The eyes may occasionally analysis may be necessary in any case of acute coma where the diag-
turn paradoxically away from the side of a deep hemispheral lesion nosis is not immediately clear. However, the presence of exogenous
(“wrong-way eyes”). The eyes turn down and inward with tha- drugs or toxins, especially alcohol, does not exclude the possibility
lamic and upper midbrain lesions, typically thalamic hemorrhage. that other factors, particularly head trauma, are also contributing to
“Ocular bobbing” describes brisk downward and slow upward the clinical state. An ethanol level of 43 mmol/L (0.2 g/dL) in nonhab-
movements of the eyes associated with loss of horizontal eye ituated patients generally causes impaired mental activity; a level of
movements and is diagnostic of bilateral pontine damage, usually >65 mmol/L (0.3 g/dL) is associated with stupor. The development of
from thrombosis of the basilar artery. “Ocular dipping” is a slower, tolerance may allow some chronic alcoholics to remain awake at levels
arrhythmic downward movement followed by a faster upward >87 mmol/L (0.4 g/dL).
movement in patients with normal reflex horizontal gaze; it usually The availability of CT and MRI has focused attention on causes
indicates diffuse cortical anoxic damage. of coma that are detectable by imaging (e.g., hemorrhage, tumor, or
The oculocephalic reflexes, elicited by moving the head from side hydrocephalus). Resorting primarily to this approach, although at
to side or vertically and observing eye movements in the direction times expedient, is imprudent because most cases of coma (and con-
opposite to the head movement, depend on the integrity of the ocu- fusion) are metabolic or toxic in origin. A normal CT scan does not
lar motor nuclei and their interconnecting tracts that extend from exclude an anatomic lesion as the cause of coma; early bilateral hemi-
the midbrain to the pons and medulla (Fig. 300-3). The movements, sphere infarction, acute brainstem infarction, encephalitis, meningitis,
called somewhat inappropriately “doll’s eyes,” are normally sup- mechanical shearing of axons as a result of closed head trauma, sagittal
pressed in the awake patient with intact frontal lobes. The ability sinus thrombosis, hypoxic injury and subdural hematoma isodense
to elicit them therefore reflects both reduced cortical influence on to adjacent brain are some of the disorders that may not be detected.
the brainstem and intact brainstem pathways. The opposite, an Sometimes imaging results can be misleading such as when small
absence of reflex eye movements, usually signifies damage within subdural hematomas or old strokes are found, but the patient’s coma
the brainstem but can result from overdoses of certain drugs. In this is due to intoxication.
circumstance, normal pupillary size and light reaction distinguishes The EEG (Chap. 418) provides clues in metabolic or drug-induced
most drug-induced comas from structural brainstem damage. states but is rarely diagnostic. However, it is the essential test to reveal
Oculocephalic reflexes should never be elicited in patients with coma due to nonconvulsive seizures, and shows fairly characteristic
possible head or neck trauma, as vigorous head movements can patterns in herpesvirus encephalitis and prion (Creutzfeldt-Jakob) dis-
precipitate or worsen a spinal cord injury. ease. The EEG may be further helpful in disclosing generalized slowing

of the background activity, a reflection of the severity of an encepha- The diagnosis of coma due to cerebrovascular disease can be diffi- 2073
lopathy. Predominant high-voltage slowing (δ or triphasic waves) in cult (Chap. 419). The most common diseases are (1) basal ganglia and
the frontal regions is typical of metabolic coma, as from hepatic failure, thalamic hemorrhage (acute but not instantaneous onset, vomiting,
and widespread fast (β) activity implicates sedative drugs (e.g., benzo- headache, hemiplegia, and characteristic eye signs); (2) pontine hemor-
diazepines). A special pattern of “alpha coma,” defined by widespread, rhage (sudden onset, pinpoint pupils, loss of reflex eye movements and
variable 8- to 12-Hz activity, superficially resembles the normal α corneal responses, ocular bobbing, posturing, and hyperventilation);
rhythm of waking but, unlike normal α activity, is not altered by envi- (3) cerebellar hemorrhage (occipital headache, vomiting, gaze paresis,
ronmental stimuli. Alpha coma results from pontine or diffuse cortical and inability to stand and walk); (4) basilar artery thrombosis (neuro-
damage and is associated with a poor prognosis. Normal α activity on logic prodrome or warning spells, diplopia, dysarthria, vomiting, eye
the EEG, which is suppressed by stimulating the patient, also alerts the movement and corneal response abnormalities, and asymmetric limb
clinician to the locked-in syndrome or to hysteria or catatonia. paresis); and (5) subarachnoid hemorrhage (precipitous coma after
Lumbar puncture should be performed if no cause is readily appar- sudden severe headache and vomiting). The most common stroke,
ent, as examination of the CSF remains indispensable in the diagnosis infarction in the territory of the middle cerebral artery, does not cause
of various forms of meningitis and encephalitis. An imaging study coma, but edema surrounding large infarctions may expand over sev-
should be performed prior to lumbar puncture to exclude a large intra- eral days and cause coma from mass effect.
cranial mass lesion which could lead to herniation with lumbar punc- The syndrome of acute hydrocephalus accompanies many intracra-
CHAPTER 300 Coma

ture. Blood cultures and administration of antibiotics should precede nial diseases, particularly subarachnoid hemorrhage. It is characterized
the imaging study if infectious meningitis is suspected (Chap. 133). by headache and sometimes vomiting that may progress quickly to
coma with extensor posturing of the limbs, bilateral Babinski signs,
■■DIFFERENTIAL DIAGNOSIS OF COMA small unreactive pupils, and impaired oculocephalic movements in the
(Table 300-1) The causes of coma can be divided into three broad cat- vertical direction. At times, the coma may be featureless without later-
egories: cases without focal neurologic signs (e.g., metabolic and toxic alizing signs, although papilledema is often present.
encephalopathies); cases with prominent focal signs (e.g., stroke, cere-
bral hemorrhage); and meningitis syndromes, characterized by fever or ■■BRAIN DEATH
stiff neck and an excess of cells in the spinal fluid (e.g., bacterial menin- This is a state of irreversible cessation of all cerebral and brainstem
gitis, subarachnoid hemorrhage, encephalitis). Causes of sudden coma function with preservation of cardiac activity and maintenance of
include drug ingestion, cerebral hemorrhage, trauma, cardiac arrest, respiratory and somatic function by artificial means. Brain death is the
epilepsy, and basilar artery occlusion. Coma that appears subacutely is only type of brain damage recognized as morally, ethically, and legally
usually related to a preexisting medical or neurologic problem or, less equivalent to death. Criteria have been advanced for the diagnosis of
often, to secondary brain swelling surrounding a mass such as tumor brain death, and it is essential to adhere to consensus standards as
or cerebral infarction. multiple studies have shown variability in local practice. Given the
implications of such a diagnosis, clinicians must be thorough and pre-
TABLE 300-1 Differential Diagnosis of Coma cise in determining brain death. Established criteria are simple, can be
1. Diseases that cause no focal brainstem or lateralizing neurologic signs assessed at the bedside, and allow no chance of diagnostic error. They
(CT scan is often normal) contain two essential elements, after assuring that no confounding fac-
a. Intoxications: alcohol, sedative drugs, opiates, etc. tors (e.g., hypothermia, drug intoxication) are present: (1) widespread
b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia, cortical destruction that is reflected by deep coma and unresponsive-
hypercalcemia, diabetic acidosis, nonketotic hyperosmolar ness to all forms of stimulation; (2) global brainstem damage demon-
hyperglycemia, hypoglycemia, uremia, hepatic coma, hypercarbia, strated by absent pupillary light reaction, absent corneal reflexes, loss
Addisonian crisis, hypo- and hyperthyroid states, profound nutritional of oculovestibular reflexes, and destruction of the medulla, manifested
deficiency
by complete and irreversible apnea. Diabetes insipidus is usually pres-
c. Severe systemic infections: pneumonia, septicemia, typhoid fever, ent, but may only develop hours or days after the other clinical signs
malaria, Waterhouse-Friderichsen syndrome
of brain death appear. The pupils are usually midsized but may be
d. Shock from any cause
enlarged. Loss of deep tendon reflexes is not required because the spi-
e. Status epilepticus, nonconvulsive status epilepticus, postictal states nal cord remains functional. Occasionally other reflexes that originate
f. Hyperperfusion syndromes including hypertensive encephalopathy, from the spine may be present and should not preclude a diagnosis of
eclampsia, posterior reversible encephalopathy syndrome (PRES)
brain death.
g. Severe hyperthermia, hypothermia Demonstration that apnea is due to medullary damage requires
h. Concussion that the Pco2 be high enough to stimulate respiration during a test
i. Acute hydrocephalus of spontaneous breathing. Apnea testing can be done safely by the use
2. Diseases that cause focal brainstem or lateralizing cerebral signs (CT scan of preoxygenation with 100% oxygen prior to and following removal of
is typically abnormal) the ventilator. CO2 tension increases ~0.3–0.4 kPa/min (2–3 mmHg/min)
a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large during apnea. Apnea is confirmed if no respiratory effort has been
middle cerebral artery territory) with secondary brainstem compression observed in the presence of a sufficiently elevated Pco2. The apnea test
b. Brainstem infarction due to basilar artery thrombosis or embolism is usually stopped if there is serious cardiovascular instability.
c. Brain abscess, subdural empyema An isoelectric EEG may be used as an optional confirmatory test
d. Epidural and subdural hemorrhage, brain contusion for total cerebral damage. Radionuclide brain scanning, cerebral angi-
e. Brain tumor with surrounding edema ography, or transcranial Doppler measurements may also be included
f. Cerebellar and pontine hemorrhage and infarction to demonstrate the absence of blood flow when a confirmatory study
g. Widespread traumatic brain injury is desired.
h. Metabolic coma (see above) in the setting of preexisting focal damage Some period of observation, usually 6–24 h, is recommended, dur-
ing which the clinical signs of brain death are sustained. It is advisable
3. Diseases that cause meningeal irritation with or without fever, and with an
excess of WBCs or RBCs in the CSF to delay clinical testing for at least 24 h if a cardiac arrest has caused
a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous
brain death or if the inciting disease is not known.
malformation, trauma It is largely accepted in Western society that the ventilator can be
b. Infectious meningitis and meningoencephalitis disconnected from a brain-dead patient and that organ donation is
c. Paraneoplastic and autoimmune meningitis
subsequently possible. Good communication between the physician
and the family is important with appropriate preparation of the family
d. Carcinomatous and lymphomatous meningitis
for brain death testing and diagnosis.

2074 could be established. There are also reports in exceptional patients of
TREATMENT
improvement in cognitive function with the implantation of thalamic-
Coma stimulating electrodes or the use of novel activating agents including
zolpidem. It is prudent to avoid generalizations from these findings,
The immediate goal in a comatose patient is prevention of further but the need for future studies of novel techniques to help communica-
nervous system damage. Hypotension, hypoglycemia, hypercalce- tion and possibly recovery is needed.
mia, hypoxia, hypercapnia, and hyperthermia should be corrected
rapidly. An oropharyngeal airway is adequate to keep the pharynx ■■FURTHER READING
open in a drowsy patient who is breathing normally. Tracheal intuba- Edlow JA et al: Diagnosis of reversible causes of coma. Lancet 384:2064,
tion is indicated if there is apnea, upper airway obstruction, hypoven- 2014.
tilation, or emesis, or if the patient is at risk for aspiration. Mechanical Greer DM et al: Variability of brain death policies in the United States.
ventilation is required if there is hypoventilation or a need to induce JAMA Neurol 73:213, 2016.
hypocapnia in order to lower ICP. IV access is established, and nalox- Monti MM et al: Willful modulation of brain activity in disorders of
one and dextrose are administered if narcotic overdose or hypogly- consciousness. N Engl J Med 362:579, 2010.
cemia is a possibility; thiamine is given along with glucose to avoid Posner JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 4th ed.
provoking Wernicke’s encephalopathy in malnourished patients. In New York, Oxford University Press, 2007.
cases of suspected ischemic stroke including basilar thrombosis with Rossetti AO et al: Neurologic prognostication of outcome in patients
brainstem ischemia, IV tissue plasminogen activator or mechanical in coma after cardiac arrest. Lancet Neurol 15:597, 2016.
PART 8
embolectomy is often used after cerebral hemorrhage has been

excluded and when the patient presents within established time
windows for these interventions (Chap. 420). Physostigmine may
awaken patients with anticholinergic-type drug overdose but should
301 Severe
be used only with careful monitoring; many physicians believe that
it should only be used to treat anticholinergic overdose–associated Acute

cardiac arrhythmias. The use of benzodiazepine antagonists offers
some prospect of improvement after overdose; however, these drugs
Encephalopathies and
are not commonly used empirically in part due to their tendency to Critical Care Weakness
provoke seizures. Certain other toxic and drug-induced comas have
specific treatments such as fomepizole for ethylene glycol ingestion. J. Claude Hemphill, III, Wade S. Smith,
Administration of hypotonic intravenous solutions should be S. Andrew Josephson, Daryl R. Gress
monitored carefully in any serious acute brain illness because of
the potential for exacerbating brain swelling. Cervical spine injuries
must not be overlooked, particularly before attempting intubation
Life-threatening neurologic illness may be caused by a primary disor-
or evaluation of oculocephalic responses. Fever and meningismus
der affecting any region of the neuraxis or may occur as a consequence
indicate an urgent need for examination of the CSF to diagnose men-
of a systemic disorder such as hepatic failure, multisystem organ
ingitis. Whenever acute bacterial meningitis is suspected, antibiotics
failure, or cardiac arrest (Table 301-1). Neurologic critical care focuses
including vancomycin and a third-generation cephalosporin should
on preservation of neurologic tissue and prevention of secondary
be administered along with dexamethasone, preferably after obtain-
brain injury caused by ischemia, hemorrhage, edema, herniation, and
ing blood cultures (see Chap. 133). The management of raised ICP
elevated intracranial pressure (ICP). Encephalopathy is a general term
is discussed in Chap. 301.
describing brain dysfunction that is diffuse, global, or multi-focal.
Severe acute encephalopathies represent a group of various disorders
due to different neurological or systemic etiologies, but that share the
■■PROGNOSIS common themes of primary and secondary brain injury.
Some patients, especially children and young adults, may have omi-
nous early clinical findings such as abnormal brainstem reflexes and ■■PATHOPHYSIOLOGY
yet recover; ultra-early prognostication outside of brain death therefore Brain Edema Swelling, or edema, of brain tissue occurs with many
is unwise. Metabolic comas have a far better prognosis than traumatic types of brain injury. The two principal types of edema are vasogenic
ones. All systems for estimating prognosis in adults should be taken and cytotoxic. Vasogenic edema refers to the influx of fluid and solutes
as approximations, and medical judgments must be tempered by into the brain through an incompetent blood-brain barrier (BBB). In
factors such as age, underlying systemic disease, and general medical the normal cerebral vasculature, endothelial tight junctions associated
condition. In an attempt to collect prognostic information from large with astrocytes create an impermeable barrier (the BBB), through
numbers of patients with head injury, the Glasgow Coma Scale was which access into the brain interstitium is dependent upon specific
devised; empirically, it has predictive value in cases of brain trauma transport mechanisms. The BBB may be compromised in ischemia,
(see Chap. 435). For anoxic coma, clinical signs such as the pupillary trauma, infection, and metabolic derangements. Vasogenic edema results
and motor responses after 1 day, 3 days, and 1 week have been shown from abnormal permeability of the BBB, and typically develops rapidly
to have predictive value; however, some of these prediction rules are following injury. Cytotoxic edema results from cellular swelling, mem-
less reliable in the setting of therapeutic hypothermia and therefore brane breakdown, and ultimately cell death. Clinically significant brain
serial examinations are advised in this setting. The absence of the cor- edema usually represents a combination of vasogenic and cytotoxic
tical responses of the somatosensory evoked potentials has also been components. Edema can lead to increased ICP as well as tissue shifts
shown to be a strong indicator of poor outcome following hypoxic and brain displacement or herniation from focal processes (Chap. 300).
injury. These tissue shifts can cause injury by mechanical distention and com-
The uniformly poor outcome of persistent vegetative state has pression in addition to the ischemia of impaired perfusion consequent
already been mentioned, but recent reports of a number of such to the elevated ICP.
patients displaying consistent cortical activation on functional MRI in
response to salient stimuli have begun to alter the perception of such Ischemic Cascade and Cellular Injury When delivery of
individuals. In one series, about 10% of vegetative patients (mainly substrates, principally oxygen and glucose, is inadequate to sustain
following traumatic brain injury) could activate their frontal or tem- cellular function, a series of interrelated biochemical reactions known
poral lobes in response to requests by an examiner to imagine certain as the ischemic cascade is initiated (see Fig. 419-2). The release of exci-
visuospatial tasks. In one case, a rudimentary form of communication tatory amino acids, especially glutamate, leads to influx of calcium

TABLE 301-1 Neurologic Disorders in Critical Illness and sodium ions, which disrupt cellular homeostasis. An increased 2075
intracellular calcium concentration may activate proteases and lipases,
LOCALIZATION ALONG
NEUROAXIS SYNDROME which then lead to lipid peroxidation and free radical–mediated cell
membrane injury. Cytotoxic edema ensues, and ultimately necrotic
Central Nervous System
cell death and tissue infarction occur. This pathway to irreversible
Brain: Cerebral hemispheres Global encephalopathy cell death is common to ischemic stroke, global cerebral ischemia, and
Delirium traumatic brain injury.
Sepsis Penumbra refers to areas of ischemic brain tissue that have not yet
Organ failure—hepatic, renal undergone irreversible infarction, implying that these regions are
Medication related—sedatives, hypnotics, potentially salvageable if ischemia can be reversed. Factors that may
analgesics, H2 blockers, antihypertensives exacerbate ischemic brain injury include systemic hypotension and
Drug overdose hypoxia, which further reduce substrate delivery to vulnerable brain
Electrolyte disturbance—hyponatremia, tissue, and fever, seizures, and hyperglycemia, which can increase
hypoglycemia cellular metabolism, outstripping compensatory processes. Clinically,
Hypotension/hypoperfusion these events are known as secondary brain insults because they lead to
Hypoxia exacerbation of the primary brain injury. Prevention, identification,
CHAPTER 301 Severe Acute Encephalopathies and Critical Care Weakness

Meningitis and treatment of secondary brain insults are fundamental goals of
Subarachnoid hemorrhage management.
Wernicke’s disease
An alternative pathway of cellular injury is apoptosis. This process
implies programmed cell death, which may occur in the setting of
Seizure—postictal or nonconvulsive status
epilepticus ischemic stroke, global cerebral ischemia, traumatic brain injury, and
possibly intracerebral hemorrhage. Apoptotic cell death can be distin-
Hypertensive encephalopathy
guished histologically from the necrotic cell death of ischemia and is
Hypothyroidism—myxedema
mediated through a different set of biochemical pathways; apoptotic
Focal deficits cell death occurs without cerebral edema and therefore is often not
Ischemic stroke seen on brain imaging. At present, interventions for prevention and
Tumor treatment of apoptotic cell death remain less well defined than those
Abscess, subdural empyema for ischemia.
Intraparenchymal hemorrhage
Cerebral Perfusion and Autoregulation Brain tissue requires
Subdural/epidural hematoma constant perfusion in order to ensure adequate delivery of substrate.
Brainstem/cerebellum Mass effect and compression The hemodynamic response of the brain has the capacity to preserve
Basilar artery thrombosis perfusion across a wide range of systemic blood pressures. Cerebral
Intraparenchymal hemorrhage perfusion pressure (CPP), defined as the mean systemic arterial pres-
Central pontine myelinolysis sure (MAP) minus the ICP, provides the driving force for circulation
Spinal cord Mass effect and compression across the capillary beds of the brain. Autoregulation refers to the phys-
Disk herniation iologic response whereby cerebral blood flow (CBF) is regulated via
Epidural hematoma alterations in cerebrovascular resistance in order to maintain perfusion
Ischemia—hypotension/embolic
over wide physiologic changes such as neuronal activation or changes
in hemodynamic function. If systemic blood pressure drops, cerebral
Epidural abscess
perfusion is preserved through vasodilation of arterioles in the brain;
Trauma
likewise, arteriolar vasoconstriction occurs at high systemic pressures
Myelitis to prevent hyperperfusion, resulting in fairly constant perfusion across
Peripheral Nervous System a wide range of systemic blood pressures (Fig. 301-1). At the extreme
Peripheral nerve limits of MAP or CPP (high or low), flow becomes directly related to
Axonal Critical illness polyneuropathy perfusion pressure. These autoregulatory changes occur in the micro-
Neuromuscular blocking agent complications circulation and are mediated by vessels below the resolution of those
Metabolic disturbances, uremia, hyperglycemia seen on angiography. CBF is also strongly influenced by pH and Paco2.
CBF increases with hypercapnia and acidosis and decreases with
Medication effects—chemotherapeutic,
antiretroviral hypocapnia and alkalosis because of pH related changes in cerebral
Demyelinating Guillain-Barré syndrome
vascular resistance. This forms the basis for the use of hyperventilation
to lower ICP, and this effect on ICP is mediated through a decrease in
Chronic inflammatory demyelinating
polyneuropathy both CBF and intracranial blood volume. Cerebral autoregulation is a
complex process critical to the normal homeostatic functioning of the
Neuromuscular junction Prolonged effect of neuromuscular blockade
brain, and this process may be disordered focally and unpredictably in
Medication effects—aminoglycosides
disease states such as traumatic brain injury and severe focal cerebral
Myasthenia gravis, Lambert-Eaton syndrome, ischemia.
botulism
Muscle Critical illness myopathy Cerebrospinal Fluid (CSF) and ICP The cranial contents con-
Cachectic myopathy sist essentially of brain, CSF, and blood. CSF is produced principally
Acute necrotizing myopathy in the choroid plexus of each lateral ventricle, exits the brain via the
Thick-filament myopathy foramens of Luschka and Magendie, and flows over the cortex to be
absorbed into the venous system along the superior sagittal sinus. In
Electrolyte disturbances—hypokalemia/
hyperkalemia, hypophosphatemia adults, ~150 mL of CSF are contained within the ventricles and sur-
Rhabdomyolysis
rounding the brain and spinal cord; the cerebral blood volume is also
~150 mL. The bony skull offers excellent protection for the brain but
allows little tolerance for additional volume. Significant increases in
volume eventually result in increased ICP. Obstruction of CSF outflow,
edema of cerebral tissue, or increases in volume from tumor or hema-
toma may increase ICP. Elevated ICP diminishes cerebral perfusion and

2076
), ml/100 g/min
Cerebral Blood Flow (CBF),
F), g 55
0
50 150
A Mean Arterial Pressure (MAP), mmHg
PART 8
g/min
), ml/100 g
Cerebral Blood Flow (CBF),
55
50 150
B Mean Arterial Pressure (MAP), mmHg
FIGURE 301-1 Pressure autoregulation of cerebral blood flow. In the normal state where autoregulation is intact A, cerebral perfusion is constant over a wide range of
systemic blood pressures (BP). This is mediated by dilation and constriction of small cerebral arterioles (round circles). Below the blood pressure threshold for maximal
dilation, cerebral blood flow becomes pressure-dependent and decreases whereas above the threshold for maximum constriction cerebral blood flow increases
with increasing systemic blood pressure. In severe brain injury, autoregulatory mechanisms may be impaired and cerebral blood flow becomes pressure-dependent
throughout (B). At the extremes of BP there may be vascular collapse (very low BP) or forced vasodilation (very high BP).
can lead to tissue ischemia. Ischemia in turn may lead to vasodilation and traumatic brain injury, especially with intracranial hemato-
via autoregulatory mechanisms designed to restore cerebral perfusion. mas. Because these two categories of disorders have fundamentally
However, vasodilation also increases cerebral blood volume, which in different causes, treatments, and prognoses, the initial focus is on
turn then increases ICP, lowers CPP, and provokes further ischemia. making this distinction rapidly and accurately. The approach to the
This vicious cycle is commonly seen in traumatic brain injury, massive comatose patient is discussed in Chap. 300; etiologies are listed in
intracerebral hemorrhage, and large hemispheric infarcts with signifi- Table 300-1.
cant tissue shifts. Minor focal deficits may be present on the neurologic examination
in patients with metabolic encephalopathies. However, the finding
APPROACH TO THE PATIENT of prominent focal signs such as pupillary asymmetry, hemiparesis,
Severe Brain Dysfunction gaze palsy, or visual field deficit should suggest the possibility of a
structural lesion. All patients with a decreased level of consciousness
Critically ill patients with severe central nervous system (CNS) dys- associated with focal findings should undergo an urgent neuroim-
function require rapid evaluation and intervention in order to limit aging procedure, as should all patients with coma of unknown
primary and secondary brain injury. Initial neurologic evaluation etiology. Computed tomography (CT) scanning is usually the most
should be performed concurrent with stabilization of basic respi- appropriate initial study because it can be performed quickly in criti-
ratory, cardiac, and hemodynamic parameters. Significant barriers cally ill patients and demonstrates hemorrhage, hydrocephalus, and
may exist to neurologic assessment in the critical care unit, including intracranial tissue shifts well. Magnetic resonance imaging (MRI)
endotracheal intubation and the use of sedative or paralytic agents may provide more specific information in some situations, such as
to facilitate procedures. acute ischemic stroke (diffusion-weighted imaging [DWI]). Any sug-
An impaired level of consciousness is common in critically gestion of trauma from the history or examination should alert the
ill patients. The essential first task in assessment is to determine examiner to the possibility of cervical spine injury and prompt an
whether the cause of dysfunction is related to a diffuse, usually imaging evaluation using CT or MRI. Neurovascular imaging using
metabolic, process or whether a focal, usually structural, process is CT or MRI angiography or venography is increasingly available and
implicated. Examples of diffuse processes include metabolic enceph- may suggest arterial occlusion or cerebral venous thrombosis.
alopathies related to organ failure, drug overdose, or hypoxia- Acute brainstem ischemia due to basilar artery thrombosis may
ischemia. Focal processes include ischemic and hemorrhagic stroke cause brief episodes of spontaneous extensor posturing superficially

2077
resembling generalized seizures. Coma of sudden onset, accompanied
by these movements and cranial nerve abnormalities, necessitates Lateral ventricle
emergency imaging. A noncontrast CT scan of the brain may reveal Brain tissue
Ventriculostomy
oxygen probe
a hyperdense basilar artery indicating thrombus in the vessel, and
subsequent CT or MR angiography can assess basilar artery patency.
Other diagnostic studies are best used in specific circumstances,
usually when neuroimaging studies fail to reveal a structural lesion
and the etiology of the altered mental state remains uncertain.
Electroencephalography (EEG) can be important in the evaluation
of critically ill patients with severe brain dysfunction. The EEG of
Fiberoptic
metabolic encephalopathy typically reveals generalized slowing.
intraparenchymal
One of the most important uses of EEG is to help exclude inappar- ICP monitor
ent seizures, especially nonconvulsive status epilepticus. Untreated
continuous or frequently recurrent seizures may cause neuronal
injury, making the diagnosis and treatment of seizures crucial in
this patient group. Lumbar puncture (LP) may be necessary to

exclude infectious or inflammatory processes, and an elevated
opening pressure may be an important clue to cerebral venous sinus FIGURE 301-2 Intracranial pressure (ICP) and brain tissue oxygen monitoring.
thrombosis. In patients with coma or profound encephalopathy, it is A ventriculostomy allows for drainage of cerebrospinal fluid to treat elevated
ICP. Fiberoptic ICP and brain tissue oxygen monitors are usually secured using
preferable to perform a neuroimaging study prior to LP. If bacterial a screw-like skull bolt. Cerebral blood flow and microdialysis probes (not shown)
meningitis is suspected, an LP may be performed first or antibiotics may be placed in a manner similar to the brain tissue oxygen probe.
may be empirically administered before the diagnostic studies are
completed. Standard laboratory evaluation of critically ill patients
should include assessment of serum electrolytes (especially sodium and stroke, cytotoxic edema may be most responsible, and the use
and calcium), glucose, renal and hepatic function, complete blood of osmotic agents such as mannitol or hypertonic saline becomes an
count, and coagulation. Serum or urine toxicology screens should appropriate early step. As described above, elevated ICP may cause
be performed in patients with encephalopathy of unknown cause. tissue ischemia, and, if cerebral autoregulation is intact, the resulting
EEG and LP are most useful when the mechanism of the altered level vasodilation can lead to a cycle of worsening ischemia. Paradoxi-
of consciousness is uncertain; they are not routinely performed for cally, administration of vasopressor agents to increase mean arterial
diagnosis in clear-cut cases of stroke or traumatic brain injury. pressure may actually lower ICP by improving perfusion, thereby
Monitoring of ICP can be an important tool in selected patients. In allowing autoregulatory vasoconstriction as ischemia is relieved and
general, patients who should be considered for ICP monitoring are ultimately decreasing intracranial blood volume.
those with primary neurologic disorders, such as stroke or traumatic Early signs of elevated ICP include drowsiness and a diminished
brain injury, who are at significant risk for secondary brain injury level of consciousness. Neuroimaging studies may reveal evidence
due to elevated ICP and decreased CPP. Included are patients with of edema and mass effect. Hypotonic IV fluids should be avoided,
the following: severe traumatic brain injury (Glasgow Coma Scale and elevation of the head of the bed is recommended. Patients
[GCS] score ≤8 [Table 435-2]); large tissue shifts from supratentorial must be carefully observed for risk of aspiration and compromise
ischemic or hemorrhagic stroke; or hydrocephalus from subarach- of the airway as the level of alertness declines. Coma and unilateral
noid hemorrhage (SAH), intraventricular hemorrhage, or posterior
fossa stroke. An additional disorder in which ICP monitoring can
add important information is fulminant hepatic failure, in which TABLE 301-2 Stepwise Approach to Treatment of Elevated
elevated ICP may be treated with barbiturates or, eventually, liver Intracranial Pressure (ICP)a
transplantation. In general, ventriculostomy is preferable to ICP Insert ICP monitor—ventriculostomy versus parenchymal device
monitoring devices that are placed in the brain parenchyma, because General goals: maintain ICP <20 mmHg and CPP ≥60 mmHg. For ICP
ventriculostomy allows CSF drainage as a method of treating ele- >20–25 mmHg for >5 min:
vated ICP. However, parenchymal ICP monitoring is most appro- 1. Elevate head of the bed; midline head position
priate for patients with diffuse edema and small ventricles (which 2. Drain CSF via ventriculostomy (if in place)
may make ventriculostomy placement more difficult) or any degree 3. Osmotherapy—mannitol 25–100 g q4h as needed (maintain serum
of coagulopathy (in which ventriculostomy carries a higher risk of osmolality <320 mosmol) or hypertonic saline (30 mL, 23.4% NaCl bolus)
hemorrhagic complications) (Fig 301-2). 4. Glucocorticoids—dexamethasone 4 mg q6h for vasogenic edema from
tumor, abscess (avoid glucocorticoids in head trauma, ischemic and
TREATMENT OF ELEVATED ICP hemorrhagic stroke)
Elevated ICP may occur in a wide range of disorders, including head 5. Sedation (e.g., morphine, propofol, or midazolam); add neuromuscular
trauma, intracerebral hemorrhage, SAH with hydrocephalus, and paralysis if necessary (patient will require endotracheal intubation and
fulminant hepatic failure. Because CSF and blood volume can be mechanical ventilation at this point, if not before)
redistributed initially, by the time elevated ICP occurs, intracranial 6. Hyperventilation—to Paco2 30–35 mmHg (short-term use or skip this step)
compliance is severely impaired. At this point, any small increase 7. Pressor therapy—phenylephrine, dopamine, or norepinephrine to maintain
in the volume of CSF, intravascular blood, edema, or a mass lesion adequate MAP to ensure CPP ≥60 mmHg (maintain euvolemia to minimize
may result in a significant increase in ICP and a decrease in cerebral deleterious systemic effects of pressors). May adjust target CPP in
individual patients based on autoregulation status.
perfusion. This is a fundamental mechanism of secondary ischemic
brain injury and constitutes an emergency that requires immediate 8. Consider second-tier therapies for refractory elevated ICP
attention. In general, ICP should be maintained at <20 mmHg and a. Decompressive craniectomy
CPP should be maintained at ≥60 mmHg. b. High-dose barbiturate therapy (“pentobarb coma”)
Interventions to lower ICP are ideally based on the underlying c. Hypothermia to 33°C
mechanism responsible for the elevated ICP (Table 301-2). For exam- a
Throughout ICP treatment algorithm, consider repeat head computed tomography
ple, in hydrocephalus from SAH, the principal cause of elevated ICP to identify mass lesions amenable to surgical evacuation. May alter order of
is impairment of CSF drainage. In this setting, ventricular drainage steps based on directed treatment to specific cause of elevated ICP.
of CSF is likely to be sufficient and most appropriate. In head trauma Abbreviations: CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; MAP,
mean arterial pressure; PaCO2, arterial partial pressure of carbon dioxide.

2078
pupillary changes are late signs and require immediate intervention. Clinical Manifestations Mild degrees of pure hypoxia, such
Emergent treatment of elevated ICP is most quickly achieved by as occur at high altitudes, cause impaired judgment, inattentiveness,
intubation and hyperventilation, which causes vasoconstriction and motor incoordination, and, at times, euphoria. However, with hypoxia-
reduces cerebral blood volume. To avoid provoking or worsening ischemia, such as occurs with circulatory arrest, consciousness is lost
cerebral ischemia, hyperventilation, if used at all, is best adminis- within seconds. If circulation is restored within 3–5 min, full recovery
tered only for short periods of time until a more definitive treatment may occur, but if hypoxia-ischemia lasts beyond 3–5 min, some degree
can be instituted. Furthermore, the effects of hyperventilation on of permanent cerebral damage often results. Except in extreme cases, it
ICP are short-lived, often lasting only for several hours because may be difficult to judge the precise degree of hypoxia-ischemia, and
of the buffering capacity of the cerebral interstitium, and rebound some patients make a relatively full recovery after even 8–10 min of
elevations of ICP may accompany abrupt discontinuation of hyper- global cerebral ischemia. The brain is more tolerant to pure hypoxia
ventilation. As the level of consciousness declines to coma, the than it is to hypoxia-ischemia. For example, a Pao2 as low as 20 mmHg
ability to follow the neurologic status of the patient by examination (2.7 kPa) can be well tolerated if it develops gradually, and normal
lessens and measurement of ICP assumes greater importance. If a blood pressure is maintained, whereas short durations of very low or
ventriculostomy device is in place, direct drainage of CSF to reduce absent cerebral circulation may result in permanent impairment.
ICP is possible. Finally, high-dose barbiturates, decompressive hemi- Clinical examination at different time points after a hypoxic-ischemic
craniectomy, and hypothermia are sometimes used for refractory insult (especially cardiac arrest) is useful in assessing prognosis for
elevations of ICP, although these have significant side effects and long-term neurologic outcome. The prognosis is better for patients
with intact brainstem function, as indicated by normal pupillary
PART 8
only decompressive hemicraniectomy has been shown to improve

outcome in select patients. light responses and intact oculocephalic (doll’s eyes), oculovestibu-
lar (caloric), and corneal reflexes. Absence of these reflexes and the
SECONDARY BRAIN INSULTS presence of persistently dilated pupils that do not react to light are
Patients with primary brain injuries, whether due to trauma or grave prognostic signs. A low likelihood of a favorable outcome from
stroke, are at risk for ongoing secondary ischemic brain injury. hypoxic-ischemic coma is strongly suggested by an absent pupillary
Because secondary brain injury can be a major determinant of a light reflex or extensor or absent motor response to pain on day 3 fol-
poor outcome, strategies for minimizing secondary brain insults are lowing the injury, excluding patients with metabolic disturbances and
an integral part of the critical care of all patients. Although elevated those treated with high-dose barbiturates or hypothermia, which con-
ICP may lead to secondary ischemia, most secondary brain injury is found interpretation of these signs. Electrophysiologically, the bilateral
mediated through other clinical events that exacerbate the ischemic absence of the N20 component of the somatosensory evoked potential
cascade already initiated by the primary brain injury. Episodes of (SSEP) in the first several days also conveys a poor prognosis. Also, the
secondary brain insults are usually not associated with apparent presence of a burst-suppression pattern of myoclonic status epilepti-
neurologic worsening. Rather, they lead to cumulative injury limit- cus on EEG (Fig 301-3) or a nonreactive EEG is associated with a low
ing eventual recovery, which manifests as a higher mortality rate or likelihood of good functional outcome. A very elevated serum level
worsened long-term functional outcome. Thus, close monitoring of (>33 μg/L) of the biochemical marker neuron-specific enolase (NSE)
vital signs is important, as is early intervention to prevent secondary within the first 3 days is indicative of brain damage after resuscitation
ischemia. Avoiding hypotension and hypoxia is critical, as signifi- from cardiac arrest and predicts a poor outcome. Current approaches to
cant hypotensive events (systolic blood pressure <90 mmHg) as prognostication after cardiac arrest encourage the use of a multimodal
short as 10 min in duration have been shown to adversely influence approach that includes these diagnostic tests, along with CT or MRI
outcome after traumatic brain injury. Even in patients with stroke or neuroimaging, in conjunction with clinical neurological assessment.
head trauma who do not require ICP monitoring, close attention to Recent studies suggest that the administration of mild hypothermia
adequate cerebral perfusion is warranted. Hypoxia (pulse oximetry after cardiac arrest (see “Treatment”) may affect the time points when
saturation <90%), particularly in combination with hypotension, these clinical and electrophysiologic predictors become reliable in
also leads to secondary brain injury. Likewise, fever and hypergly- identifying patients with a very low likelihood of clinically meaningful
cemia both worsen experimental ischemia and have been associated recovery. For example, the false-positive rate for incorrect prediction
with worsened clinical outcome after stroke and head trauma. of poor neurologic outcome may be as high as 21% (95% confidence
Aggressive control of fever with a goal of normothermia is war- interval [CI] 8–43%) for patients treated with mild hypothermia who
ranted but may be difficult to achieve with antipyretic medications exhibit 3-day motor function no better than extensor posturing. Thus,
and cooling blankets. The value of newer surface or intravascular sufficient time from injury is important to ensure accuracy of prognos-
temperature control devices for the management of refractory fever tic assessment. Long-term consequences of hypoxic-ischemic enceph-
is under investigation. The use of IV insulin infusion is encouraged alopathy include persistent coma or a vegetative state (Chap. 300),
for control of hyperglycemia because this allows better regulation dementia (Chap. 25), visual agnosia (Chap. 26), parkinsonism, choreo-
of serum glucose levels than SC insulin. A reasonable goal is to athetosis, cerebellar ataxia, myoclonus, seizures, and an amnestic state,
maintain the serum glucose level at <10.0 mmol/L (<180 mg/dL), which may be a consequence of selective damage to the hippocampus.
although episodes of hypoglycemia appear equally detrimental and
Pathology Principal histologic findings are extensive multifocal
the optimal targets remain uncertain. New cerebral monitoring tools
or diffuse laminar cortical necrosis (Fig. 301-4), with frequent involve-
that allow continuous evaluation of brain tissue oxygen tension,
ment of the hippocampus. The hippocampal CA1 neurons are vulner-
CBF, and metabolism (via microdialysis) may further improve the
able to even brief episodes of hypoxia-ischemia, perhaps explaining
management of secondary brain injury.
why selective persistent memory deficits may occur after brief cardiac
arrest. Scattered small areas of infarction or neuronal loss may be pres-
ent in the basal ganglia, hypothalamus, or brainstem. In some cases,
CRITICAL CARE DISORDERS OF THE CNS extensive bilateral thalamic scarring may affect pathways that medi-
ate arousal, and this pathology may be responsible for the persistent
■■HYPOXIC-ISCHEMIC ENCEPHALOPATHY
vegetative state. A specific form of hypoxic-ischemic encephalopathy,
This occurs from lack of delivery of oxygen to the brain because of
so-called watershed infarcts, occurs at the distal territories between
extreme hypotension (hypoxia-ischemia) or hypoxia due to respiratory
the major cerebral arteries and can cause cognitive deficits, including
failure. Causes include myocardial infarction, cardiac arrest, shock,
visual agnosia, and weakness that is greater in proximal than in distal
asphyxiation, paralysis of respiration, and carbon monoxide or cyanide
muscle groups.
poisoning. In some circumstances, hypoxia may predominate. Carbon
monoxide and cyanide poisoning are sometimes termed histotoxic Diagnosis Diagnosis is based on the history of a hypoxic-ischemic
hypoxia because they cause a direct impairment of the respiratory chain. event such as cardiac arrest. Blood pressure <70 mmHg systolic or

2079

FIGURE 301-3 Electroencephalography (EEG) after cardiac arrest. A burst-suppression pattern is seen in a comatose patient with severe hypoxic-ischemic
encephalopathy after cardiac arrest. In this patient, each burst on EEG was associated with a whole-body jerking movement leading to the clinical and electrophysiological
diagnosis of myoclonic status epilepticus.
Pao2 <40 mmHg is usually necessary, although both absolute levels cascade and has substantial neuroprotective properties in exper-
and duration of exposure are important determinants of cellular injury. imental models of brain injury. In two trials, mild hypothermia
Carbon monoxide intoxication can be confirmed by measurement of (33°C) improved functional outcome in patients who remained
carboxyhemoglobin and is suggested by a cherry red color of the venous comatose after resuscitation from a cardiac arrest. Treatment was
blood and skin, although the latter is an inconsistent clinical finding. initiated within minutes of cardiac resuscitation and continued
for 12 h in one study and 24 h in the other. In a more recent study,
targeted temperature management (TTM) to 33 or 36°C resulted in
TREATMENT similar outcomes. Potential complications of hypothermia include
Hypoxic-Ischemic Encephalopathy coagulopathy and an increased risk of infection. Current guidelines
recommend TTM for cardiac arrest patients who have no mean-
Treatment should be directed at restoration of normal cardiore- ingful response to verbal commands after return of spontaneous
spiratory function. This includes securing a clear airway, ensuring circulation, with temperature maintained constant between 32 and
adequate oxygenation and ventilation, and restoring cerebral per- 36°C for at least 24 h.
fusion, whether by cardiopulmonary resuscitation, fluid, pressors, Severe carbon monoxide intoxication may be treated with hyper-
or cardiac pacing. Hypothermia may target the neuronal cell injury baric oxygen. Anticonvulsants may be needed to control seizures,
although these are not usually given prophylactically. Posthypoxic
myoclonus may respond to oral administration of clonazepam at
doses of 1.5–10 mg daily or valproate at doses of 300–1200 mg daily
in divided doses. Myoclonic status epilepticus within 24 h after a
primary circulatory arrest generally portends a very poor prognosis,
even if seizures are controlled.
Carbon monoxide and cyanide intoxication can also cause a
delayed encephalopathy. Little clinical impairment is evident when
the patient first regains consciousness, but a parkinsonian syndrome
characterized by akinesia and rigidity without tremor may develop.
Symptoms can worsen over months, accompanied by increasing evi-
dence of damage in the basal ganglia as seen on both CT and MRI.
■■POSTCARDIAC BYPASS BRAIN INJURY

CNS injuries following open heart or coronary artery bypass graft-
ing (CABG) surgery are common and include acute encephalopathy,
FIGURE 301-4 Cortical laminar necrosis in hypoxic-ischemic encephalopathy. stroke, and a chronic syndrome of cognitive impairment. Hypoperfu-
T1-weighted postcontrast magnetic resonance imaging shows cortical sion and embolic disease are frequently involved in the pathogenesis
enhancement in a watershed distribution consistent with laminar necrosis. of these syndromes, although multiple mechanisms may be involved

2080 in these critically ill patients who are at risk for various metabolic and mediators that appear to contribute to encephalopathy. Critical illness,
polypharmaceutical complications. in association with the systemic inflammatory response syndrome
The frequency of hypoxic injury secondary to inadequate blood flow (SIRS), can lead to multisystem organ failure. This syndrome can occur
intraoperatively has been markedly decreased by the use of modern sur- in the setting of apparent sepsis, severe burns, or trauma, even without
gical and anesthetic techniques. Despite these advances, some patients clear identification of an infectious agent. Many patients with critical
still experience neurologic complications from cerebral hypoperfusion illness, sepsis, or SIRS develop encephalopathy without obvious expla-
or may suffer focal ischemia from carotid or focal intracranial stenoses in nation. This condition is broadly termed sepsis-associated encephalopathy.
the setting of regional hypoperfusion. Postoperative infarcts in the border Although the specific mediators leading to neurologic dysfunction
zones between vascular territories commonly are blamed on systemic remain uncertain, it is clear that the encephalopathy is not simply the
hypotension, although these infarcts can also result from embolic disease. result of metabolic derangements of multiorgan failure. The cytokines
Embolic disease is likely the predominant mechanism of cerebral tumor necrosis factor, interleukin (IL)-1, IL-2, and IL-6 are thought to
injury during cardiac surgery as evidenced by diffusion-weighted MRI play a role in this syndrome.
and intraoperative transcranial Doppler ultrasound studies. Thrombus
in the heart itself as well as atheromas in the aortic arch can become
Diagnosis Sepsis-associated encephalopathy presents clinically as
a diffuse dysfunction of the brain without prominent focal findings.
dislodged during cardiac surgeries, releasing a shower of particulate
Confusion, disorientation, agitation, and fluctuations in level of alert-
matter into the cerebral circulation. Cross-clamping of the aorta, manip-
ness are typical. In more profound cases, especially with hemodynamic
ulation of the heart, extracorporeal circulation techniques (“bypass”),
compromise, the decrease in level of alertness can be more prominent,
arrhythmias such as atrial fibrillation, and introduction of air through
PART 8
at times resulting in coma. Hyperreflexia and frontal release signs such

suctioning have all been implicated as potential sources of emboli.
as a grasp or snout reflex (Chap. 26) can be seen. Abnormal movements
This shower of microemboli results in a number of clinical syn-
such as myoclonus, tremor, or asterixis can occur. Sepsis-associated
dromes. Occasionally, a single large embolus leads to an isolated
encephalopathy is quite common, occurring in the majority of patients
large-vessel stroke that presents with obvious clinical focal deficits.
with sepsis and multisystem organ failure. Diagnosis is often difficult
When there is a high burden of very small emboli, an acute encepha-

because of the multiple potential causes of neurologic dysfunction in
lopathy can occur postoperatively, presenting as either a hyperactive
critically ill patients and requires exclusion of structural, metabolic,
or hypoactive confusional state, the latter of which is frequently and
toxic, and infectious (e.g., meningitis or encephalitis) causes. The mor-
incorrectly ascribed to depression or a sedative-induced delirium.
tality rate of patients with sepsis-associated encephalopathy severe
When the burden of microemboli is lower, no acute syndrome is recog-
enough to produce coma approaches 50%, although this principally
nized, but the patient may suffer a chronic cognitive deficit.
reflects the severity of the underlying critical illness and is not a
■■METABOLIC ENCEPHALOPATHIES direct result of the encephalopathy. Patients dying from severe sepsis
Altered mental states, variously described as confusion, delirium, or septic shock may have elevated levels of the serum brain injury
disorientation, and encephalopathy, are present in many patients biomarker S-100β and neuropathologic findings of neuronal apoptosis
with severe illness in an intensive care unit (ICU). Older patients are and cerebral ischemic injury. Successful treatment of the underlying
particularly vulnerable to delirium, a confusional state characterized critical illness almost always results in substantial improvement of
by disordered perception, frequent hallucinations, delusions, and the encephalopathy. However, although severe disability to the level
sleep disturbance. This is often attributed to medication effects, sleep of chronic vegetative or minimally conscious states is uncommon,
deprivation, pain, and anxiety. The presence of delirium is associated long-term cognitive dysfunction clinically similar to dementia is being
with worsened outcome in critically ill patients, even in those without increasingly recognized in some survivors, especially in older patients.
an identifiable CNS pathology such as stroke or brain trauma. In these
patients, the cause of delirium is often multifactorial, resulting from ■■OSMOTIC DEMYELINATION SYNDROME (CENTRAL
organ dysfunction, sepsis, and especially the use of medications given PONTINE MYELINOLYSIS)
to treat pain, agitation, or anxiety. Critically ill patients are often treated This disorder often presents in a devastating fashion as quadriplegia
with a variety of sedative and analgesic medications, including opiates, and pseudobulbar palsy although less severe presentations may occur.
benzodiazepines, neuroleptics, and sedative-anesthetic medications, Predisposing factors include severe underlying medical illness or
such as propofol. In critically ill patients requiring sedation, use of the nutritional deficiency; most cases are associated with rapid correction
centrally acting α2 agonist dexmedetomidine may reduce delirium and of hyponatremia or with hyperosmolar states and clinical symptoms
shorten the duration of mechanical ventilation compared to the use of are usually identified a few days after sodium correction. Previously
benzodiazepines such as lorazepam or midazolam. The presence of termed central pontine myelinolysis, the more accurate term osmotic
family members in the ICU may also help to calm and orient agitated demyelination syndrome is now preferred. The pathology consists of
patients, and in severe cases, low doses of neuroleptics (e.g., haloperi- demyelination without inflammation in the base of the pons, with
dol 0.5–1 mg) can be useful. Current strategies focus on limiting the use relative sparing of axons and nerve cells. MRI is useful in establishing
of sedative medications when this can be done safely. the diagnosis (Fig. 301-5) and may also identify partial forms that pres-
In the ICU setting, several metabolic causes of an altered level of ent as confusion, dysarthria, and/or disturbances of conjugate gaze
consciousness predominate. Hypercarbic encephalopathy can present without quadriplegia. Occasional cases present with lesions outside
with headache, confusion, stupor, or coma. Hypoventilation syndrome of the brainstem. Therapeutic guidelines for the restoration of severe
occurs most frequently in patients with a history of chronic CO2 reten- hyponatremia should aim for gradual correction, i.e., by ≤10 mmol/L
tion who are receiving oxygen therapy for emphysema or chronic (10 meq/L) within 24 h and 20 mmol/L (20 meq/L) within 48 h.
pulmonary disease (Chap. 290). The elevated Paco2 leading to CO2 ■■WERNICKE’S DISEASE
narcosis may have a direct anesthetic effect, and cerebral vasodilation Wernicke’s disease is a common and preventable disorder due to a defi-
from increased Paco2 can lead to increased ICP. Hepatic encephalopa- ciency of thiamine (Chap. 326). In the United States, alcoholics account
thy is suggested by asterixis and can occur in chronic liver failure or for most cases, but patients with malnutrition due to hyperemesis,
acute fulminant hepatic failure. Both hyperglycemia and hypoglycemia starvation, renal dialysis, cancer, HIV/AIDS, or rarely gastric surgery
can cause encephalopathy, as can hypernatremia and hyponatremia. are also at risk. The characteristic clinical triad is ophthalmoplegia,
Confusion, impairment of eye movements, and gait ataxia are the hall- ataxia, and global confusion. However, only one-third of patients
marks of acute Wernicke’s disease (see below). with acute Wernicke’s disease present with the classic clinical triad.
■■SEPSIS-ASSOCIATED ENCEPHALOPATHY Most patients are profoundly disoriented, indifferent, and inattentive,
although rarely they have an agitated delirium related to ethanol
Pathogenesis In patients with sepsis, the systemic response to withdrawal. If the disease is not treated, stupor, coma, and death may
infectious agents leads to the release of circulating inflammatory ensue. Ocular motor abnormalities include horizontal nystagmus on

2081

FIGURE 301-5 Osmotic demyelination syndrome. Axial T2-weighted magnetic FIGURE 301-6 Wernicke’s disease. Coronal T1-weighted postcontrast magnetic
resonance scan through the pons reveals a symmetric area of abnormal high resonance imaging reveals abnormal enhancement of the mammillary bodies
signal intensity within the basis pontis (arrows). (arrows), typical of acute Wernicke’s encephalopathy.
lateral gaze, lateral rectus palsy (usually bilateral), conjugate gaze pal- and should be begun prior to treatment with IV glucose solutions.
sies, and rarely ptosis. Gait ataxia probably results from a combination Larger doses, 100 mg four times a day or more, have been advocated
of polyneuropathy, cerebellar involvement, and vestibular paresis. The by some. Glucose infusions may precipitate Wernicke’s disease in a
pupils are usually spared, but they may become miotic with advanced previously unaffected patient or cause a rapid worsening of an early
disease. form of the disease. For this reason, thiamine should be adminis-
Wernicke’s disease is usually associated with other manifestations tered to all alcoholic patients requiring parenteral glucose.
of nutritional disease, such as polyneuropathy. Rarely, amblyopia or
myelopathy occurs. Tachycardia and postural hypotension may be
related to impaired function of the autonomic nervous system or to ■■HYPERPERFUSION DISORDERS (POSTERIOR
the coexistence of cardiovascular beriberi. Patients who recover show REVERSIBLE ENCEPHALOPATHY SYNDROME)
improvement in ocular palsies within hours after the administration Several seemingly diverse syndromes including hypertensive encepha-
of thiamine, but horizontal nystagmus may persist. Ataxia improves lopathy, eclampsia, postcarotid endarterectomy syndrome, and toxicity
more slowly than the ocular motor abnormalities. Approximately from calcineurin-inhibitor and other medications share the common
half recover incompletely and are left with a slow, shuffling, wide- pathogenesis of hyperperfusion likely due to endothelial dysfunction.
based gait and an inability to tandem walk. Apathy, drowsiness, and Vasogenic edema is typically the primary process leading to neurologic
confusion improve more gradually. As these symptoms recede, an dysfunction and this is thought to result from one of two mechanisms:
amnestic state with impairment in recent memory and learning may exceeding the cerebral autoregulatory threshold leading to increased
become more apparent (Korsakoff’s psychosis). Korsakoff’s psychosis is CBF and capillary leakage into the interstitium, or direct impairment
frequently persistent; the residual mental state is characterized by gaps of the BBB itself. The predilection of all of the hyperperfusion disorders
in memory, confabulation, and disordered temporal sequencing. to affect the posterior rather than anterior portions of the brain may
Pathology Periventricular lesions surround the third ventricle, be due to a lower threshold for autoregulatory breakthrough in the
aqueduct, and fourth ventricle, with petechial hemorrhages in occa- posterior circulation or a vasculopathy that is more common in these
sional acute cases and atrophy of the mammillary bodies in most blood vessels.
chronic cases. There is frequently endothelial proliferation, demyeli- These disorders of hyperperfusion can be divided into those caused
nation, and some neuronal loss. These changes may be detected by primarily by increased pressure and those due to endothelial dysfunc-
MRI (Fig. 301-6). The amnestic defect is related to lesions in the dorsal tion from a toxic or autoimmune etiology (Table 301-3). In reality, both
medial nuclei of the thalamus. of these processes likely play some role in each of these disorders. The
clinical presentation of all of the hyperperfusion syndromes is simi-
Pathogenesis Thiamine is a cofactor of several enzymes, including lar with prominent headaches, seizures, or focal neurologic deficits.
transketolase, pyruvate dehydrogenase, and α-ketoglutarate dehydro- Headaches have no specific characteristics, range from mild to severe,
genase. Thiamine deficiency produces a diffuse decrease in cerebral and may be accompanied by alterations in consciousness ranging
glucose utilization and results in mitochondrial damage. Glutamate from confusion to coma. Seizures may be present, and these can be of
accumulates due to impairment of α-ketoglutarate dehydrogenase multiple types depending on the severity and location of the edema.
activity and, in combination with the energy deficiency, may result in Nonconvulsive seizures have been described in hyperperfusion states;
excitotoxic cell damage. therefore, a low threshold for obtaining an electroencephalogram
(EEG) in these patients should be maintained. The typical focal deficit
in hyperperfusion states is cortical visual loss, given the tendency of
TREATMENT the process to involve the occipital lobes. However, any focal deficit can
Wernicke’s Disease occur depending on the area affected, as evidenced by patients who,
after carotid endarterectomy, exhibit neurologic dysfunction referable
Wernicke’s disease is a medical emergency and requires immediate to the ipsilateral newly reperfused hemisphere. It appears as if the
administration of thiamine, in a dose of 100 mg either IV or IM. The rapidity of rise, rather than the absolute value of pressure, is the most
dose should be given daily until the patient resumes a normal diet important risk factor.

2082 TABLE 301-3 Common Etiologies of Posterior Reversible ■■POST-SOLID ORGAN TRANSPLANT BRAIN INJURY
Encephalopathy Syndrome Immunosuppressive medications are administered in high doses to
Disorders in which increased capillary pressure dominates the patients after solid organ transplant, and many of these compounds
pathophysiology have well-described neurologic complications. In patients with head-
Hypertensive encephalopathy, including secondary causes such as ache, seizures, or focal neurologic deficits taking calcineurin inhibitors,
renovascular hypertension, pheochromocytoma, cocaine use, etc. the diagnosis of hyperperfusion syndrome should be considered, as
Postcarotid endarterectomy syndrome discussed above. This neurotoxicity occurs mainly with cyclosporine
Preeclampsia/eclampsia and tacrolimus and can present even in the setting of normal serum
Disorders in which endothelial dysfunction dominates the pathophysiology drug levels. Treatment primarily involves lowering the drug dosage
Calcineurin-inhibitor toxicity (e.g. cyclosporine, tacrolimus) or discontinuing the drug. Sirolimus has very few recorded cases of
neurotoxicity and may be a reasonable alternative for some patients.
Chemotherapeutic agent toxicity (e.g., cytarabine, azathioprine,
5-fluorouracil, cisplatin, methotrexate, tumor necrosis factor α antagonists) Other examples of immunosuppressive medications and their neu-
HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet
rologic complications include OKT3-associated akinetic mutism and
count) the leukoencephalopathy seen with methotrexate, especially when it
Hemolytic-uremic syndrome (HUS) is administered intrathecally or with concurrent radiotherapy. In any
solid organ transplant patient with neurologic complaints, a careful
examination of the medication list is required to search for these pos-
sible drug effects.
PART 8
MRI classically exhibits the high T2 signal of edema primarily Cerebrovascular complications of solid organ transplant are often
in the posterior occipital lobes, not respecting any single vascular first recognized in the immediate postoperative period. Border zone
territory (Figure 301-7). CT is less sensitive but may show a pattern territory infarctions can occur, especially in the setting of systemic
of patchy hypodensity in the involved territory. The term posterior hypotension during cardiac transplant surgery. Embolic infarctions
reversible encephalopathy syndrome (PRES) is often used to describe these
classically complicate cardiac transplantation, but all solid organ trans-

conditions; however, the clinical syndrome is not always reversible or plant procedures place patients at risk for systemic emboli. When cere-
limited just to the posterior brain regions. Vessel imaging may demon- bral embolization accompanies renal or liver transplantation surgery,
strate narrowing of the cerebral vasculature, especially in the posterior a careful search for right-to-left shunting should include evaluation of
circulation; whether this noninflammatory vasculopathy is a primary the heart with agitated saline echocardiography (i.e., “bubble study”),
cause of the edema or occurs as a secondary phenomenon remains as well as looking for intrapulmonary shunting. Renal and some car-
unclear. Other ancillary studies such as CSF analysis often yield non- diac transplant patients often have advanced atherosclerosis, provid-
specific results. Many of the substances that have been implicated, such ing a risk for stroke. Imaging with CT or MRI should be done when
as cyclosporine, can cause this syndrome even at low doses or after cerebrovascular complications are suspected to confirm the diagnosis
years of treatment. Therefore, normal serum levels of these medications and to exclude intracerebral hemorrhage, which most often occurs in
do not exclude them as inciting agents. the setting of coagulopathy secondary to liver failure or after cardiac
Treatment involves judicious lowering of the blood pressure with bypass procedures.
IV agents such as labetalol or nicardipine, removal of the offending Given that patients with solid organ transplants are chronically
medication, and treatment of an underlying medical condition such immunosuppressed, infections are a common concern (Chap. 138).
as eclampsia. If the blood pressure is very elevated, it is reasonable to In any transplant patient with new CNS signs or symptoms such as
lower the MAP by ~20% initially, as further lowering of the pressure seizure, confusion, or focal deficit, the diagnosis of a CNS infection
may cause secondary ischemia and possibly infarction as pressure should be considered and evaluated through imaging (usually MRI)
drops below the lower range of the patient’s autoregulatory capa- and possibly lumbar puncture. The most common pathogens responsi-
bility. Seizures must be identified and controlled, often necessitating ble for CNS infections in these patients vary based on time since trans-
continuous EEG monitoring. Anticonvulsants are effective when plant. In the first month posttransplant, common pathogens include
seizure activity is identified, but in the special case of eclampsia, the usual bacterial organisms associated with surgical procedures and
there is evidence to support the use of magnesium sulfate for seizure indwelling catheters. Starting in the second month posttransplant,
control. opportunistic infections of the CNS become more common, including
Nocardia and Toxoplasma species as well as fungal infections such as
aspergillosis. Viral infections that can affect the brain of the immuno-
suppressed patient, such as herpes simplex virus, cytomegalovirus,
human herpesvirus type 6 (HHV-6), and varicella, also become more
common after the first month posttransplant. Beyond 6 months,
immunosuppressed posttransplant patients still remain at risk for
these opportunistic bacterial, fungal, and viral infections but can also
suffer late CNS infectious complications such as progressive multifocal
leukoencephalopathy (PML) associated with JC virus (Chap. 132), and
Epstein-Barr virus–driven clonal expansions of B cells resulting in post-
transplant lymphoproliferative disorder or CNS lymphoma (Chap. 86).
CRITICAL CARE DISORDERS OF THE

PERIPHERAL NERVOUS SYSTEM (PNS)
Critical illness with disorders of the PNS arises in two contexts: (1)
primary neurologic diseases that require critical care interventions
such as intubation and mechanical ventilation, and (2) secondary
PNS manifestations of systemic critical illness, often involving mul-
FIGURE 301-7 Axial fluid-attenuated inversion recovery (FLAIR) magnetic tisystem organ failure. The former include acute polyneuropathies such as
resonance imaging (MRI) of the brain in a patient taking cyclosporine after liver
transplantation, who presented with seizures, headache, and cortical blindness. Guillain-Barré syndrome (Chap. 439), neuromuscular junction disor-
Increased signal is seen bilaterally in the occipital lobes predominantly involving ders including myasthenia gravis (Chap. 440) and botulism (Chap. 148),
the white matter, consistent with a hyperperfusion state secondary to calcineurin- and primary muscle disorders such as polymyositis (Chap. 358). The
inhibitor exposure. latter result either from the systemic disease itself or as a consequence

of interventions and as a group are often referred to as ICU acquired administration of drugs. A number of medications impair neuromuscu- 2083
weakness (ICUAW). lar transmission; these include antibiotics, especially aminoglycosides,
General principles of respiratory evaluation in patients with PNS and beta-blocking agents. In the ICU, the nondepolarizing neuromus-
involvement, regardless of cause, include assessment of pulmonary cular blocking agents (nd-NMBAs), also known as muscle relaxants,
mechanics, such as maximal inspiratory force (MIF) and vital capac- are most commonly responsible. Included in this group of drugs are
ity (VC), and evaluation of strength of bulbar muscles. Regardless of such agents as pancuronium, vecuronium, rocuronium, and cisatracu-
the cause of weakness, endotracheal intubation should be considered rium. They are often used to facilitate mechanical ventilation or other
when the MIF falls to below –25 cmH2O or the VC is <1 L. Also, patients critical care procedures, but with prolonged use persistent neuromus-
with severe palatal weakness may require endotracheal intubation in cular blockade may result in weakness even after discontinuation of
order to prevent acute upper airway obstruction or recurrent aspira- these agents hours or days earlier. Risk factors for this prolonged action
tion. Arterial blood gases and oxygen saturation from pulse oximetry of neuromuscular blocking agents include female sex, metabolic acido-
are used to follow patients with potential respiratory compromise sis, and renal failure.
from PNS dysfunction. However, intubation and mechanical ventila- Prolonged neuromuscular blockade does not appear to produce
tion should be undertaken based on clinical assessment rather than permanent damage to the PNS. Once the offending medications are
waiting until oxygen saturation drops or CO2 retention develops from discontinued, full strength is restored, although this may take days.
hypoventilation. Noninvasive mechanical ventilation may be consid- In general, the lowest dose of neuromuscular blocking agent should

ered initially in lieu of endotracheal intubation in myasthenia gravis be used to achieve the desired result and, when these agents are used
but is generally insufficient in patients with severe bulbar weakness or in the ICU, a peripheral nerve stimulator should be used to monitor
ventilatory failure with hypercarbia. Principles of mechanical ventila- neuromuscular junction function.
tion are discussed in Chap. 295.
■■MYOPATHY
■■NEUROPATHY Critically ill patients, especially those with sepsis, frequently develop
Although encephalopathy may be the most obvious neurologic dys- muscle weakness and wasting, often in the face of seemingly adequate
function in critically ill patients, dysfunction of the PNS is also quite nutritional support. Critical illness myopathy is an overall term that
common. It is typically present in patients with prolonged critical describes several different discrete muscle disorders that may occur in
illnesses lasting several weeks and involving sepsis; clinical suspicion critically ill patients. The assumption has been that a catabolic myopa-
is aroused when there is failure to wean from mechanical ventilation thy may develop as a result of multiple factors, including elevated cor-
despite improvement of the underlying sepsis and critical illness. tisol and catecholamine release and other circulating factors induced by
Critical illness polyneuropathy refers to the most common PNS compli- the SIRS. In this syndrome, known as cachectic myopathy, serum creatine
cation related to critical illness; it is seen in the setting of prolonged kinase levels and electromyography (EMG) are normal. Muscle biopsy
critical illness, sepsis, and multisystem organ failure. Neurologic find- shows type II fiber atrophy. Panfascicular muscle fiber necrosis may
ings include diffuse weakness, decreased reflexes, and distal sensory also occur in the setting of profound sepsis. This less common acute
loss. Electrophysiologic studies demonstrate a diffuse, symmetric, necrotizing intensive care myopathy is characterized clinically by weak-
distal axonal sensorimotor neuropathy, and pathologic studies have ness progressing to a profound level over just a few days. There may
confirmed axonal degeneration. The precise mechanism of critical be associated elevations in serum creatine kinase and urine myoglobin.
illness polyneuropathy remains unclear, but circulating factors such Both EMG and muscle biopsy may be normal initially but eventually
as cytokines, which are associated with sepsis and SIRS, are thought show abnormal spontaneous activity and panfascicular necrosis with
to play a role. It has been reported that up to 70% of patients with the an accompanying inflammatory reaction. Acute rhabdomyolysis can
sepsis syndrome have some degree of neuropathy, although far fewer occur from alcohol ingestion or from compartment syndromes.
have a clinical syndrome profound enough to cause severe respira- A thick-filament myopathy may occur in the setting of glucocorticoid
tory muscle weakness requiring prolonged mechanical ventilation or and nd-NMBA use. The most frequent scenario in which this is encoun-
resulting in failure to wean. Aggressive glycemic control with insulin tered is the asthmatic patient who requires high-dose glucocorticoids
infusions appears to decrease the risk of critical illness polyneuropathy. and nd-NMBA to facilitate mechanical ventilation. This muscle disor-
Treatment is otherwise supportive, with specific intervention directed der is not due to prolonged action of nd-NMBAs at the neuromuscular
at treating the underlying illness. Although spontaneous recovery junction but, rather, is an actual myopathy with muscle damage; it
is usually seen, the time course may extend over weeks to months has occasionally been described with high-dose glucocorticoid use or
and necessitate long-term ventilatory support and care even after the sepsis alone. Clinically this syndrome is most often recognized when
underlying critical illness has resolved. a patient fails to wean from mechanical ventilation despite resolution
of the primary pulmonary process. Pathologically, there may be loss of
thick (myosin) filaments. Thick-filament critical illness myopathy has
■■DISORDERS OF NEUROMUSCULAR TRANSMISSION a good prognosis. If patients survive their underlying critical illness,
A defect in neuromuscular transmission may be a source of weakness the myopathy invariably improves and most patients return to normal.
in critically ill patients. Botulism (Chap. 148) may be acquired by However, because this syndrome is a result of true muscle damage,
ingesting botulinum toxin from improperly stored food or may arise not just prolonged blockade at the neuromuscular junction, this pro-
from an anaerobic abscess from Clostridium botulinum (wound botu- cess may take weeks or months, and tracheotomy with prolonged
lism). Infants can present with generalized weakness from gut-derived ventilatory support may be necessary. Some patients do have residual
Clostridium infection, especially if they are fed honey. Diplopia and long-term weakness, with atrophy and fatigue limiting ambulation.
dysphagia are early signs of food-borne botulism. Treatment is mostly At present, it is unclear how to prevent this myopathic complication,
supportive, although use of antitoxin early in the course may limit the except by avoiding use of nd-NMBAs, a strategy not always possible.
duration of the neuromuscular blockade. General ICU care is similar Monitoring with a peripheral nerve stimulator can help to avoid the
to patients with Guillain-Barré syndrome or myasthenia gravis with overuse of these agents. However, this is more likely to prevent the
focused care to avoid ulcer formation at pressure points, deep venous complication of prolonged neuromuscular junction blockade than it is
thromboprophylaxis, and infection prevention. Public health officers to prevent this myopathy.
should be rapidly informed when the diagnosis is made to prevent
further exposure to others from the tainted food or source of wound ■■FURTHER READING
botulism (such as injection drug use). Callaway CW et al: Part 4: Advanced life support: 2015 international
Undiagnosed myasthenia gravis (Chap. 440) may be a consideration consensus on cardiopulmonary resuscitation and emergency cardio-
in weak ICU patients; however, persistent weakness secondary to vascular care science with treatment recommendations. Circulation
impaired neuromuscular junction transmission is almost always due to 132:S84, 2015.

2084 Dhar R: Neurologic complications of transplantation. Handb Clin cerebral artery (MCA) bifurcation, and top of the basilar artery. Their
Neurol 141:545, 2017. risk of rupture is ~6% in the first year after identification and may
Donnelly J et al: Regulation of the cerebral circulation: bedside assess- remain high indefinitely. They often cause symptoms by compressing
ment and clinical implications. Crit Care 20:129, 2016. the adjacent brain or cranial nerves.
Latronico N et al: Critical illness polyneuropathy and myopathy: A Mycotic aneurysms are usually located distal to the first bifurcation
major cause of muscle weakness and paralysis. Lancet Neurol 10:931, of major arteries of the circle of Willis. Most result from infected emboli
2011. due to bacterial endocarditis causing septic degeneration of arteries
Nielsen N et al: Targeted temperature management at 33 degrees C and subsequent dilation and rupture. Whether these lesions should be
versus 36 degrees C after cardiac arrest. N Engl J Med 369:2197, 2013. sought and repaired prior to rupture or left to heal spontaneously with
Pandharipande PP et al: Long-term cognitive impairment after critical antibiotic treatment remains controversial.
illness. N Engl J Med 369:1306, 2013.
Posner JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 4th ed. Pathophysiology Saccular aneurysms occur at the bifurcations
New York, Oxford University Press, 2007. of the large- to medium-sized intracranial arteries; rupture is into
Quillinan N at al: Neuropathophysiology of brain injury. Anesthesiol the subarachnoid space in the basal cisterns and sometimes into the
Clin 34:453, 2016. parenchyma of the adjacent brain. Approximately 85% of aneurysms
Sandroni C et al: Prognostication in comatose survivors of cardiac occur in the anterior circulation, mostly on the circle of Willis. About
arrest: An advisory statement from the European Resuscitation Coun- 20% of patients have multiple aneurysms, many at mirror sites bilater-
cil and the European Society of Intensive Care Medicine. Intensive
PART 8
ally. As an aneurysm develops, it typically forms a neck with a dome.

Care Med 40:1816, 2014. The length of the neck and the size of the dome vary greatly and are
Toledano M, Fugate JE: Posterior reversible encephalopathy in the important factors in planning neurosurgical obliteration or endovas-
intensive care unit. Handb Clin Neurol 141:467, 2017. cular embolization. The arterial internal elastic lamina disappears at
the base of the neck. The media thins, and connective tissue replaces
smooth-muscle cells. At the site of rupture (most often the dome), the
wall thins, and the tear that allows bleeding is often ≤0.5 mm long.
Aneurysm size and site are important in predicting risk of rupture.
302 Subarachnoid Hemorrhage

Those >7 mm in diameter and those at the top of the basilar artery and
at the origin of the posterior communicating artery are at greater risk
of rupture.
J. Claude Hemphill, III, Wade S. Smith,
Daryl R. Gress Clinical Manifestations Most unruptured intracranial aneu-
rysms are completely asymptomatic. Symptoms are usually due to
rupture and resultant SAH, although some unruptured aneurysms
Subarachnoid hemorrhage (SAH) renders the brain critically ill from present with mass effect on cranial nerves or brain parenchyma. At
both primary and secondary brain insults. Excluding head trauma, the the moment of aneurysmal rupture with major SAH, the intracra-
most common cause of SAH is rupture of a saccular aneurysm. Other nial pressure (ICP) suddenly rises. This may account for the sudden
causes include bleeding from a vascular malformation (arteriovenous transient loss of consciousness that occurs in nearly half of patients.
malformation or dural arteriovenous fistula) and extension into the Sudden loss of consciousness may be preceded by a brief moment of
subarachnoid space from a primary intracerebral hemorrhage. Some excruciating headache, but most patients first complain of headache
idiopathic SAHs are localized to the perimesencephalic cisterns and upon regaining consciousness. In 10% of cases, aneurysmal bleeding is
are benign; they probably have a venous or capillary source, and angi- severe enough to cause loss of consciousness for several days. In ~45%
ography is unrevealing. of cases, severe headache associated with exertion is the presenting
complaint. The patient often calls the headache “the worst headache of
■■SACCULAR (“BERRY”) ANEURYSM my life”; however, the most important characteristic is sudden onset.
Autopsy and angiography studies have found that about 2% of adults Occasionally, these ruptures may present as headache of only moderate
harbor intracranial aneurysms, for a prevalence of 4 million persons intensity or as a change in the patient’s usual headache pattern. The
in the United States; the aneurysm will rupture, producing SAH, in headache is usually generalized, often with neck stiffness, and vomit-
25,000–30,000 cases per year. For patients who arrive alive at hospital, ing is common.
the mortality rate over the next month is about 45%. Of those who sur- Although sudden headache in the absence of focal neurologic
vive, more than half are left with major neurologic deficits as a result of symptoms is the hallmark of aneurysmal rupture, focal neurologic
the initial hemorrhage, cerebral vasospasm with infarction, or hydro- deficits may occur. Anterior communicating artery or MCA bifurcation
cephalus. If the patient survives but the aneurysm is not obliterated, aneurysms may rupture into the adjacent brain or subdural space and
the rate of rebleeding is about 20% in the first 2 weeks, 30% in the first form a hematoma large enough to produce mass effect. The deficits that
month, and about 3% per year afterward. Given these alarming figures, result can include hemiparesis, aphasia, and mental slowness (abulia).
the major therapeutic emphasis is on preventing the predictable early Occasionally, prodromal symptoms suggest the location of a pro-
complications of the SAH. gressively enlarging unruptured aneurysm. A third cranial nerve palsy,
Unruptured, asymptomatic aneurysms are much less dangerous particularly when associated with pupillary dilation, loss of ipsilateral
than a recently ruptured aneurysm. The annual risk of rupture for (but retained contralateral) light reflex, and focal pain above or behind
aneurysms <10 mm in size is ~0.1%, and for aneurysms ≥10 mm in size the eye, may occur with an expanding aneurysm at the junction of the
is ~0.5–1%; the surgical morbidity rate far exceeds these percentages. posterior communicating artery and the internal carotid artery. A sixth
Aneurysm location may also factor into risk, with basilar bifurca- nerve palsy may indicate an aneurysm in the cavernous sinus, and
tion aneurysms appearing to have a somewhat higher rupture risk. visual field defects can occur with an expanding supraclinoid carotid
Because of the longer length of exposure to risk of rupture, younger or anterior cerebral artery (ACA) aneurysm. Occipital and posterior
patients with aneurysms >10 mm in size may benefit from prophylac- cervical pain may signal a posterior inferior cerebellar artery or ante-
tic treatment. As with the treatment of asymptomatic carotid stenosis, rior inferior cerebellar artery aneurysm (Chap. 419). Pain in or behind
this risk-benefit ratio strongly depends on the complication rate of the eye and in the low temple can occur with an expanding MCA aneu-
treatment. rysm. Thunderclap headache is a variant of migraine that simulates an
Giant aneurysms, those >2.5 cm in diameter, occur at the same sites SAH. Before concluding that a patient with sudden, severe headache
(see below) as small aneurysms and account for 5% of cases. The three has thunderclap migraine, a definitive workup for aneurysm or other
most common locations are the terminal internal carotid artery, middle intracranial pathology is required.

TABLE 302-1 Grading Scales for Subarachnoid Hemorrhage the MCA and proximal ACA, carotid terminus, and vertebral and 2085
basilar arteries on a daily or every-other-day basis, vasospasm
WORLD FEDERATION
OF NEUROSURGICAL can be reliably detected and treatments initiated to prevent cere-
SOCIETIES (WFNS) bral ischemia (see below). CT angiography is another method
GRADE HUNT-HESS SCALE SCALE that can detect vasospasm.
1 Mild headache, normal mental status, GCSa score 15, no motor c. Severe cerebral edema in patients with infarction from vaso-
no cranial nerve or motor findings deficits spasm may increase the ICP enough to reduce cerebral perfusion
2 Severe headache, normal mental GCS score 13–14, no pressure. Treatment may include mannitol, hyperventilation, and
status, may have cranial nerve deficit motor deficits for intractable cases hemicraniectomy; moderate hypothermia
3 Somnolent, confused, may have cranial GCS score 13–14, with may have a role as well.
nerve or mild motor deficit motor deficits 4. Hyponatremia. Hyponatremia may be profound and can develop
4 Stupor, moderate to severe motor GCS score 7–12, with or quickly in the first 2 weeks following SAH. There is both natriure-
deficit, may have intermittent reflex without motor deficits sis and volume depletion with SAH, so that patients become both
posturing hyponatremic and hypovolemic. Both atrial natriuretic peptide
5 Coma, reflex posturing or flaccid GCS score 3–6, with or and brain natriuretic peptide have a role in producing this “cere-
without motor deficits
bral salt-wasting syndrome.” Typically, it clears over the course of
CHAPTER 302 Subarachnoid Hemorrhage

a
Glasgow Coma Scale; see Table 435-1. 1–2 weeks and, in the setting of SAH, should not be treated with
free-water restriction as this may increase the risk of stroke (see
below).
Aneurysms can undergo small ruptures and leaks of blood into
the subarachnoid space, so-called sentinel bleeds. Sudden unexplained Laboratory Evaluation and Imaging (Fig. 302-1) The hall-
headache at any location should raise suspicion of SAH and be investi- mark of aneurysmal rupture is blood in the cerebrospinal fluid (CSF).
gated, because a major hemorrhage may be imminent. More than 95% of cases have enough blood to be visualized on a
The initial clinical manifestations of SAH can be graded using the high-quality noncontrast CT scan obtained within 72 h. If the scan fails
Hunt-Hess or World Federation of Neurosurgical Societies classifica- to establish the diagnosis of SAH and no mass lesion or obstructive
tion schemes (Table 302-1). For ruptured aneurysms, prognosis for hydrocephalus is found, a lumbar puncture should be performed to
good outcomes falls as the grade increases. For example, it is unusual establish the presence of subarachnoid blood. Lysis of the red blood
for a Hunt-Hess grade 1 patient to die if the aneurysm is treated, but cells and subsequent conversion of hemoglobin to bilirubin stains the
the mortality rate for grade 4 and 5 patients may be as high as 60%. spinal fluid yellow within 6–12 h. This xanthochromic spinal fluid
Delayed Neurologic Deficits There are four major causes of
delayed neurologic deficits: rerupture, hydrocephalus, delayed cere-
bral ischemia (DCI), and hyponatremia.
1. Rerupture. The incidence of rerupture of an untreated aneurysm in
the first month following SAH is ~30%, with the peak in the first
7 days. Rerupture is associated with a 50% mortality rate and poor
outcome. Early treatment eliminates this risk.
2. Hydrocephalus. Acute hydrocephalus can cause stupor and coma and
can be mitigated by placement of an external ventricular drain. More
often, subacute hydrocephalus may develop over a few days or
weeks and causes progressive drowsiness or slowed mentation with
incontinence. Hydrocephalus is differentiated from cerebral vaso-
spasm with a CT scan, CT angiogram, transcranial Doppler (TCD)
ultrasound, or conventional x-ray angiography. Hydrocephalus
may clear spontaneously or require temporary ventricular drainage.
Chronic hydrocephalus may develop weeks to months after SAH A B
and manifest as gait difficulty, incontinence, or impaired mentation.
Subtle signs may be a lack of initiative in conversation or a failure to
recover independence.
3. Delayed cerebral ischemia. Vasospasm is the narrowing of the arteries
at the base of the brain following SAH. This may cause symptomatic
ischemia and infarction in ~30% of patients and is the major cause of
delayed morbidity and death. Signs of DCI appear 4–14 days after
the hemorrhage, most often at 7 days. The severity and distribution
of vasospasm determine whether infarction will occur.
a. Vasospasm is believed to result from direct effects of clotted
blood and its breakdown products on the arteries within the
subarachnoid space. In general, the more blood that surrounds
the arteries, the greater the chance of symptomatic vasospasm.
Spasm of major arteries produces symptoms referable to the
appropriate vascular territory (Chap. 419). All of these focal C D
symptoms may present abruptly, fluctuate, or develop over a FIGURE 302-1 Subarachnoid hemorrhage. A. Computed tomography (CT)
few days. In most cases, focal spasm is preceded by a decline in angiography revealing an aneurysm of the left superior cerebellar artery.
mental status. B. Noncontrast CT scan at the level of the third ventricle revealing subarachnoid
b. Vasospasm can be detected reliably with conventional x-ray blood (bright) in the left sylvian fissure and within the left lateral ventricle.
C. Conventional anteroposterior x-ray angiogram of the right vertebral and basilar
angiography, but this procedure is invasive and carries the risk of
artery showing the large aneurysm. D. Conventional angiogram following coil
stroke and other complications. TCD ultrasound is based on the embolization of the aneurysm, whereby the aneurysm body is filled with platinum
principle that the velocity of blood flow within an artery will rise coils delivered through a microcatheter navigated from the femoral artery into the
as the lumen diameter is narrowed. By directing the probe along aneurysm neck.

2086 peaks in intensity at 48 h and lasts for 1–4 weeks, depending on the to endovascular treatment, surgery remains an important treatment
amount of subarachnoid blood. option. Newer endovascular techniques using balloon-assisted coil-
The extent and location of subarachnoid blood on a noncontrast CT ing or placement of flow-diverting stents are increasing the types
scan help locate the underlying aneurysm, identify the cause of any of aneurysms amenable to endovascular intervention. Centers that
neurologic deficit, and predict the occurrence of vasospasm. A high combine both endovascular and neurosurgical expertise likely offer
incidence of symptomatic vasospasm in the MCA and ACA has been the best outcomes for patients, and there are reliable data showing
found when early CT scans show subarachnoid clots >5 × 3 mm in the that specialized aneurysm treatment centers can improve mortality
basal cisterns, or layers of blood >1 mm thick in the cerebral fissures. rates.
CT scans less reliably predict vasospasm in the vertebral, basilar, or The medical management of SAH focuses on protecting the air-
posterior cerebral arteries. way, managing blood pressure before and after aneurysm treatment,
Lumbar puncture prior to an imaging procedure is indicated only preventing rebleeding prior to treatment, managing vasospasm
if a CT scan is not available at the time of the suspected SAH. Once and DCI, treating hydrocephalus, treating hyponatremia, limiting
the diagnosis of hemorrhage from a ruptured saccular aneurysm is secondary brain insults, and preventing pulmonary embolus (PE).
suspected, four-vessel conventional x-ray angiography (both carotids Intracranial hypertension following aneurysmal rupture occurs
and both vertebrals) is generally performed to localize and define the secondary to subarachnoid blood, parenchymal hematoma, acute
anatomic details of the aneurysm and to determine if other unruptured hydrocephalus, or loss of vascular autoregulation. Patients who are
aneurysms exist (Fig. 302-1C). At some centers, the ruptured aneurysm stuporous should undergo emergent ventriculostomy to measure
can be treated using endovascular techniques at the time of the initial ICP and to treat high ICP in order to prevent cerebral ischemia.
PART 8
angiogram as a way to expedite treatment and minimize the number Medical therapies designed to combat raised ICP (e.g., osmotic ther-
of invasive procedures. CT angiography is an alternative method for apy and sedation) can also be used as needed. High ICP refractory
locating the aneurysm and may be sufficient to plan definitive therapy. to treatment is a poor prognostic sign.
Close monitoring (daily or twice daily) of electrolytes is important Prior to definitive treatment of the ruptured aneurysm, care is
because hyponatremia can occur precipitously during the first 2 weeks required to maintain adequate cerebral perfusion pressure while
following SAH (see above). avoiding excessive elevation of arterial pressure. If the patient is
The electrocardiogram (ECG) frequently shows ST-segment and alert, it is reasonable to lower the systolic blood pressure to below
T-wave changes similar to those associated with cardiac ischemia. 160 mmHg using nicardipine, labetalol, or esmolol. If the patient has
A prolonged QRS complex, increased QT interval, and prominent a depressed level of consciousness, ICP should be measured and the
“peaked” or deeply inverted symmetric T waves are usually second- cerebral perfusion pressure targeted to 60–70 mmHg. If headache
ary to the intracranial hemorrhage. There is evidence that structural or neck pain is severe, mild sedation and analgesia are prescribed.
myocardial lesions produced by circulating catecholamines and exces- Extreme sedation is avoided if possible because it can obscure the
sive discharge of sympathetic neurons may occur after SAH, causing ability to clinically detect changes in neurologic status. Adequate
these ECG changes and a reversible cardiomyopathy sufficient to hydration is necessary to avoid a decrease in blood volume predis-
cause shock or congestive heart failure. Echocardiography reveals a posing to brain ischemia.
pattern of regional wall motion abnormalities that follow the distri- Seizures are uncommon at the onset of aneurysmal rupture. The
bution of sympathetic nerves rather than the major coronary arteries, quivering, jerking, and extensor posturing that often accompany
with relative sparing of the ventricular wall apex. The sympathetic loss of consciousness with SAH are probably related to the sharp
nerves themselves appear to be injured by direct toxicity from the rise in ICP rather than seizures. However, anticonvulsants are
excessive catecholamine release. An asymptomatic troponin elevation sometimes given as prophylactic therapy because a seizure could
is common. Serious ventricular dysrhythmias occurring in-hospital are theoretically promote rebleeding.
unusual. Glucocorticoids may help reduce the head and neck ache caused
by the irritative effect of the subarachnoid blood. There is no good
evidence that they reduce cerebral edema, are neuroprotective,
TREATMENT or reduce vascular injury, and their routine use therefore is not
Subarachnoid Hemorrhage recommended.
Antifibrinolytic agents are not routinely prescribed but may be
Early aneurysm repair prevents rerupture and allows the safe considered in patients in whom aneurysm treatment cannot pro-
application of techniques to improve blood flow (e.g., induced ceed immediately. They are associated with a reduced incidence
hypertension) should vasospasm and DCI develop. An aneurysm of aneurysmal rerupture but may also increase the risk of DCI and
can be “clipped” by a neurosurgeon or “coiled” by an endovascular deep-vein thrombosis (DVT). Several recent studies suggest that a
surgeon. Surgical repair involves placing a metal clip across the shorter duration of use (until the aneurysm is secured or for the first
aneurysm neck, thereby immediately eliminating the risk of rebleed- 3 days) may decrease rerupture and be safer than found in earlier
ing. This approach requires craniotomy and brain retraction, which studies of longer duration treatment.
is associated with neurologic morbidity. Endovascular techniques DCI due to vasospasm remains the leading cause of morbidity
involve placing platinum coils, or other embolic material, within the and mortality following aneurysmal SAH. Treatment with the cal-
aneurysm via a catheter that is passed from the femoral artery. The cium channel antagonist nimodipine (60 mg PO every 4 h) improves
aneurysm is packed tightly to enhance thrombosis and over time outcome, perhaps by preventing ischemic injury rather than
is walled off from the circulation (Fig. 302-1D). There have been reducing the risk of vasospasm. Nimodipine can cause significant
two prospective randomized trials of surgery versus endovascular hypotension in some patients, which may worsen cerebral ischemia
treatment for ruptured aneurysms: the first was the International in patients with vasospasm. Symptomatic cerebral vasospasm can
Subarachnoid Aneurysm Trial (ISAT), which was terminated early also be treated by increasing the cerebral perfusion pressure by rais-
when 24% of patients treated with endovascular therapy were dead ing mean arterial pressure through plasma volume expansion and
or dependent at 1 year compared to 31% treated with surgery, a sig- the judicious use of IV vasopressor agents, usually phenylephrine or
nificant 23% relative reduction. After 5 years, risk of death was lower norepinephrine. Raised perfusion pressure has been associated with
in the coiling group, although the proportion of survivors who were clinical improvement in many patients, but high arterial pressure
independent was the same in both groups. Risk of rebleeding was may promote rebleeding in unprotected aneurysms. Treatment with
low, but more common in the coiling group. These results favoring induced hypertension and hypervolemia generally requires mon-
coiling at 1 year were confirmed in a second trial, although the dif- itoring of arterial and central venous pressures; it is best to infuse
ferences in functional outcome were no longer significant at 3 years. pressors through a central venous line as well. Volume expansion
Because some aneurysms have a morphology that is not amenable helps prevent hypotension and augments cardiac output.

chronic hydrocephalus develops, ventricular shunting is the treat- 2087
ment of choice.
Free-water restriction is contraindicated in patients with SAH at
risk for DCI because hypovolemia and hypotension may occur and
precipitate cerebral ischemia. Many patients continue to experience
a decline in serum sodium despite receiving parenteral fluids con-
taining normal saline. Frequently, supplemental oral salt coupled
with normal saline will mitigate hyponatremia, but often patients
also require intravenous hypertonic saline. Care must be taken not to
correct serum sodium too quickly in patients with marked hypona-
tremia of several days’ duration, as the osmotic demyelination syn-
drome (Chap. 301) may occur.
All patients should have pneumatic compression stockings
applied to prevent pulmonary embolism. Unfractionated heparin
administered subcutaneously for DVT prophylaxis can be initiated
within 1–2 days following endovascular treatment or craniotomy
CHAPTER 302 Subarachnoid Hemorrhage

with surgical clipping and is a useful adjunct to pneumatic compres-
sion stockings. Treatment of PE depends on whether the aneurysm
has been treated and whether or not the patient has had a craniot-
omy. Systemic anticoagulation with heparin is contraindicated in
A B patients with ruptured and untreated aneurysms. It is a relative
FIGURE 302-2 Vasospasm of the right middle cerebral artery. A. Catheter contraindication following craniotomy for several days, and it may
angiography demonstrates significant narrowing of the right middle cerebral delay thrombosis of a coiled aneurysm. If DVT or PE occurs within
artery (MCA). B. Because of symptomatic delayed cerebral ischemia, soft-balloon the first days following craniotomy, use of an inferior vena cava
angioplasty was used to dilate the proximal portion of the main MCA stem. filter may be considered to prevent additional PEs, whereas sys-
temic anticoagulation with heparin is preferred following successful
endovascular treatment.
If DCI due to vasospasm persists despite optimal medical
therapy, intraarterial vasodilators and percutaneous transluminal ■■FURTHER READING
angioplasty are considered (Fig. 302-2). Vasodilatation by direct Diringer MN et al: Critical care management of patients following
angioplasty appears to be permanent, allowing hypertensive therapy aneurysmal subarachnoid hemorrhage: Recommendations from the
to be tapered sooner. The pharmacologic vasodilators (verapamil Neurocritical Care Society’s Multidisciplinary Consensus Confer-
and nicardipine) do not last more than about 24 h, and therefore ence. Neurocrit Care 15:211, 2011.
multiple treatments may be required until the subarachnoid blood is Etminan N, MacDonald RL: Management of aneurysmal subarach-
reabsorbed. Although intraarterial papaverine is an effective vasodi- noid hemorrhage. Handb Clin Neurol 140:195, 2017.
lator, there is evidence that papaverine may be neurotoxic, so its use Molyneux AJ et al: The durability of endovascular coiling versus neu-
should generally be avoided. rosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up
Acute hydrocephalus can cause stupor or coma. It may clear of the UK cohort of the International Subarachnoid Aneurysm Trial
spontaneously or require temporary ventricular drainage. When (ISAT). Lancet 385:691, 2015.

Disorders of the Kidney and Urinary Tract PART 9
supporting these emerging endothelial capillaries. Podocytes are
303 Cellular and Molecular

Biology of the Kidney
partially polarized and periodically slough into the urinary space by
epithelial-mesenchymal transition, and to a lesser extent apoptosis,
only to be replenished by migrating parietal epithelia from Bowman
capsule. Impaired replenishment results in heavy proteinuria. Podo-
Alfred L. George, Jr., Eric G. Neilson cytes attach to the basement membrane by special foot processes and
share a slit-pore membrane with their neighbor. The slit-pore mem-
brane forms a filter for plasma water and solute by the synthetic inter-
The kidney is one of the most highly differentiated organs in the body. action of nephrin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin,
At the conclusion of embryologic development, nearly 30 different cell TRPC6, PLCE1, and Neph 1-3 proteins. Mutations in many of these
types form a multitude of filtering capillaries and segmented nephrons proteins also result in heavy proteinuria. The glomerular capillaries are
enveloped by a dynamic interstitium. This cellular diversity modulates embedded in a mesangial matrix shrouded by parietal and proximal
a variety of complex physiologic processes. Endocrine functions, the tubular epithelia forming Bowman capsule. Mesangial cells have an
regulation of blood pressure and intraglomerular hemodynamics, embryonic lineage consistent with arteriolar or juxtaglomerular cells
solute and water transport, acid-base balance, and removal of drug and contain contractile actin-myosin fibers. These mesangial cells make
metabolites are all accomplished by intricate mechanisms of renal contact with glomerular capillary loops, and their local matrix holds
response. This breadth of physiology hinges on the clever ingenuity of them in condensed arrangement.
nephron architecture that evolved as complex organisms came out of Between nephrons lies the renal interstitium. This region forms a
water to live on land. functional space surrounding glomeruli and their downstream tubules,
which are home to resident and trafficking cells such as fibroblasts,
EMBRYOLOGIC DEVELOPMENT dendritic cells, occasional lymphocytes, and lipid-laden macrophages.
Kidneys develop from intermediate mesoderm under the timed The cortical and medullary peritubular capillaries, which siphon off
or sequential control of a growing number of genes, described in solute and water following tubular reclamation of glomerular filtrate,
Fig. 303-1. The transcription of these genes is guided by morphogenic are also part of the interstitial fabric as well as a web of connective
cues that invite two ureteric buds to each penetrate bilateral meta- tissue that supports the kidney’s emblematic architecture of folding
nephric blastema, where they induce primary mesenchymal cells to tubules. The relational precision of these structures determines the
form early nephrons. The two ureteric buds emerge from posterior unique physiology of the kidney.
nephric ducts and mature into separate collecting systems that even- Each nephron is partitioned during embryologic development
tually form a renal pelvis and ureter. Induced mesenchyme undergoes into a proximal tubule, descending and ascending limbs of the loop
mesenchymal epithelial transitions to form comma-shaped bodies of Henle, distal tubule, and the collecting duct. These classic tubular
at the proximal end of each ureteric bud leading to the formation of segments build from subsegments lined by highly unique epithelia
S-shaped nephrons that cleft and enjoin with penetrating endothelial serving regional physiology. All nephrons have the same structural
cells derived from sprouting angioblasts. Under the influence of vas- components, but there are two types whose structures depend on
cular endothelial growth factor A (VEGF-A), these penetrating cells their location within the kidney. The majority of nephrons are cortical,
form capillaries with surrounding mesangial cells that differentiate with glomeruli located in the mid-to-outer cortex. Fewer nephrons
into a glomerular filter for plasma water and solute. The ureteric buds are juxtamedullary, with glomeruli at the boundary of the cortex and
branch and each branch produce a new set of nephrons. The number of outer medulla. Cortical nephrons have short loops of Henle, whereas
branching events ultimately determines the total number of nephrons juxtamedullary nephrons have long loops of Henle. There are critical
in each kidney. There are ~900,000 glomeruli in each kidney in normal differences in blood supply as well. The peritubular capillaries sur-
birth weight adults and as few as 225,000 in low-birth-weight adults, rounding cortical nephrons are shared among adjacent nephrons. By
with the latter producing numerous comorbid risks. contrast, juxtamedullary nephrons depend on individual capillaries
Glomeruli evolve as complex capillary filters with fenestrated called vasa recta that run alongside the long loops of Henle. Cortical
endothelia under the guiding influence of VEGF-A and angiopoietin-1 nephrons perform most of the glomerular filtration because there
secreted by adjacently developing podocytes. Epithelial podocytes are more of them and because their afferent arterioles are larger than
facing the urinary space envelop the exterior basement membrane their respective efferent arterioles. The juxtamedullary nephrons, with
Foxd1
VEGF-A / Kdr (Flk-1) Tcf21
Wnt4 Foxc2
Emx2 Comma-shape S-shape Pdgfb / Pdgfbr
Pax2 Lmx1b
Fgf8 Itga3 / Itgb1 Cxcr4 / Cxcl12
Gdnf / Ret
Notch2
Lhx1 Pretubular Capillary Nphs1
Eya1 aggregation loop Nck1 / Nck2
Six1
Cd36
Itga8 / Itgb1
CD2AP
Fgfr2
Neph1
Hoxa11 / Hoxd11
Nphs2
Foxc1
Lamb2
Slit2 / Robo2
Wt1 Mature
glomerulus
Ureteric bud induction
and condensation Nephrogenesis
FIGURE 303-1 Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in
the mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney
development postulated by Saxen in 1987.

2090 longer loops of Henle, create an osmotic gradient for concentrating A
Proximal Peritubular
urine. How developmental instructions specify the differentiation convoluted tubule capillaries
of all these unique epithelia among various tubular segments is still Efferent
arteriole
unknown.
Distal
Bowman convoluted
DETERMINANTS AND REGULATION OF capsule tubule
GLOMERULAR FILTRATION
Renal blood flow normally drains ~20% of the cardiac output, or Glomerulus
1000 mL/min. Blood reaches each nephron through the afferent arte-
riole leading into a glomerular capillary where large amounts of fluid
and solutes are filtered to form the tubular fluid. The distal ends of the Afferent
glomerular capillaries coalesce to form an efferent arteriole leading to arteriole
Proximal Thick
the first segment of a second capillary network (cortical peritubular cap- tubule ascending
illaries or medullary vasa recta) surrounding the tubules (Fig. 303-2A). limb
Thus, nephrons have two capillary beds arranged in a series separated
by the efferent arteriole that regulates the hydrostatic pressure in both
Collecting
capillary beds. The distal capillaries empty into small venous branches duct
that coalesce into larger veins to eventually form the renal vein.
The hydrostatic pressure gradient across the glomerular capillary
wall is the primary driving force for glomerular filtration. Oncotic Peritubular
pressure within the capillary lumen, determined by the concentration venules
of unfiltered plasma proteins, partially offsets the hydrostatic pressure
gradient and opposes filtration. As the oncotic pressure rises along the
PART 9
length of the glomerular capillary, the driving force for filtration falls to
zero en route to the efferent arteriole. Approximately 20% of the renal
plasma flow is filtered into Bowman space, and the ratio of glomerular
filtration rate (GFR) to renal plasma flow determines the filtration frac- B
tion. Several factors, mostly hemodynamic, contribute to the regulation Glomerulus
Disorders of the Kidney and Urinary Tract
of filtration under physiologic conditions.

Although glomerular filtration is affected by renal artery pressure, Efferent
this relationship is not linear across the range of physiologic blood arteriole
pressures due to autoregulation of GFR. Autoregulation of glomeru-
lar filtration is the result of three major factors that modulate either
Macula
afferent or efferent arteriolar tone: these include an autonomous densa
vasoreactive (myogenic) reflex in the afferent arteriole, tubuloglomeru-
lar feedback (TGF), and angiotensin II-mediated vasoconstriction of the
efferent arteriole. The myogenic reflex is a first line of defense against
fluctuations in renal blood flow. Acute changes in renal perfusion
pressure evoke reflex constriction or dilatation of the afferent arteriole Afferent
in response to increased or decreased pressure, respectively. This phe- arteriole
nomenon helps protect the glomerular capillary from sudden changes Renin-secreting
in systolic pressure. granular cells
Thick Proximal
TGF changes the rate of filtration and tubular flow by reflex vaso- ascending tubule
constriction or dilatation of the afferent arteriole. TGF is mediated by limb
specialized cells in the thick ascending limb of the loop of Henle called
the macula densa that act as sensors of solute concentration and tubular C
fluid flow rate. With high tubular flow rates, a proxy for an inappropri- Renin
ately high filtration rate, there is increased solute delivery to the macula Angiotensinogen
densa (Fig. 303-2B) that evokes vasoconstriction of the afferent arteriole Asp-Arg-Val-Tyr-IIe-His-Pro-Phe-His-Leu - Val-IIe-His
causing GFR to return toward normal. One component of the soluble
signal from the macula densa is adenosine triphosphate (ATP) released
by the cells during increased NaCl reabsorption. ATP is metabolized in ACE
Angiotensin I
the extracellular space to generate adenosine, a potent vasoconstrictor
of the afferent arteriole. During conditions associated with a fall in Asp-Arg-Val-Tyr-IIe-His-Pro-Phe - His-Leu
filtration rate, reduced solute delivery to the macula densa attenuates
ACE2
TGF, allowing afferent arteriolar dilatation and restoring GFR to nor- Angiotensin II
mal levels. Angiotensin II and reactive oxygen species enhance, while Asp-Arg-Val-Tyr-IIe-His-Pro-Phe
nitric oxide (NO) blunts TGF.
The third component underlying autoregulation of GFR involves
Angiotensin (I-VII)
angiotensin II. During states of reduced renal blood flow, renin is
released from granular cells within the wall of the afferent arteriole Asp-Arg-Val-Tyr-IIe-His-Pro
near the macula densa in a region called the juxtaglomerular apparatus
(Fig. 303-2B). Renin, a proteolytic enzyme, catalyzes the conversion of FIGURE 303-2 Renal microcirculation and the renin-angiotensin system.
A. Diagram illustrating relationships of the nephron with glomerular and peritubular
angiotensinogen to angiotensin I, which is subsequently converted to capillaries. B. Expanded view of the glomerulus with its juxtaglomerular apparatus
angiotensin II by angiotensin-converting enzyme (ACE) (Fig. 303-2C). including the macula densa and adjacent afferent arteriole. C. Proteolytic
Angiotensin II evokes vasoconstriction of the efferent arteriole, and the processing steps in the generation of angiotensins.
resulting increased glomerular hydrostatic pressure elevates GFR to
normal levels.

MECHANISMS OF RENAL TUBULAR ■■EPITHELIAL SOLUTE TRANSPORT 2091
TRANSPORT There are two types of epithelial transport. Movement of fluid and
The renal tubules are composed of highly differentiated epithelia that solutes sequentially across the apical and basolateral cell membranes
vary dramatically in morphology and function along the nephron (or vice versa) mediated by transporters, channels, or pumps is called
(Fig. 303-3). The cells lining the various tubular segments form mono- cellular transport. By contrast, movement of fluid and solutes through
layers connected to one another by a specialized region of the adja- the narrow passageway between adjacent cells is called paracellular
cent lateral membranes called the tight junction. Tight junctions form transport. Paracellular transport occurs through tight junctions, indi-
an occlusive barrier that separates the lumen of the tubule from the cating that they are not completely “tight” or occlusive. Indeed, some
interstitial spaces surrounding the tubule and also apportions the cell epithelial cell layers allow rather robust paracellular transport to occur
membrane into discrete domains: the apical membrane facing the tubu- (leaky epithelia), whereas other epithelia have more restrictive tight
lar lumen and the basolateral membrane facing the interstitium. This junctions (tight epithelia). In addition, because the ability of ions to flow
regionalization allows cells to allocate membrane proteins and lipids through the paracellular pathway determines the electrical resistance
asymmetrically. Owing to this feature, renal epithelial cells are said to across the epithelial monolayer, leaky and tight epithelia are also
be polarized. The asymmetric assignment of membrane proteins, espe- referred to as low- or high-resistance epithelia, respectively. The proxi-
cially proteins mediating transport processes, provides the machinery mal tubule contains leaky epithelia, whereas distal nephron segments,
for directional movement of fluid and solutes by the nephron. such as the collecting duct, contain tight epithelia. Leaky epithelia are
PROXIMAL TUBULE
CHAPTER 303 Cellular and Molecular Biology of the Kidney

Lumen Interstitium
Apical Basolateral
HPO4 + H
Na 3Na
H 2K
H2PO4 H2O
Na
Phosphate
Na
Glucose Glucose
Na
Amino Amino
acids acids
H2O, solutes
Na
H
NH4 NH3 3Na

2K
Formic
acid
HCO3 + H Cl
Formate K
Cl
H
Na
H2CO3 H2CO3 HCO3
carbonic carbonic
anhydrase anhydrase
H2O + CO2 CO2
A
FIGURE 303-3 Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical
membrane) facing left and interstitial side (basolateral membrane) facing right. A. Proximal tubular cells. B. Typical cell in the thick ascending limb of the loop of
Henle. C. Distal convoluted tubular cell. D. Overview of entire nephron. E. Cortical collecting duct cells. F. Typical cell in the inner medullary collecting duct. The major
membrane transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of
transport is indicated by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions of hormones are illustrated by arrows with plus signs
for stimulatory effects and lines with perpendicular ends for inhibitory events. The dashed line indicates water impermeability of cell membranes in the thick ascending
limb and distal convoluted tubule.

2092
THICK ASCENDING LIMB
Loop diuretics
3Na
Na
2K
K
2Cl
Cl
H2O
Ca
+ –
Ca, Mg
PART 9
DISTAL CONVOLUTED TUBULE
Lumen Interstitium
Thiazides
3Na
Na
2K
Cl
Cl
Ca Ca
3Na
H2O
C
FIGURE 303-3 (Continued)

2093
CORTEX
Macula densa Distal Cortical
convoluted collecting
Proximal tubule duct
tubule
Bowman
capsule CORTICAL COLLECTING DUCT
Lumen Interstitium
Amiloride
Principal cell
Vein 3Na
Na 2K
Artery +
+
MEDULLA
K Aldosterone
Loop of Henle: + +
Thin descending Vasopressin

limb +
Thick ascending H2O + H 2O
limb

Thin ascending
limb
Inner medullary Type A
collecting duct intercalated cell
3Na
H 2K
carbonic
anhydrase
H
K HCO3
Cl
D E
INNER MEDULLARY COLLECTING DUCT

Lumen Interstitium
ANP
Na
3Na
K 2K
Urea Vasopressin
+ +
H2O H2O
F
most well suited for bulk fluid reabsorption, whereas tight epithelia proteins, including channels, pumps, and transporters. These different
allow for more refined control and regulation of transport. mechanisms mediate specific types of transport activities, including
active transport (pumps), passive transport (channels), facilitated diffusion
■■MEMBRANE TRANSPORT (transporters), and secondary active transport (cotransporters). Active
Cell membranes are composed of hydrophobic lipids that repel water transport requires metabolic energy generated by the hydrolysis of
and aqueous solutes. The movement of solutes and water across cell ATP. Active transport pumps are ion-translocating ATPases, including
membranes is made possible by discrete classes of integral membrane the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases.

2094 TABLE 303-1 Inherited Disorders Affecting Renal Tubular Ion and Solute Transport
DISEASE OR SYNDROME GENE OMIMa
Disorders Involving the Proximal Tubule
Proximal renal tubular acidosis Sodium bicarbonate cotransporter (SLC4A4, 4q21) 604278
Fanconi-Bickel syndrome Glucose transporter, GLUT2 (SLC2A2, 3q26.2) 227810
Isolated renal glycosuria Sodium glucose cotransporter (SLC5A2, 16p11.2) 233100
Cystinuria
Type I Cystine, dibasic and neutral amino acid transporter (SLC3A1, 2p16.3) 220100
Non-type I Amino acid transporter, light subunit (SLC7A9, 19q13.1) 600918
Lysinuric protein intolerance Amino acid transporter (SLC7A7, 4q11.2) 222700
Hartnup disorder Neutral amino acid transporter (SLC6A19, 5p15.33) 34500
Hereditary hypophosphatemic rickets with hypercalcemia Sodium phosphate cotransporter (SLC34A3, 9q34) 241530
Renal hypouricemia
Type 1 Urate-anion exchanger (SLC22A12, 11q13) 220150
Type 2 Urate transporter, GLUT9 (SLC2A9, 4p16.1) 612076
Dent disease Chloride channel, ClC-5 (CLCN5, Xp11.22) 300009
X-linked recessive nephrolithiasis with renal failure Chloride channel, ClC-5 (CLCN5, Xp11.22) 310468
X-linked recessive hypophosphatemic rickets Chloride channel, ClC-5 (CLCN5, Xp11.22) 307800
Disorders Involving the Loop of Henle
Bartter’s syndrome
Type 1 Sodium, potassium chloride cotransporter (SLC12A1, 15q21.1) 241200
PART 9
Type 2 Potassium channel, ROMK (KCNJ1, 11q24) 601678

Type 3 Chloride channel, ClC-Kb (CLCNKB, 1p36) 602023
with sensorineural deafness Chloride channel accessory subunit, Barttin (BSND, 1p31) 602522
Autosomal dominant hypocalcemia with Bartter-like syndrome Calcium-sensing receptor (CASR, 3q13.33) 601199
Familial hypocalciuric hypercalcemia Calcium-sensing receptor (CASR, 3q13.33) 145980

Primary hypomagnesemia Claudin-16 or paracellin-1 (CLDN16 or PCLN1, 3q27) 248250
Isolated renal magnesium loss Sodium potassium ATPase, γ1-subunit (ATP1G1, 11q23) 154020
Disorders Involving the Distal Tubule and Collecting Duct
Gitelman syndrome Sodium chloride cotransporter (SLC12A3, 16q13) 263800
Primary hypomagnesemia with secondary hypocalcemia Melastatin-related transient receptor potential cation channel 6 (TRPM6, 602014
9q22)
Pseudoaldosteronism (Liddle’s syndrome) Epithelial sodium channel β and γ subunits (SCNN1B, SCNN1G, 16p12.1) 177200
Recessive pseudohypoaldosteronism type 1 Epithelial sodium channel, a, β, and γ subunits (SCNN1A, 12p13; 264350
SCNN1B, SCNN1G, 16pp12.1)
Pseudohypoaldosteronism type 2 (Gordon’s hyperkalemia- Kinases WNK-1, WNK-4 (WNK1, 12p13; WNK4, 17q21.31) 145260
hypertension syndrome)
X-linked nephrogenic diabetes insipidus Vasopressin V2 receptor (AVPR2, Xq28) 304800
Nephrogenic diabetes insipidus (autosomal) Water channel, aquaporin-2 (AQP2, 12q13) 125800
Distal renal tubular acidosis
autosomal dominant Anion exchanger-1 (SLC4A1, 17q21.31) 179800
autosomal recessive Anion exchanger-1 (SLC4A1, 17q21.31) 602722
with neural deafness Proton ATPase, β1 subunit (ATP6V1B1, 2p13.3) 192132
with normal hearing Proton ATPase, 116-kD subunit (ATP6V0A4, 7q34) 602722
Online Mendelian Inheritance in Man database (http://www.ncbi.nlm.nih.gov/Omim).
a
Active transport creates asymmetric ion concentrations across a cell either in the same direction (symporters or cotransporters) or in opposite
membrane and can move ions against a chemical gradient. The poten- directions (antiporters or exchangers) across the cell membrane. The
tial energy stored in a concentration gradient of an ion such as Na+ can movement of two or more ions/solutes may produce no net change
be used to drive transport through other mechanisms (secondary active in the balance of electrostatic charges across the membrane (electroneu-
transport). Pumps are often electrogenic, meaning they can create an tral), or a transport event may alter the balance of charges (electrogenic).
asymmetric distribution of electrostatic charges across the membrane Several inherited disorders of renal tubular solute and water transport
and establish a voltage or membrane potential. The movement of sol- occur as a consequence of mutations in genes encoding a variety of
utes through a membrane protein by simple diffusion is called passive channels, transporter proteins, and their regulators (Table 303-1).
transport. This activity is mediated by channels created by selectively
permeable membrane proteins, and it allows solute or water to move SEGMENTAL NEPHRON FUNCTIONS
across a membrane driven by favorable concentration gradients or elec- Each anatomic segment of the nephron has unique characteristics and
trochemical potential. Facilitated diffusion is a specialized type of passive specialized functions enabling selective transport of solutes and water
transport mediated by simple transporters called carriers or uniporters. (Fig. 303-3). Through sequential events of reabsorption and secretion
For example, hexose transporters such as GLUT2 mediate glucose along the nephron, tubular fluid is progressively conditioned into
transport by tubular cells. These transporters are driven by the concen- urine. Knowledge of the major tubular mechanisms responsible for
tration gradient for glucose that is highest in extracellular fluids and solute and water transport is critical for understanding hormonal
lowest in the cytoplasm due to rapid metabolism. Many other trans- regulation of kidney function and the pharmacologic manipulation of
porters operate by translocating two or more ions/solutes in concert renal excretion.

PROXIMAL TUBULE The proximal tubule possesses specific transporters capable of 2095
The proximal tubule is responsible for reabsorbing ~60% of filtered secreting a variety of organic acids (carboxylate anions) and bases
NaCl and water, as well as ~90% of filtered bicarbonate and most crit- (mostly primary amine cations). Organic anions transported by these
ical nutrients such as glucose and amino acids. The proximal tubule systems include urate, dicarboxylic acid anions (succinate), ketoacid
uses both cellular and paracellular transport mechanisms. The apical anions, and several protein-bound drugs not filtered at the glomerulus
membrane of proximal tubular cells has an expanded surface area (penicillins, cephalosporins, and salicylates). Probenecid inhibits renal
available for reabsorptive work created by a dense array of microvilli organic anion secretion and can be clinically useful for raising plasma
called the brush border, and leaky tight junctions enable high-capacity concentrations of certain drugs like penicillin and oseltamivir. Organic
fluid reabsorption. cations secreted by the proximal tubule include various biogenic amine
Solute and water pass through these tight junctions to enter the lat- neurotransmitters (dopamine, acetylcholine, epinephrine, norepineph-
eral intercellular space where absorption by the peritubular capillaries rine, and histamine) and creatinine. The ATP-dependent transporter
occurs. Bulk fluid reabsorption by the proximal tubule is driven by P-glycoprotein is highly expressed in brush border membranes and
high oncotic pressure and low hydrostatic pressure within the peritu- secretes several medically important drugs, including cyclosporine,
bular capillaries. Cellular transport of most solutes by the proximal digoxin, tacrolimus, and various cancer chemotherapeutic agents. Cer-
tubule is coupled to the Na+ concentration gradient established by the tain drugs like cimetidine and trimethoprim compete with endogenous
activity of a basolateral Na+/K+-ATPase (Fig. 303-3A). This active trans- compounds for transport by the organic cation pathways. Although
port mechanism maintains a steep Na+ gradient by keeping intracellu- these drugs elevate serum creatinine levels, there is no actual change
lar Na+ concentrations low. Solute reabsorption from the tubular lumen in GFR in this setting.
is coupled to the Na+ gradient by Na+-dependent transporters such as Calcium and phosphorus homeostasis depends upon normal func-
Na+-glucose and Na+-phosphate cotransporters present in apical mem- tioning of the proximal tubule. Approximately 60–70% of filtered
branes. In addition to the paracellular route, water reabsorption also calcium and ~85% of filtered phosphorus (in the form of inorganic
occurs through the cellular pathway enabled by constitutively active phosphate) are reabsorbed by the proximal tubule. Whereas calcium

water channels (aquaporin-1) present on both apical and basolateral reabsorption is mostly by passive diffusion through the paracellular
membranes. route, phosphate reabsorption is mediated by sodium-coupled cotrans-
Proximal tubular cells reclaim nearly all filtered bicarbonate by a port. In addition to direct reabsorption, the proximal tubule contributes
mechanism dependent on carbonic anhydrases. Filtered bicarbonate to systemic mineral balance by participating in specific endocrine
is first titrated by protons delivered to the lumen mainly by Na+/H+ pathways. Circulating 25-hydroxy vitamin D (calcidiol) is bioactivated
exchange. The resulting carbonic acid (H2CO3) is metabolized by brush by proximal tubular 1α-hydroxylase to produce 1,25-di-hydroxy vita-
border carbonic anhydrase to water and carbon dioxide. Dissolved min D (calcitriol), the most active form of the hormone, that acts on
carbon dioxide then diffuses into the cell, where it is enzymatically the small intestine to promote calcium absorption. Phosphate balance
hydrated by cytoplasmic carbonic anhydrase to re-form carbonic acid. is affected by circulating fibroblast growth hormone 23 (FGF23), a
Finally, intracellular carbonic acid dissociates into free protons and bone-derived hormone that interacts with its receptor (FGFR1) and
bicarbonate anions, and bicarbonate exits the cell through a basolateral co-receptor (Klotho) on proximal tubular cells to suppress sodium-
Na+/HCO3− cotransporter. This process is saturable, which can result phosphate cotransport and promote renal phosphate excretion. PTH
in urinary bicarbonate excretion when plasma levels exceed the physi- stimulates proximal tubular 1α-hydroxylation of vitamin D while it
ologically normal range (24–26 meq/L). Carbonic anhydrase inhibitors suppresses sodium-phosphate cotransport. Derangements in PTH and
such as acetazolamide, a class of weak diuretic agents, block proximal FGF23 account for abnormal calcium and phosphate balance in chronic
tubule bicarbonate reabsorption and are useful for alkalinizing the kidney disease.
urine. The proximal tubule, through distinct classes of Na+-dependent and
The proximal tubule contributes to acid secretion by two mecha- Na+-independent transport systems, reabsorbs amino acids efficiently.
nisms involving the titration of the urinary buffers ammonia (NH3) These transporters are specific for different groups of amino acids. For
and phosphate. Renal NH3 is produced by glutamine metabolism in the example, cystine, lysine, arginine, and ornithine are transported by a
proximal tubule. Subsequent diffusion of NH3 out of the proximal tubu- system comprising two proteins encoded by the SLC3A1 and SLC7A9
lar cell enables trapping of H+, which is secreted by Na+/H+ exchange, genes. Mutations in either SLC3A1 or SLC7A9 impair reabsorption of
in the lumen as ammonium ion (NH4+). Cellular K+ levels inversely these amino acids and cause the disease cystinuria. Peptide hormones,
modulate proximal tubular ammoniagenesis, and in the setting of high such as insulin and growth hormone, β2-microglobulin, albumin, and
serum K+ from hypoaldosteronism, reduced ammoniagenesis pro- other small proteins, are taken up by the proximal tubule through
motes type IV renal tubular acidosis. Filtered hydrogen phosphate ion a process of absorptive endocytosis and are degraded in acidified
(HPO42−) is also titrated in the proximal tubule by secreted H+ to form endocytic lysosomes. Acidification of these vesicles depends on a vac-
H2PO4−, and this reaction constitutes a major component of the urinary uolar H+-ATPase and Cl− channel. Impaired acidification of endocytic
buffer referred to as titratable acid. Most filtered phosphate ion is reab- vesicles because of mutations in a Cl− channel gene (CLCN5) causes
sorbed by the proximal tubule through a sodium-coupled cotransport low-molecular-weight proteinuria in Dent disease.
process that is regulated by parathyroid hormone (PTH).
Chloride is poorly reabsorbed throughout the first segment of the LOOP OF HENLE
proximal tubule, and a rise in Cl− concentration counterbalances the The loop of Henle consists of three major segments: descending thin
removal of bicarbonate anion from tubular fluid. In later proximal limb, ascending thin limb, and ascending thick limb. These divisions
tubular segments, cellular Cl− reabsorption is initiated by apical are based on cellular morphology and anatomic location, but also
exchange of cellular formate for higher luminal concentrations of Cl−. correlate with specialization of function. Approximately 15–25% of
Once in the lumen, formate anions are titrated by H+ (provided by filtered NaCl is reabsorbed in the loop of Henle, mainly by the thick
Na+/H+ exchange) to generate neutral formic acid, which can diffuse ascending limb. The loop of Henle has an important role in urinary
passively across the apical membrane back into the cell where it dis- concentration by contributing to the generation of a hypertonic med-
sociates a proton and is recycled. Basolateral Cl− exit is mediated by a ullary interstitium in a process called countercurrent multiplication. The
K+/Cl− cotransporter. loop of Henle is the site of action for the most potent class of diuretic
Reabsorption of glucose is nearly complete by the end of the prox- agents (loop diuretics) and also contributes to reabsorption of calcium
imal tubule. Cellular transport of glucose is mediated by apical Na+- and magnesium ions.
glucose cotransport coupled with basolateral, facilitated diffusion by The descending thin limb is highly water permeable owing to dense
a glucose transporter. This process is also saturable, leading to glyco- expression of constitutively active aquaporin-1 water channels. By
suria when plasma levels exceed 180–200 mg/dL, as seen in untreated contrast, water permeability is negligible in the ascending limb. In the
diabetes mellitus. thick ascending limb, there is a high level of secondary active NaCl

2096 transport enabled by the Na+/K+/2Cl− cotransporter on the apical collecting duct, a primary route for K+ secretion. Mutations in TRPM6
membrane in series with basolateral Cl channels and Na /K -ATPase
− + +
encoding Mg2+ permeable ion channels also cause familial hypomagne-
(Fig. 303-3B). The Na+/K+/2Cl− cotransporter is the primary target semia with hypocalcemia. A molecular complex of TRPM6 and TRPM7
for loop diuretics. Tubular fluid K+ is the limiting substrate for this proteins is critical for Mg2+ reabsorption in the distal convoluted tubule.
cotransporter (tubular concentration of K+ is similar to plasma, about
4 meq/L), but transporter activity is maintained by K+ recycling COLLECTING DUCT
through an apical potassium channel. The cotransporter also enables The collecting duct modulates the final composition of urine. The
reabsorption of NH4+ in lieu of K+, and this leads to accumulation of two major divisions, the cortical collecting duct and inner medullary
both NH4+ and NH3 in the medullary interstitium. An inherited disor- collecting duct, contribute to reabsorbing ~4–5% of filtered Na+ and
der of the thick ascending limb, Bartter’s syndrome, also results in a are important for hormonal regulation of salt and water balance. Cells
salt-wasting renal disease associated with hypokalemia and metabolic in both segments of the collecting duct express vasopressin-regulated
alkalosis. Loss-of-function mutations in one of five distinct genes water channels (aquaporin-2 on the apical membrane, aquaporin-3
encoding components of the Na+/K+/2Cl− cotransporter (NKCC2), api- and -4 on the basolateral membrane). The antidiuretic hormone vaso-
cal K+ channel (KCNJ1), basolateral Cl− channel (CLCNKB, BSND), or pressin binds to the V2 receptor on the basolateral membrane and
calcium-sensing receptor (CASR) can cause Bartter’s syndrome. triggers an intracellular signaling cascade through G-protein-mediated
Potassium recycling also contributes to a positive electrostatic activation of adenylyl cyclase, resulting in an increase in the cellular
charge in the lumen relative to the interstitium that promotes divalent levels of cyclic AMP. This signaling cascade stimulates the insertion
cation (Mg2+ and Ca2+) reabsorption through a paracellular pathway. A of water channels into the apical membrane of collecting duct cells to
Ca2+-sensing, G-protein-coupled receptor (CaSR) on basolateral mem- promote increased water permeability. This increase in permeability
branes regulates NaCl reabsorption in the thick ascending limb through enables water reabsorption and production of concentrated urine. In
dual signaling mechanisms using either cyclic AMP or eicosanoids. the absence of vasopressin, collecting duct cells are water impermeable,
This receptor enables a steep relationship between plasma Ca2+ levels and urine remains dilute.
and renal Ca2+ excretion. Loss-of-function mutations in CaSR cause The cortical collecting duct contains high-resistance epithelia with
two cell types. Principal cells are the main water, Na+-reabsorbing,
PART 9
familial hypercalcemic hypocalciuria because of a blunted response of

the thick ascending limb to extracellular Ca2+. Mutations in CLDN16 and K+-secreting cells, and the site of action of aldosterone, K+-sparing
encoding paracellin-1, a transmembrane protein located within the diuretics, and mineralocorticoid receptor antagonists such as spirono-
tight junction complex, leads to familial hypomagnesemia with hyper- lactone and eplerenone. The other cells are type A and B intercalated
calciuria and nephrocalcinosis, suggesting that the ion conductance of cells. Type A intercalated cells mediate acid secretion and bicarbonate
the paracellular pathway in the thick limb is regulated. reabsorption also under the influence of aldosterone. Type B interca-
The loop of Henle contributes to urine-concentrating ability by lated cells mediate bicarbonate secretion and acid reabsorption.
establishing a hypertonic medullary interstitium that promotes water Virtually all transport is mediated through the cellular pathway for
reabsorption by the downstream inner medullary collecting duct. both principal cells and intercalated cells. In principal cells, passive
Countercurrent multiplication produces a hypertonic medullary intersti- apical Na+ entry occurs through an amiloride-sensitive, epithelial Na+
tium using two countercurrent systems: the loop of Henle (opposing channel (ENaC) with basolateral exit mediated by the Na+/K+-ATPase
descending and ascending limbs) and the vasa recta (medullary per- (Fig. 303-3D). This Na+ reabsorptive process is tightly regulated by
itubular capillaries enveloping the loop). The countercurrent flow in aldosterone and is physiologically activated by a variety of proteo-
these two systems helps maintain the hypertonic environment of the lytic enzymes that cleave extracellular domains of ENaC; plasmin in
inner medulla, but NaCl reabsorption by the thick ascending limb is the the tubular fluid of nephrotic patients, for example, activates ENaC,
primary initiating event. Reabsorption of NaCl without water dilutes leading to sodium retention. Aldosterone enters the cell across the
the tubular fluid and adds new osmoles to medullary interstitial fluid. basolateral membrane, binds to a cytoplasmic mineralocorticoid recep-
Because the descending thin limb is highly water permeable, osmotic tor, and then translocates into the nucleus, where it modulates gene
equilibrium occurs between the descending limb tubular fluid and the transcription, resulting in increased Na+ reabsorption and K+ secretion.
interstitial space, leading to progressive solute trapping in the inner Activating mutations in ENaC increase Na+ reclamation and produce
medulla. Maximum medullary interstitial osmolality also requires hypokalemia, hypertension, and metabolic alkalosis (Liddle’s syn-
partial recycling of urea from the collecting duct. drome). The potassium-sparing diuretics amiloride and triamterene
block ENaC, causing reduced Na+ reabsorption.
Principal cells secrete K+ through an apical membrane potassium
DISTAL CONVOLUTED TUBULE channel. Several forces govern the secretion of K+. Most importantly,
The distal convoluted tubule reabsorbs ~5% of the filtered NaCl. This the high intracellular K+ concentration generated by Na+/K+-ATPase
segment is composed of a tight epithelium with little water permeabil- creates a favorable concentration gradient for K+ secretion into tubular
ity. The major NaCl-transporting pathway uses an apical membrane, fluid. With reabsorption of Na+ without an accompanying anion, the
electroneutral thiazide-sensitive Na+/Cl− cotransporter in tandem tubular lumen becomes negative relative to the cell interior, creating a
with basolateral Na+/K+-ATPase and Cl− channels (Fig. 303-3C). Apical favorable electrical gradient for secretion of potassium. When Na+ reab-
Ca2+-selective channels (TRPV5) and basolateral Na+/Ca2+ exchange sorption is blocked, the electrical component of the driving force for
mediate calcium reabsorption in the distal convoluted tubule. Ca2+ K+ secretion is blunted, and this explains lack of excess urinary K+ loss
reabsorption is inversely related to Na+ reabsorption and is stimulated during treatment with potassium-sparing diuretics or mineralocorti-
by PTH. Blocking apical Na+/Cl− cotransport will reduce intracellular coid receptor antagonists. K+ secretion is also promoted by aldosterone
Na+, favoring increased basolateral Na+/Ca2+ exchange and passive actions that increase regional Na+ transport, which favor more lumen
apical Ca2+ entry. Loss-of-function mutations of SLC12A3 encoding the electronegativity, and by increasing the number and activity of potas-
apical Na+/Cl− cotransporter cause Gitelman syndrome, a salt-wasting sium channels. Fast tubular fluid flow rates that occur during volume
disorder associated with hypokalemic alkalosis and hypocalciuria. expansion or diuretics acting “upstream” of the cortical collecting duct
Mutations in genes encoding WNK kinases, WNK-1 and WNK-4, cause also increase K+ secretion, as does the presence of relatively nonreab-
pseudohypoaldosteronism type II (Gordon syndrome) characterized sorbable anions (including bicarbonate and semisynthetic penicillins)
by familial hypertension with hyperkalemia. WNK kinases influence that contribute to the lumen-negative potential. Off-target effects of cer-
the activity of several tubular ion transporters. Mutations in this disor- tain antibiotics, such as trimethoprim and pentamidine, block ENaCs
der lead to overactivity of the apical Na+/Cl− cotransporter in the distal and predispose to hyperkalemia, especially when renal K+ handling
convoluted tubule as the primary stimulus for increased salt reabsorp- is impaired for other reasons. Principal cells, as described below, also
tion, extracellular volume expansion, and hypertension. Hyperkalemia participate in water reabsorption by increased water permeability in
may be caused by diminished activity of apical K+ channels in the response to vasopressin.

Intercalated cells do not participate in Na+ reabsorption but, instead, Any reduction in total body water, which raises the Na+ concentration, 2097
mediate acid-base secretion. These cells perform two types of transport: triggers a brisk sense of thirst and conservation of water by decreasing
active H+ transport mediated by H+-ATPase (proton pump), and Cl−/ renal water excretion mediated by release of vasopressin from the
HCO3− exchange. Intercalated cells arrange the two transport mecha- posterior pituitary. Conversely, a decrease in plasma Na+ concentra-
nisms on opposite membranes to enable either acid or base secretion. tion triggers an increase in renal water excretion by suppressing the
Type A intercalated cells have an apical proton pump that mediates secretion of vasopressin. Whereas all cells expressing mechanosensitive
acid secretion and a basolateral Cl−/HCO3− anion exchanger for bicar- TRPV1, 2, or 4 channels, among potentially other sensors, respond to
bonate reabsorption (Fig. 303-3E). Aldosterone increases the number changes in tonicity by altering their volume and Ca2+ concentration,
of H+-ATPase pumps, sometimes contributing to the development of only TRPV+ neuronal cells connected to the organum vasculosum of
metabolic alkalosis. Secreted H+ is buffered by NH3 that has diffused the lamina terminalis are osmoreceptive. Only these cells, because of
into the collecting duct lumen from the surrounding interstitium. By their neural connectivity and adjacency to a minimal blood-brain bar-
contrast, type B intercalated cells have the Cl−/HCO3− exchanger on rier, modulate the downstream release of vasopressin by the posterior
the apical membrane to mediate bicarbonate secretion while the proton lobe of the pituitary gland. Secretion is stimulated primarily by chang-
pump resides on the basolateral membrane to enable acid reabsorption. ing tonicity and secondarily by other nonosmotic signals such as vari-
Under conditions of acidemia, the kidney preferentially uses type A able blood volume, stress, pain, nausea, and some drugs. The release
intercalated cells to secrete the excess H+ and generate more HCO3−. of vasopressin by the posterior pituitary increases linearly as plasma
The opposite is true in states of bicarbonate excess with alkalemia tonicity rises above normal, although this varies, depending on the per-
where the type B intercalated cells predominate. An extracellular pro- ception of extracellular volume (one form of cross-talk between mech-
tein called hensin mediates this adaptation. anisms that adjudicate blood volume and osmoregulation). Changing
Inner medullary collecting duct cells share many similarities with the intake or excretion of water provides a means for adjusting plasma
principal cells of the cortical collecting duct. They have apical Na+ tonicity; thus, osmoregulation governs water balance.
and K+ channels that mediate Na+ reabsorption and K+ secretion, The kidneys play a vital role in maintaining water balance through

respectively (Fig. 303-3F). Sodium reabsorption by inner medullary the regulation of renal water excretion. The ability to concentrate urine
collecting duct cells is also inhibited by the natriuretic peptides called to an osmolality exceeding that of plasma enables water conservation,
atrial natriuretic peptide or renal natriuretic peptide (urodilatin); the same whereas the ability to produce urine more dilute than plasma promotes
gene encodes both peptides but uses different posttranslational pro- excretion of excess water. For water to enter or exit a cell, the cell mem-
cessing of a common preprohormone to generate different proteins. brane must express aquaporins. In the kidney, aquaporin-1 is consti-
Atrial natriuretic peptides are secreted by atrial myocytes in response tutively active in all water-permeable segments (e.g., proximal tubule,
to volume expansion, whereas urodilatin is secreted by renal tubular descending thin limb of the loop of Henle), whereas aquaporin-2, -3,
epithelia. Natriuretic peptides interact with either apical (urodilatin) and -4 in the collecting duct promote vasopressin-regulated water per-
or basolateral (atrial natriuretic peptides) receptors on inner medullary meability. Net water reabsorption is ultimately driven by the osmotic
collecting duct cells to stimulate guanylyl cyclase and increase levels gradient between dilute tubular fluid and a hypertonic medullary
of cytoplasmic cGMP. This effect in turn reduces the activity of the interstitium.
apical Na+ channel in these cells and attenuates net Na+ reabsorption,
producing natriuresis. ■■SODIUM BALANCE
The inner medullary collecting duct transports urea out of the The perception of extracellular blood volume is determined, in part,
lumen, returning urea to the interstitium, where it contributes to the by the integration of arterial tone, cardiac stroke volume, heart rate,
hypertonicity of the medullary interstitium. Urea is recycled by diffus- and the water and solute content of extracellular fluid. Na+ and
ing from the interstitium into the descending and ascending limbs of accompanying anions are the most abundant extracellular effective
the loop of Henle. osmoles and together support a blood volume around which pressure
is generated. Under normal conditions, this volume is regulated by
sodium balance (Fig. 303-4B), and the balance between daily Na+ intake
HORMONAL REGULATION OF SODIUM AND and excretion is under the influence of baroreceptors in regional blood
WATER BALANCE vessels and vascular hormone sensors modulated by atrial natriuretic
The balance of solute and water in the body is determined by the peptides, the renin-angiotensin-aldosterone system, Ca2+ signaling,
amounts ingested, distributed to various fluid compartments, and adenosine, vasopressin, and the neural adrenergic axis. If Na+ intake
excreted by skin, bowel, and kidneys. Tonicity, the osmolar state exceeds Na+ excretion (positive Na+ balance), then an increase in blood
determining the volume behavior of cells in a solution, is regulated by volume will trigger a proportional increase in urinary Na+ excretion.
water balance (Fig. 303-4A), and extracellular blood volume is regulated Conversely, when Na+ intake is less than urinary excretion (negative
by Na+ balance (Fig. 303-4B). The kidney is a critical modulator of both Na+ balance), blood volume will decrease and trigger enhanced renal
physiologic processes. Na+ reabsorption, leading to decreased urinary Na+ excretion.
The renin-angiotensin-aldosterone system is the best-understood
■■WATER BALANCE hormonal system modulating renal Na+ excretion. Renin is synthesized
Tonicity depends on the variable concentration of effective osmoles and secreted by granular cells in the wall of the afferent arteriole. Its
inside and outside the cell causing water to move in either direction secretion is controlled by several factors, including β1-adrenergic stim-
across its membrane. Classic effective osmoles, like Na+, K+, and their ulation to the afferent arteriole, input from the macula densa, and pros-
anions, are solutes trapped on either side of a cell membrane, where taglandins. Renin and ACE activity eventually produce angiotensin II
they collectively partition and obligate water to move and find equilib- that directly and indirectly promotes renal Na+ and water reabsorption.
rium in proportion to retained solute; Na+/K+-ATPase keeps most K+ Stimulation of proximal tubular Na+/H+ exchange by angiotensin II
inside cells and most Na+ outside. Normal tonicity (~280 mosmol/L) is directly increases Na+ reabsorption. Angiotensin II also promotes Na+
rigorously defended by osmoregulatory mechanisms that control water reabsorption along the collecting duct by stimulating aldosterone
balance to protect tissues from inadvertent dehydration (cell shrinkage) secretion by the adrenal cortex. Constriction of the efferent glomerular
or water intoxication (cell swelling), both of which are deleterious to cell arteriole by angiotensin II indirectly increases the filtration fraction and
function (Fig. 303-4A). raises peritubular capillary oncotic pressure to promote tubular Na+
The mechanisms that control osmoregulation are distinct from reabsorption. Finally, angiotensin II inhibits renin secretion through a
those governing extracellular volume, although there is some shared negative feedback loop. Alternative metabolism of angiotensin by ACE2
physiology in both processes. While cellular concentrations of K+ generates the vasodilatory peptide angiotensin 1-7 that acts through
have a determinant role in any level of tonicity, the routine surrogate Mas receptors to counterbalance several actions of angiotensin II on
marker for assessing clinical tonicity is the concentration of serum Na+. blood pressure and renal function (Fig. 303-2C).

2098 Cell volume Water intake Determinants Clinical result
Cell Thirst
membrane Osmoreception
Custom/habit Hyponatremia
Hypotonicity
Effective Osmols = TB Na+ + TB K+ + TB H2O Water intoxication
pNa+ = Tonicity = Net water balance
TB H2O TB H2O – TB H2O Hypernatremia
Hypertonicity
Dehydration
Renal regulation
ADH levels
V2-receptor/AP2 water flow
Medullary gradient
A Free water clearance
Extracellular blood volume and pressure Na+ intake Determinants Clinical result
Taste
Baroreception
Custom/habit
Edema
+ TB Na+
PART 9
(TB Na+ + TB H2O + vascular tone + heart rate + stroke volume) Net Na+ balance
– TB Na+
Volume depletion
Renal regulation
Na+ reabsorption
Tubuloglomerular feedback
Macula densa
Atrial natriuretic peptides
B Fractional Na+ excretion
FIGURE 303-4 Determinants of sodium and water balance. A. Plasma Na+ concentration is a surrogate marker for plasma tonicity, the volume behavior of cells in a
solution. Tonicity is determined by the number of effective osmoles in the body divided by the total body H2O (TB H2O), which translates simply into the total body Na
(TB Na+) and anions outside the cell separated from the total body K (TB K+) inside the cell by the cell membrane. Net water balance is determined by the integrated
functions of thirst, osmoreception, Na reabsorption, vasopressin release, and the strength of the medullary gradient in the kidney, keeping tonicity within a narrow
range of osmolality around 280 mosmol/L. When water metabolism is disturbed and total body water increases, hyponatremia, hypotonicity, and water intoxication
occur; when total body water decreases, hypernatremia, hypertonicity, and dehydration occur. B. Extracellular blood volume and pressure are an integrated function of
total body Na+ (TB Na+), total body H2O (TB H2O), vascular tone, heart rate, and stroke volume that modulates volume and pressure in the vascular tree of the body.
This extracellular blood volume is determined by net Na balance under the control of taste, baroreception, habit, Na+ reabsorption, macula densa/tubuloglomerular
feedback, and natriuretic peptides. When Na+ metabolism is disturbed and total body Na+ increases, edema occurs; when total body Na+ is decreased, volume
depletion occurs. ADH, antidiuretic hormone; AQP2, aquaporin-2.
Aldosterone is synthesized and secreted by granulosa cells in the Carlstrom M et al: Renal autoregulation in health and disease. Physiol
adrenal cortex. It binds to cytoplasmic mineralocorticoid receptors Rev 95:405, 2015.
in the collecting duct principal cells that increase activity of ENaC, Combes AN et al: Cell-cell interactions driving kidney morphogenesis.
apical membrane K+ channel, and basolateral Na+/K+-ATPase. These Curr Top Dev Biol 112:467, 2015.
effects are mediated in part by aldosterone-stimulated transcription Curthoys NP, Moe OW: Proximal tubule function and response to
of the gene encoding serum/glucocorticoid-induced kinase 1 (SGK1). acidosis. Clin J Am Soc Nephrol 9:1627, 2014.
The activity of ENaC is increased by SGK1-mediated phosphorylation Hadchouel J et al: Regulation of renal electrolyte transport by WNK
of Nedd4-2, a protein that promotes recycling of the Na+ channel and SPAK-OSR1 kinases. Annu Rev Physiol 78:367, 2016.
from the plasma membrane. Phosphorylated Nedd4-2 has impaired Jung HJ, Kwon TH: Molecular mechanisms regulating aquaporin-2 in
interactions with ENaC, leading to increased channel density at the kidney collecting duct. Am J Physiol Renal Physiol 331:F1318, 2016.
plasma membrane and increased capacity for Na+ reabsorption by the Mount DB: Thick ascending limb of the loop of Henle. Clin J Am Soc
collecting duct. Nephrol 9:1974, 2014.
Chronic exposure to aldosterone causes a decrease in urinary Na+ Nigam SK et al: Handling of drugs, metabolites, and uremic toxins by
excretion lasting only a few days, after which Na+ excretion returns kidney proximal tubule drug transporters. Clin J Am Soc Nephrol
to previous levels. This phenomenon, called aldosterone escape, is 10:2039, 2015.
explained by decreased proximal tubular Na+ reabsorption following Palmer LG, Schnermann J: Integrated control of Na transport along
blood volume expansion. Excess Na+ that is not reabsorbed by the the nephron. Clin J Am Soc Nephrol 10:676, 2015.
proximal tubule overwhelms the reabsorptive capacity of more distal Pearce D et al: Collecting duct principal cell transport processes and
nephron segments. This escape may be facilitated by atrial natriuretic their regulation. Clin J Am Soc Nephrol 10:135, 2015.
peptides that lose their effectiveness in the clinical settings of heart fail- Terker AS, Ellison DH: Renal mineralocorticoid receptor and electro-
ure, nephrotic syndrome, and cirrhosis, leading to severe Na+ retention lyte homeostasis. Am J Physiol Regul Integr Comp Physiol 309:R1068,
and volume overload. 2015.
Bhave G, Neilson EG: Body fluid dynamics: Back to the future. J Am
Soc Nephrol 22:2166, 2011.

■■AKI IN THE DEVELOPING WORLD 2099
304 Acute Kidney Injury

Sushrut S. Waikar, Joseph V. Bonventre
AKI is also a major medical complication in the developing
world, where the epidemiology differs from that in developed
countries due to differences in demographics, economics, envi-
ronmental factors, and comorbid disease burden. While certain features
of AKI are common in the developed and developing countries—
particularly since urban centers of some developing countries increas-
Acute kidney injury (AKI) is defined by the impairment of kidney ingly resemble those in the developed world—many etiologies for
filtration and excretory function over days to weeks, resulting in the AKI are region-specific such as envenomations from snakes, spiders,
retention of nitrogenous and other waste products normally cleared caterpillars, and bees; infectious causes such as malaria and lepto-
by the kidneys. AKI is not a single disease but, rather, a designation spirosis; and crush injuries and resultant rhabdomyolysis from
for a heterogeneous group of conditions that share common diagnostic earthquakes.
features: specifically, an increase in serum creatinine (SCr) concentration
often associated with a reduction in urine volume. It is important to rec-
ognize that AKI is a clinical diagnosis and not a structural one. A patient ETIOLOGY AND PATHOPHYSIOLOGY
may have AKI with or without injury to the kidney parenchyma. AKI The causes of AKI have traditionally been divided into three broad
can range in severity from asymptomatic and transient changes in labo- categories: prerenal azotemia, intrinsic renal parenchymal disease, and
ratory parameters of glomerular filtration rate (GFR), to overwhelming postrenal obstruction (Fig. 304-1).
and rapidly fatal derangements in effective circulating volume regula- ■■PRERENAL AZOTEMIA
tion and electrolyte and acid-base composition of the plasma. Prerenal azotemia (from “azo,” meaning nitrogen, and “-emia,” meaning
in the blood) is the most common form of AKI. It is the designation for
EPIDEMIOLOGY a rise in SCr or BUN concentration due to inadequate renal plasma flow
CHAPTER 304 Acute Kidney Injury

AKI complicates 5–7% of acute care hospital admissions and up to and intraglomerular hydrostatic pressure to support normal glomer-
30% of admissions to the intensive care unit. The incidence of AKI has ular filtration. The most common clinical conditions associated with
grown by more than fourfold in the United States since 1988 and is esti- prerenal azotemia are hypovolemia, decreased cardiac output, and
mated to have a yearly incidence of 500 per 100,000 population, higher medications that interfere with renal autoregulatory responses such
than the yearly incidence of stroke. AKI is associated with a markedly as nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors of
increased risk of death in hospitalized individuals, particularly in those angiotensin II (Fig. 304-2). Prerenal azotemia may coexist with other
admitted to the ICU where in-hospital mortality rates may exceed 50%. forms of intrinsic AKI associated with processes acting directly on
AKI increases the risk for the development or worsening of chronic the renal parenchyma. Prolonged periods of prerenal azotemia may
kidney disease (CKD). Patients who survive and recover from an lead to ischemic injury, often termed acute tubular necrosis (ATN). By
episode of severe AKI requiring dialysis are at increased risk for the definition, prerenal azotemia involves no parenchymal damage to the
later development of dialysis-requiring end-stage kidney disease. AKI kidney and is rapidly reversible once parenchymal blood flow and
may be community-acquired or hospital-acquired. Common causes of intraglomerular hemodynamics are restored.
community-acquired AKI include volume depletion, heart failure, Normal GFR is maintained in part by renal blood flow and the rela-
adverse effects of medications, obstruction of the urinary tract, or tive resistances of the afferent and efferent renal arterioles, which deter-
malignancy. The most common clinical settings for hospital-acquired mine the glomerular plasma flow rate and the transcapillary hydraulic
AKI are sepsis, major surgical procedures, critical illness involving pressure gradient that drive glomerular ultrafiltration. Mild degrees
heart or liver failure, and nephrotoxic medication administration. of hypovolemia and reductions in cardiac output elicit compensatory
Acute kidney injury
Prerenal Intrinsic Postrenal
Hypovolemia Glomerular Tubules and Vascular Bladder outlet obstruction

Decreased cardiac output • Acute interstitium • Vasculitis
Decreased effective circulating glomerulo- • Malignant Bilateral pelvoureteral
volume nephritis hypertension obstruction (or unilateral
• Congestive heart failure • TTP-HUS obstruction of a solitary
• Liver failure functioning kidney)
Impaired renal autoregulation
• NSAIDs
Sepsis/ Nephrotoxins
• ACE-I/ARB Ischemia
Infection Exogenous: Iodinated
• Cyclosporine
contrast, aminoglycosides,
cisplatin, amphotericin B,
PPIs, NSAIDs
Endogenous: Hemolysis,
rhabdomyolysis,
myeloma, intratubular
crystals
FIGURE 304-1 Classification of the major causes of acute kidney injury. ACE-I, angiotensin-converting enzyme inhibitor-I; ARB, angiotensin receptor blocker; NSAIDs,
nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitors; TTP-HUS, thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome.

2100 Normal perfusion pressure Decreased perfusion pressure
Arteriolar resistances
Afferent
arteriole
Efferent Increased
arteriole vasodilatory Increased
prostaglandins angiotensin II
Glomerulus
Tubule
A Normal GFR B Normal GFR maintained

PART 9
Decreased perfusion pressure in the presence of NSAIDs Decreased perfusion pressure in the presence of ACE-I or ARB
Decreased Slightly increased

vasodilatory Increased vasodilatory Decreased
prostaglandins angiotensin II prostaglandins angiotensin II
C Low GFR D Low GFR

FIGURE 304-2 Intrarenal mechanisms for autoregulation of the glomerular filtration rate (GFR) under decreased perfusion pressure and reduction of the GFR by
drugs. A. Normal conditions and a normal GFR. B. Reduced perfusion pressure within the autoregulatory range. Normal glomerular capillary pressure is maintained
by afferent vasodilatation and efferent vasoconstriction. C. Reduced perfusion pressure with a nonsteroidal anti-inflammatory drug (NSAID). Loss of vasodilatory
prostaglandins increases afferent resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. D. Reduced
perfusion pressure with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). Loss of angiotensin II action reduces efferent
resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. (From JG Abuelo: N Engl J Med 357:797-805, 2007;
with permission.)
renal physiologic changes. Because renal blood flow accounts for and possibly nitric oxide (NO) also increase in response to low renal
20% of the cardiac output, renal vasoconstriction and salt and water perfusion pressure. Autoregulation is also accomplished by tubuloglo-
reabsorption occur as homeostatic responses to decreased effective cir- merular feedback, in which decreases in solute delivery to the macula
culating volume or cardiac output in order to maintain blood pressure densa (specialized cells within the distal tubule) elicit dilation of the
and increase intravascular volume to sustain perfusion to the cerebral juxtaposed afferent arteriole in order to maintain glomerular perfusion,
and coronary vessels. Mediators of this response include angiotensin II, a mechanism mediated, in part, by NO. There is a limit, however, to the
norepinephrine, and vasopressin (also termed antidiuretic hormone). ability of these counterregulatory mechanisms to maintain GFR in the
Glomerular filtration can be maintained despite reduced renal blood face of systemic hypotension. Even in healthy adults, renal autoregula-
flow by angiotensin II–mediated renal efferent vasoconstriction, which tion usually fails once the systolic blood pressure falls below 80 mmHg.
maintains glomerular capillary hydrostatic pressure closer to normal A number of factors determine the robustness of the autoregu-
and thereby prevents marked reductions in GFR if renal blood flow latory response and the risk of prerenal azotemia. Atherosclerosis,
reduction is not excessive. long-standing hypertension, and older age can lead to hyalinosis and
In addition, a myogenic reflex within the afferent arteriole leads myointimal hyperplasia, causing structural narrowing of the intrare-
to dilation in the setting of low perfusion pressure, thereby main- nal arterioles and impaired capacity for renal afferent vasodilation.
taining glomerular perfusion. Intrarenal biosynthesis of vasodilator In CKD, renal afferent vasodilation may be operating at maximal
prostaglandins (prostacyclin, prostaglandin E2), kallikrein and kinins, capacity in order to maximize GFR in response to reduced functional

renal mass. Drugs can affect the compensatory changes evoked to main- syndrome is a less severe form characterized mainly by refractory 2101
tain GFR. Nonsteroidal anti-inflammatory agents (NSAIDs) inhibit ascites. The hepatorenal syndrome, defined as it is above, is difficult
renal prostaglandin production, limiting renal afferent vasodilation. to distinguish from prerenal azotemia. An older way of characterizing
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin hepatorenal was prerenal azotemia that would not improve, often
receptor blockers (ARBs) limit renal efferent vasoconstriction; this leading to intrinsic renal AKI, unless a definitive procedure to improve
effect is particularly pronounced in patients with bilateral renal artery hemodynamics, such as porto-systemic shunt placement or liver
stenosis or unilateral renal artery stenosis (in the case of a solitary transplant, was performed. We still find this latter construct of use.
functioning kidney) because, as indicated above, efferent arteriolar
vasoconstriction is needed to maintain GFR due to low renal perfusion. ■■INTRINSIC AKI
The combined use of NSAIDs with ACE inhibitors or ARBs poses a The most common causes of intrinsic AKI are sepsis, ischemia, and
particularly high risk for developing prerenal azotemia. nephrotoxins, both endogenous and exogenous (Fig. 304-3). In many
Many individuals with advanced liver disease exhibit a hemo- cases, prerenal azotemia advances to tubular injury. Although clas-
dynamic profile that resembles prerenal azotemia in the setting of sically termed “acute tubular necrosis,” human biopsy confirmation
total-body volume overload. Systemic vascular resistance is markedly of tubular necrosis is, in general, often lacking in cases of sepsis and
reduced due to primary arterial vasodilation in the splanchnic circu- ischemia; indeed, processes such as inflammation, apoptosis, and
lation, resulting ultimately in activation of vasoconstrictor responses altered regional perfusion may be important contributors pathophys-
similar to those seen in hypovolemia. AKI is a common complication iologically. ATN is also often diagnosed clinically without biopsy con-
in this setting, and it can be triggered by volume depletion and sponta- firmation in settings such as sepsis with multiple alternate potential
neous bacterial peritonitis. A particularly poor prognosis is seen in the diagnoses, including drug-induced interstitial nephritis and immune
case of type 1 hepatorenal syndrome, in which AKI, defined as >two- complex glomerulonephritis. These and other causes of intrinsic AKI
fold increase in SCr to >2.5 mg/dL, within 2 weeks without an alter- are considered to be less common and can be conceptualized anatom-
nate cause (e.g., shock and nephrotoxic drugs), persists despite volume ically according to the major site of renal parenchymal damage: glom-

administration and withholding of diuretics. Type 2 hepatorenal eruli, tubulointerstitium, and vessels.
Intrinsic Renal Failure

Tubules Intratubular
• Toxic ATN • Endogenous
Small vessels • Endogenous • Myeloma proteins
• Glomerulonephritis • Atheroemboli (rhabdomyolysis, • Uric acid (tumor
Cortical Proximal
• Vasculitis • Malignant HTN glomerulus convoluted hemolysis) lysis syndrome)
• TTP/HUS • Calcineurin tubule • Exogenous (contrast, • Cellular debris
• DIC inhibitors cisplatin, gentamicin) • Exogenous
• Sepsis • Ischemic ATN • Acyclovir,
• Sepsis methotrexate
Juxtamedullary
glomerulus
Distal
Cortex
convoluted Distal
Proximal tubule convoluted
convoluted tubule
tubule
Thick ascending
limb
Pars recta
Outer
Interstitium
Pars recta • Allergic (PCN, PPIs,
Loop of Large vessels NSAIDs, rifampin, etc.)
Thick Henle • Renal artery embolus, • Infection (severe
ascending dissection, vasculitis pyelonephritis,
limb • Renal vein thrombosis Legionella, sepsis)
• Abdominal compartment • Infiltration
syndrome (lymphoma. leukemia)
Loop of
Henle • Inflammatory
Medulla
Collecting (Sjogren’s, tubulointerstitial

duct nephritis uveitis), sepsis
Inner
Thin
descending
limb
FIGURE 304-3 Major causes of intrinsic acute kidney injury. ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation; HTN, hypertension; PCN,
penicillin; PPI, proton pump inhibitors; TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome; TINU, tubulointerstitial nephritis-uveitis.

2102 ■■SEPSIS-ASSOCIATED AKI the postoperative period, especially after major operations involving
In the United States, more than one million cases of sepsis occur each significant blood loss and intraoperative hypotension. The procedures
year. AKI complicates more than 50% of cases of severe sepsis and most commonly associated with AKI are cardiac surgery with car-
greatly increases the risk of death. Sepsis is also a very important cause diopulmonary bypass (particularly for combined valve and bypass
of AKI in the developing world. Decreases in GFR with sepsis can procedures), vascular procedures with aortic cross clamping, and
occur even in the absence of overt hypotension, although most cases intraperitoneal procedures. Severe AKI requiring dialysis occurs in ~1%
of severe AKI typically occur in the setting of hemodynamic collapse of cardiac and vascular surgery procedures. The risk of severe AKI has
requiring vasopressor support. While there is clearly tubular injury been less well studied for major intraperitoneal procedures but appears
associated with AKI in sepsis as manifest by the presence of tubular to be of comparable magnitude. Common risk factors for postoperative
debris and casts in the urine, postmortem examinations of kidneys AKI include underlying CKD, older age, diabetes mellitus, congestive
from individuals with severe sepsis suggest that other factors, perhaps heart failure, and emergency procedures. The pathophysiology of AKI
related to inflammation, mitochondrial dysfunction, and interstitial following cardiac surgery is multifactorial. Major AKI risk factors are
edema, must also be considered in the pathophysiology of sepsis- common in the population undergoing cardiac surgery. The use of
induced AKI. nephrotoxic agents, including iodinated contrast for cardiac imaging
The hemodynamic effects of sepsis—arising from generalized prior to surgery, may increase the risk of AKI. Cardiopulmonary
arterial vasodilation, mediated in part by cytokines that upregulate bypass is a unique hemodynamic state characterized by nonpulsatile
the expression of inducible NO synthase in the vasculature—can lead flow and exposure of the circulation to extracorporeal circuits. Longer
to a reduction in GFR. The operative mechanisms may be excessive duration of cardiopulmonary bypass is a risk factor for AKI. In addition
efferent arteriole vasodilation, particularly early in the course of sepsis, to ischemic injury from sustained hypoperfusion, cardiopulmonary
or renal vasoconstriction from activation of the sympathetic nervous bypass may cause AKI through a number of mechanisms including
system, the renin-angiotensin-aldosterone system, vasopressin, and extracorporeal circuit activation of leukocytes and inflammatory pro-
endothelin. Sepsis may lead to endothelial damage, which results in cesses, hemolysis with resultant pigment nephropathy (see below),
increased microvascular leukocyte adhesion and migration, thrombo- and aortic injury with resultant atheroemboli. AKI from atheroembolic
PART 9
sis, permeability, increased interstitial pressure, reduction in local flow disease, which can also occur following percutaneous catheterization of
to tubules, and activation of reactive oxygen species, all of which may the aorta, or spontaneously, is due to cholesterol crystal embolization
injure renal tubular cells. resulting in partial or total occlusion of multiple small arteries within
the kidney. Over time, a foreign body reaction can result in intimal pro-
■■ISCHEMIA-ASSOCIATED AKI liferation, giant cell formation, and further narrowing of the vascular
Healthy kidneys receive 20% of the cardiac output and account for lumen, accounting for the generally subacute (over a period of weeks
10% of resting oxygen consumption, despite constituting only 0.5% of rather than days) decline in renal function.
the human body mass. The kidneys are also the site of one of the most
hypoxic regions in the body, the renal medulla. The outer medulla is
particularly vulnerable to ischemic damage because of the architecture Burns and Acute Pancreatitis Extensive fluid losses into the
of the blood vessels that supply oxygen and nutrients to the tubules. extravascular compartments of the body frequently accompany severe
In the outer medulla enhanced leukocyte-endothelial interactions in burns and acute pancreatitis. AKI is an ominous complication of burns,
the small vessels lead to inflammation and reduced local blood flow to affecting 25% of individuals with >10% total body surface area involve-
the metabolically very active S3 segment of the proximal tubule, which ment. In addition to severe hypovolemia resulting in decreased cardiac
depends on oxidative metabolism for survival. Mitochondrial dys- output and increased neurohormonal activation, burns and acute
function due to ischemia and mitochondrial release of reactive oxygen pancreatitis both lead to dysregulated inflammation and an increased
species also play a role in renal tubular injury. Ischemia alone in a nor- risk of sepsis and acute lung injury, all of which may facilitate the
mal kidney is usually not sufficient to cause severe AKI, as evidenced development and progression of AKI. Individuals undergoing massive
by the relatively low risk of severe AKI even after total interruption of fluid resuscitation for trauma, burns, and acute pancreatitis can also
renal blood flow during suprarenal aortic clamping or cardiac arrest. develop the abdominal compartment syndrome, where markedly ele-
Clinically, AKI more commonly develops when ischemia occurs in the vated intraabdominal pressures, usually >20 mmHg, lead to renal vein
context of limited renal reserve (e.g., CKD or older age) or coexisting compression and reduced GFR.
insults such as sepsis, vasoactive or neph-
rotoxic drugs, rhabdomyolysis, or the
systemic inflammatory states associated Pathophysiology of Ischemic Acute Renal Failure
with burns and pancreatitis. Prerenal
azotemia and ischemia-associated AKI
represent a continuum of the manifes- MICROVASCULAR O2 TUBULAR
tations of renal hypoperfusion. Persis- Glomerular Medullary
tent preglomerular vasoconstriction may
Vasoconstriction in response to: Cytoskeletal breakdown
be a common underlying cause of the endothelin, adenosine, angiotensin II,
reduction in GFR seen in AKI; impli- thromboxane A2, leukotrienes,
cated factors for vasoconstriction include Loss of polarity
sympathetic nerve activity
activation of tubuloglomerular feedback
from enhanced delivery of solute to the Vasodilation in response to: Apoptosis and necrosis
macula densa following proximal tubule nitric oxide, PGE2, acetylcholine,
injury, increased basal vascular tone and bradykinin
Inflammatory and Desquamation of viable
reactivity to vasoconstrictive agents, and vasoactive mediators and necrotic cells
Endothelial and vascular smooth
decreased vasodilator responsiveness.
muscle cell structural damage
Other contributors to low GFR include
backleak of filtrate across damaged Tubular obstruction
Leukocyte-endothelial adhesion,
and denuded tubular epithelium and vascular obstruction, leukocyte
mechanical obstruction of tubules from activation, and inflammation Backleak
necrotic debris (Fig. 304-4).
Postoperative AKI Ischemia-asso- FIGURE 304-4 Interacting microvascular and tubular events contributing to the pathophysiology of ischemic
ciated AKI is a serious complication in acute kidney injury. PGE2, prostaglandin E2. (From JV Bonventre, JM Weinberg: J Am Soc Nephrol 14:2199, 2003.)

Diseases of the Microvasculature Leading to Ischemia high doses (500 mg/m2) or in the setting of hypovolemia. Foscarnet, 2103
Microvascular causes of AKI include the thrombotic microangiopathies pentamidine, tenofovir, and cidofovir are also frequently associated with
(due to cocaine, certain chemotherapeutic agents, antiphospholipid AKI due to tubular toxicity. AKI secondary to acute interstitial nephri-
antibody syndrome, radiation nephritis, malignant hypertensive neph- tis can occur as a consequence of exposure to many antibiotics, includ-
rosclerosis, and thrombotic thrombocytopenic purpura/hemolytic- ing penicillins, cephalosporins, quinolones, sulfonamides, and rifampin.
uremic syndrome [TTP-HUS]), scleroderma, and atheroembolic dis-
ease. Large-vessel diseases associated with AKI include renal artery Chemotherapeutic Agents Cisplatin and carboplatin are accu-
dissection, thromboembolism, or thrombosis, and renal vein compres- mulated by proximal tubular cells and cause necrosis and apoptosis.
sion or thrombosis. Intensive hydration regimens have reduced the incidence of cisplatin
nephrotoxicity, but it remains a dose-limiting toxicity. Ifosfamide may
■■NEPHROTOXIN-ASSOCIATED AKI cause hemorrhagic cystitis and tubular toxicity, manifested as type II
The kidney has very high susceptibility to nephrotoxic agents due to renal tubular acidosis (Fanconi’s syndrome), polyuria, hypokalemia,
extremely high blood perfusion and concentration of circulating sub- and a modest decline in GFR. Antiangiogenesis agents, such as
stances along the nephron where water is reabsorbed and in the med- bevacizumab, can cause proteinuria and hypertension via injury to the
ullary interstitium; this results in high-concentration exposure of toxins glomerular microvasculature (thrombotic microangiopathy). Other
to tubular, interstitial, and endothelial cells. Nephrotoxic injury occurs antineoplastic agents such as mitomycin C and gemcitabine may cause
in response to a number of pharmacologic compounds with diverse thrombotic microangiopathy with resultant AKI.
structures, endogenous substances, and environmental exposures. All
structures of the kidney are vulnerable to toxic injury, including the Toxic Ingestions Ethylene glycol, present in automobile anti-
tubules, interstitium, vasculature, and collecting system. As with other freeze, is metabolized to oxalic acid, glycolaldehyde, and glyoxylate,
forms of AKI, risk factors for nephrotoxicity include older age, CKD, which may cause AKI through direct tubular injury and tubular
and prerenal azotemia. Hypoalbuminemia may increase the risk of obstruction. Diethylene glycol is an industrial agent that has caused
some forms of nephrotoxin-associated AKI due to increased free circu- outbreaks of severe AKI around the world due to adulteration of

lating drug concentrations. pharmaceutical preparations. The metabolite 2-hydroxyethoxyacetic
acid (HEAA) is thought to be responsible for tubular injury. Melamine
Contrast Agents Iodinated contrast agents used for cardiovas- contamination of foodstuffs has led to nephrolithiasis and AKI, either
cular and computed tomography (CT) imaging are a cause of AKI. through intratubular obstruction or possibly direct tubular toxicity.
The risk of AKI, or “contrast nephropathy,” is negligible in those with Aristolochic acid was found to be the cause of “Chinese herb nephrop-
normal renal function but increases in the setting of CKD, particularly athy” and “Balkan nephropathy” due to contamination of medicinal
diabetic nephropathy. The most common clinical course of contrast herbs or farming. The list of environmental toxins is likely to grow
nephropathy is characterized by a rise in SCr beginning 24–48 h follow- and contribute to a better understanding of previously catalogued
ing exposure, peaking within 3–5 days, and resolving within 1 week. “idiopathic” chronic tubular interstitial disease, a common diagnosis in
More severe, dialysis-requiring AKI is uncommon except in the setting both the developed and developing world.
of significant preexisting CKD, often in association with congestive
heart failure or other coexisting causes for ischemia-associated AKI. Endogenous Toxins AKI may be caused by a number of endoge-
Patients with multiple myeloma and renal disease are particularly nous compounds, including myoglobin, hemoglobin, uric acid, and
susceptible. Low fractional excretion of sodium (FeNa) and relatively myeloma light chains. Myoglobin can be released by injured muscle
benign urinary sediment without features of tubular necrosis (see cells, and hemoglobin can be released during massive hemolysis
below) are common findings. Contrast nephropathy is thought to occur leading to pigment nephropathy. Rhabdomyolysis may result from
from a combination of factors, including (1) hypoxia in the renal outer traumatic crush injuries, muscle ischemia during vascular or orthope-
medulla due to perturbations in renal microcirculation and occlusion dic surgery, compression during coma or immobilization, prolonged
of small vessels; (2) cytotoxic damage to the tubules directly or via seizure activity, excessive exercise, heat stroke or malignant hyper-
the generation of oxygen-free radicals, especially because the concen- thermia, infections, metabolic disorders (e.g., hypophosphatemia,
tration of the agent within the tubule is markedly increased; and (3) severe hypothyroidism), and myopathies (drug-induced, metabolic,
transient tubule obstruction with precipitated contrast material. Other or inflammatory). Pathogenic factors for AKI due to endogenous
diagnostic agents implicated as a cause of AKI are high-dose gadol- toxins include intrarenal vasoconstriction, direct proximal tubular
inium used for magnetic resonance imaging (MRI) and oral sodium toxicity, and mechanical obstruction of the distal nephron lumen when
phosphate solutions used as bowel purgatives. myoglobin or hemoglobin precipitates with Tamm-Horsfall protein
(uromodulin, the most common protein in urine and produced in the
Antibiotics Several antimicrobial agents are commonly associated thick ascending limb of the loop of Henle), a process favored by acidic
with AKI. Vancomycin may be associated with AKI, particularly when urine. Tumor lysis syndrome may follow initiation of cytotoxic therapy
trough levels are high and when used in combination with other neph- in patients with high-grade lymphomas and acute lymphoblastic leu-
rotoxic antibiotics. Aminoglycosides and amphotericin B both cause tubu- kemia; massive release of uric acid (with serum levels often exceeding
lar necrosis. Nonoliguric AKI (i.e., with a urine volume >400 mL/day) 15 mg/dL) leads to precipitation of uric acid in the renal tubules and
accompanies 10–30% of courses of aminoglycoside antibiotics, even AKI (Chap. 71). Other features of tumor lysis syndrome include hyper-
when plasma levels are in the therapeutic range. Aminoglycosides kalemia and hyperphosphatemia. The tumor lysis syndrome can also
are freely filtered across the glomerulus and then accumulate within occasionally occur spontaneously or with treatment for solid tumors or
the renal cortex, where concentrations can greatly exceed those of the multiple myeloma. Myeloma light chains can also cause AKI by direct
plasma. AKI typically manifests after 5–7 days of therapy and can tubular toxicity and by binding to Tamm-Horsfall protein to form
present even after the drug has been discontinued. Hypomagnesemia obstructing intratubular casts. Hypercalcemia, which can also be seen
is a common finding. in multiple myeloma, may cause AKI by intense renal vasoconstriction
Amphotericin B causes renal vasoconstriction from an increase in and volume depletion.
tubuloglomerular feedback as well as direct tubular toxicity mediated
by reactive oxygen species. Nephrotoxicity from amphotericin B is Other Causes of Acute Tubulointerstitial Disease Leading
dose and duration dependent. This drug binds to tubular membrane to AKI While many of the ischemic and toxic causes of AKI previ-
cholesterol and introduces pores. Clinical features of amphotericin B ously described result in tubulointerstitial disease, many drugs are also
nephrotoxicity include polyuria, hypomagnesemia, hypocalcemia, and associated with the development of an allergic response characterized
nongap metabolic acidosis. by an inflammatory infiltrate and often peripheral and urinary eosino-
Acyclovir can precipitate in tubules and cause AKI by tubular philia. Proton pump inhibitors and NSAIDS are commonly used drugs
obstruction, particularly when given as an intravenous bolus at that have been associated with acute tubulointerstitial nephritis. AKI

2104 may be also caused by severe infections and infiltrative malignant or a reduction in NO production. Secondary reductions in glomerular
nonmalignant (e.g., sarcoidosis) diseases. function are due to underperfusion of glomeruli and, possibly, changes
Glomerulonephritis Diseases involving the glomerular podo- in the glomerular ultrafiltration coefficient.
cytes, mesangial and endothelial cells can lead to AKI by compromis-
ing the filtration barrier and blood flow within the renal circulation. DIAGNOSTIC EVALUATION (TABLE 304-1)
Although glomerulonephritis is a less common (~5%) cause of AKI, By current definitions the presence of AKI is defined by an elevation
early recognition is particularly important because the diseases can in the SCr concentration or reduction in urine output. AKI is currently
respond to timely treatment with immunosuppressive agents or thera- defined by a rise from baseline of at least 0.3 mg/dL within 48 h or at
peutic plasma exchange, and the treatment may reverse the AKI. least 50% higher than baseline within 1 week, or a reduction in urine
output to <0.5 mL/kg per h for longer than 6 h. As indicated above,
■■POSTRENAL AKI it is important to recognize that given this definition, some patients
(See also Chap. 313) Postrenal AKI occurs when the normally uni- with AKI will not have tubular or glomerular damage (e.g., prerenal
directional flow of urine is acutely blocked either partially or totally, azotemia). The distinction between AKI and CKD is important for
leading to increased retrograde hydrostatic pressure and interference proper diagnosis and treatment. The distinction is straightforward
with glomerular filtration. Obstruction to urinary flow may be caused when a recent baseline SCr concentration is available, but more difficult
by functional or structural derangements anywhere from the renal in the many instances in which the baseline is unknown. In such cases,
pelvis to the tip of the urethra (Fig. 304-5). Normal urinary flow rate clues suggestive of CKD can come from radiologic studies (e.g., small,
does not rule out the presence of partial obstruction, because the GFR shrunken kidneys with cortical thinning on renal ultrasound, or evi-
is normally two orders of magnitude higher than the urinary flow rate dence of renal osteodystrophy) or laboratory tests such as normocytic
and hence a preservation of urine output may be misleading in hiding anemia in the absence of blood loss or secondary hyperparathyroidism
the postrenal partial obstruction. For AKI to occur in individuals with with hyperphosphatemia and hypocalcemia, consistent with CKD. No
two healthy functional kidneys, obstruction must affect both kidneys set of tests, however, can rule out AKI superimposed on CKD because
in order to observe large increases in SCr. Unilateral obstruction may AKI is a frequent complication in patients with CKD, further compli-
PART 9
cause AKI in the setting of significant underlying CKD or, in rare cating the distinction. Serial blood tests showing a continued substan-
cases, from reflex vasospasm of the contralateral kidney. Bladder neck tial rise of SCr represents clear evidence of AKI. Once the diagnosis of
obstruction is a common cause of postrenal AKI which impacts both AKI is established, its cause needs to be determined since the elevation
kidneys. This can be due to prostate disease (benign prostatic hyper- of SCr or reduction in urine output can be due to a large number of
trophy or prostate cancer), neurogenic bladder, or therapy with anti- physiological and pathophysiological processes.
cholinergic drugs. Obstructed Foley catheters can cause postrenal AKI

if not recognized and relieved. Other causes of lower tract obstruction ■■HISTORY AND PHYSICAL EXAMINATION
are blood clots, calculi, and urethral strictures. Ureteric obstruction can The clinical context, careful history taking, and physical examination
occur from intraluminal obstruction (e.g., calculi, blood clots, sloughed often narrow the differential diagnosis for the cause of AKI. Prerenal
renal papillae), infiltration of the ureteric wall (e.g., neoplasia), or azotemia should be suspected in the setting of vomiting, diarrhea,
external compression (e.g., retroperitoneal fibrosis, neoplasia, abscess, glycosuria causing polyuria, and several medications including diuret-
or inadvertent surgical damage). The pathophysiology of postrenal ics, NSAIDs, ACE inhibitors, and ARBs. Physical signs of orthostatic
AKI involves hemodynamic alterations triggered by an abrupt increase hypotension, tachycardia, reduced jugular venous pressure, decreased
in intratubular pressures. An initial period of hyperemia from afferent skin turgor, and dry mucous membranes are often present in prerenal
arteriolar dilation is followed by intrarenal vasoconstriction from the azotemia. Congestive heart failure, liver disease, and nephrotic syn-
generation of angiotensin II, thromboxane A2, and vasopressin, and drome can be associated with reductions in renal blood flow and/or
alterations in intrarenal hemodynam-
ics leading to reduced GFR. Extensive
Postrenal vascular disease raises the possibility
of renal artery disease, especially if
kidneys are known to be asymmetric
in size. Atheroembolic disease can
be associated with livedo reticularis
Stones, blood clots, and other signs of emboli to the legs.
Kidney external compression, The presence of sepsis is an impor-
tumor, retroperitoneal tant clue to causation although, as
fibrosis described above, the detailed patho-
physiology may be multifactorial.
A history of prostatic disease,
nephrolithiasis, or pelvic or paraaor-
tic malignancy would suggest the
Ureter possibility of postrenal AKI. Whether
or not symptoms are present early
during obstruction of the urinary
tract depends on the location of
obstruction. Colicky flank pain radi-
ating to the groin suggests acute
Prostatic enlargement, ureteric obstruction. Nocturia and
blood clots, cancer urinary frequency or hesitancy can
Bladder be seen in prostatic disease. Abdom-
inal fullness and suprapubic pain
Strictures
can accompany bladder enlargement.
Sphincter Obstructed Foley Definitive diagnosis of obstruction
Urethra catheter requires radiologic investigations.
A careful review of all medications
FIGURE 304-5 Anatomic sites and causes of obstruction leading to postrenal acute kidney injury. is imperative in the evaluation of an

TABLE 304-1 Major Causes, Clinical Features, and Diagnostic Studies for Prerenal and Intrinsic Acute Kidney Injury 2105
ETIOLOGY CLINICAL FEATURES LABORATORY FEATURES COMMENTS

Prerenal azotemia History of poor fluid intake or fluid BUN/creatinine ratio above 20, FeNa Low FeNa, high specific gravity and
loss (hemorrhage, diarrhea, vomiting, <1%, hyaline casts in urine sediment, osmolality may not be seen in the setting
sequestration into extravascular urine specific gravity >1.018, urine of CKD, diuretic use; BUN elevation out of
space); NSAID/ACE-I/ARB; heart osmolality >500 mOsm/kg proportion to creatinine may alternatively
failure; evidence of volume depletion indicate upper GI bleed or increased
(tachycardia, absolute or postural catabolism. Response to restoration of
hypotension, low jugular venous hemodynamics is most diagnostic.
pressure, dry mucous membranes),
decreased effective circulatory volume
(cirrhosis, heart failure)
Sepsis-associated AKI Sepsis, sepsis syndrome, or septic Positive culture from normally sterile FeNa may be low (<1%), particularly early
shock. Overt hypotension not always body fluid; urine sediment often in the course, but is usually >1% with
seen in mild to moderate AKI contains granular casts, renal tubular osmolality <500 mOsm/kg
epithelial cell casts
Ischemia-associated AKI Systemic hypotension, often Urine sediment often contains granular
superimposed upon sepsis and/or casts, renal tubular epithelial cell
reasons for limited renal reserve such casts. FeNa typically >1%.
as older age, CKD
Nephrotoxin-Associated AKI: Endogenous
Rhabdomyolysis Traumatic crush injuries, seizures, Elevated myoglobin, creatine kinase; FeNa may be low (<1%)
immobilization urine heme positive with few red blood
cells

Hemolysis Recent blood transfusion with Anemia, elevated LDH, low haptoglobin FeNa may be low (<1%); evaluation for
transfusion reaction transfusion reaction
Tumor lysis Recent chemotherapy Hyperphosphatemia, hypocalcemia,
hyperuricemia
Multiple myeloma Age >60 years, constitutional Monoclonal spike in urine or serum Bone marrow or renal biopsy can be
symptoms, bone pain electrophoresis; low anion gap; anemia diagnostic
Nephrotoxin-Associated AKI: Exogenous
Contrast nephropathy Exposure to iodinated contrast Characteristic course is rise in SCr FeNa may be low (<1%)
within 1–2 d, peak within 3–5 d,
recovery within 7 d
Tubular injury Aminoglycoside antibiotics, cisplatin, Urine sediment often contains granular Can be oliguric or nonoliguric
tenofovir, vancoycin, zoledronate, casts, renal tubular epithelial cell
ethylene glycol, aristolochic acid, casts. FeNa typically >1%.
protein pump inhibitors, tacrolimus and
melamine (to name a few)
Interstitial nephritis Recent medication exposure (e.g., Eosinophilia, sterile pyuria; often Urine eosinophils have limited diagnostic
proton pump inhibitors, NSAIDs, nonoliguric accuracy; systemic signs of drug reaction
antibiotics), can have fever, rash, often absent; kidney biopsy may be helpful
arthralgias
Other Causes of Intrinsic AKI
Glomerulonephritis/vasculitis Variable (Chap. 308) features include ANA, ANCA, AGBM antibody, hepatitis Kidney biopsy may be necessary
skin rash, arthralgias, sinusitis (AGBM serologies, cryoglobulins, blood
disease), lung hemorrhage (AGBM, culture, decreased complement levels,
ANCA, lupus), recent skin infection or ASO titer (abnormalities of these tests
pharyngitis (poststreptococcal) depending on etiology)
Interstitial nephritis Nondrug-related causes include Eosinophilia, sterile pyuria; often Urine eosinophils have limited diagnostic
tubulointerstitial nephritis-uveitis nonoliguric accuracy; kidney biopsy may be necessary
(TINU) syndrome, Legionella infection
TTP/HUS Neurologic abnormalities and/or Schistocytes on peripheral blood “Typical HUS” refers to AKI with a diarrheal
AKI; recent diarrheal illness; use of smear, elevated LDH, anemia, prodrome, often due to Shiga toxin
calcineurin inhibitors; pregnancy or thrombocytopenia released from Escherichia coli or other
postpartum; spontaneous bacteria; “atypical HUS” is due to inherited
or acquired complement dysregulation.
“TTP-HUS” refers to sporadic cases in
adults. Diagnosis may involve screening for
ADAMTS13 activity, Shiga toxin–producing
E. coli, genetic evaluation of complement
regulatory proteins, and kidney biopsy.
Atheroembolic disease Recent manipulation of the aorta Hypocomplementemia, eosinophiluria Skin or kidney biopsy can be diagnostic
or other large vessels; may occur (variable), variable amounts of
spontaneously or after anticoagulation; proteinuria
retinal plaques, palpable purpura,
livedo reticularis, GI bleed
Postrenal AKI History of kidney stones, prostate No specific findings other than AKI; Imaging with computed tomography or
disease, obstructed bladder catheter, may have pyuria or hematuria ultrasound
retroperitoneal or pelvic neoplasm
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor-I; AGBM, antiglomerular basement membrane; AKI, acute kidney injury; ANA, antinuclear antibody; ANCA,
antineutrophilic cytoplasmic antibody; ARB, angiotensin receptor blocker; ASO, antistreptolysin O; BUN, blood urea nitrogen; CKD, chronic kidney disease; FeNa,
fractional excretion of sodium; GI, gastrointestinal; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; TTP/HUS, thrombotic thrombocytopenic
purpura/hemolytic-uremic syndrome.

2106
Urinary sediment in AKI
Normal or few RBC or Abnormal

WBC or hyaline casts
Renal tubular
epithelial
RBCs WBCs
(RTE) cells Granular casts Eosinophiluria Crystalluria
RBC casts WBC casts
RTE casts
Pigmented casts
Prerenal GN Interstitial ATN ATN Allergic Acute uric acid

Vasculitis nephritis Tubulointerstitial GN interstitial nephropathy
Postrenal
GN nephritis nephritis Calcium oxalate
Arterial thrombosis Malignant Vasculitis
hypertension Pyelonephritis Acute cellular Atheroembolic (ethylene glycol
or embolism Tubulo-
allograft rejection disease intoxication)
Preglomerular Thrombotic Allograft interstitial
microangiopathy rejection Myoglobinuria nephritis Pyelonephritis Drugs or toxins
vasculitis
Cystitis (acyclovir,
HUS or TTP Malignant Hemoglobinuria
Glomerulo- indinavir,
infiltration of the
Scleroderma crisis nephritis sulfadiazine,
kidney
amoxicillin)
PART 9
FIGURE 304-6 Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute tubular necrosis; GN, glomerulonephritis; HUS, hemolytic-uremic
syndrome; RBCs, red blood cells; RTE, renal tubular epithelial; TTP, thrombotic thrombocytopenic purpura; WBCs, white blood cells. (Adapted from L Yang, JV Bonventre:
Diagnosis and clinical evaluation of acute kidney injury. In Comprehensive Nephrology, 4th ed. J Floege et al [eds]. Philadelphia, Elsevier, 2010.)
individual with AKI. Not only are medications frequently a nephro- sensitivity and specificity (Fig. 304-6) (Chap. A3). In the absence of
toxic cause of AKI, but doses of administered medications must be preexisting proteinuria from CKD, AKI from ischemia or nephrotoxins
adjusted for reductions in kidney function. In this regard, it is impor- leads to mild proteinuria (<1 g/d). Greater proteinuria in AKI suggests
tant to recognize that reductions in true GFR are not reflected by equa- damage to the glomerular ultrafiltration barrier or excretion of mye-
tions which estimate GFR since those equations are dependent on SCr loma light chains; the latter are not detected with conventional urine
and the patient being in a steady state. With AKI, SCr will lag behind dipsticks (which detect albumin) and require the sulfosalicylic acid test
changes in filtration rate. Idiosyncratic reactions to a wide variety of or immunoelectrophoresis. Atheroemboli can cause a variable degree of
medications can lead to allergic interstitial nephritis, which may be proteinuria. Extremely heavy proteinuria (“nephrotic range,” >3.5 g/d)
accompanied by fever, arthralgias, and a pruritic erythematous rash. can occasionally be seen in glomerulonephritis, vasculitis, or toxins/
The absence of systemic features of hypersensitivity, however, does medications that can affect the glomerulus as well as the tubulointersti-
not exclude the diagnosis of interstitial nephritis, and a kidney biopsy tium (e.g., NSAIDs). AKI can also complicate cases of minimal change
should be considered for definitive diagnosis. disease, a cause of the nephrotic syndrome (Chap. 303). If the dipstick is
AKI accompanied by palpable purpura, pulmonary hemorrhage, or positive for hemoglobin but few red blood cells are evident in the urine
sinusitis raises the possibility of systemic vasculitis with glomerulone- sediment, then rhabdomyolysis or hemolysis should be suspected.
phritis. A history of autoimmune disease, such as systemic lupus eryth- Prerenal azotemia may present with hyaline casts or an unremark-
ematosus, should lead to consideration of the possibility that the AKI is able urine sediment examination. Postrenal AKI may also lead to
related to worsening of this underlying disease. Pregnancy should lead an unremarkable sediment, but hematuria and pyuria may be seen
to the consideration of preeclampsia as a pathophysiological contribu- depending on the cause of obstruction. AKI from ATN due to ischemic
tor to the AKI. A tense abdomen should prompt consideration of acute injury, sepsis, or certain nephrotoxins has characteristic urine sediment
abdominal compartment syndrome, which requires measurement of findings: pigmented “muddy brown” granular casts and tubular
bladder pressure. Signs of limb ischemia may be clues to the diagnosis epithelial cell casts. These findings may be absent in more than 20%
of rhabdomyolysis. of cases, however. Glomerulonephritis may lead to dysmorphic red
blood cells or red blood cell casts. Interstitial nephritis may lead to
■■URINE FINDINGS white blood cell casts. The urine sediment findings overlap somewhat
Complete anuria early in the course of AKI is uncommon except in the in glomerulonephritis and interstitial nephritis, and a diagnosis is not
following situations: complete urinary tract obstruction, renal artery always possible on the basis of the urine sediment alone. Urine eos-
occlusion, overwhelming septic shock, severe ischemia (often with cor- inophils have a limited role in differential diagnosis; they can be seen
tical necrosis), or severe proliferative glomerulonephritis or vasculitis. in interstitial nephritis, pyelonephritis, cystitis, atheroembolic disease,
A reduction in urine output (oliguria, defined as <400 mL/24 h) usu- or glomerulonephritis. Crystalluria may be important diagnostically.
ally denotes more severe AKI (i.e., lower GFR) than when urine output The finding of oxalate crystals in AKI should prompt an evaluation for
is preserved. Oliguria is associated with worse clinical outcomes in ethylene glycol toxicity. Abundant uric acid crystals may be seen in the
AKI. Preserved urine output can be seen in nephrogenic diabetes insip- tumor lysis syndrome.
idus characteristic of long-standing urinary tract obstruction, tubuloin-
terstitial disease, or nephrotoxicity from cisplatin or aminoglycosides, ■■BLOOD LABORATORY FINDINGS
among other causes. Red or brown urine may be seen with or without Certain forms of AKI are associated with characteristic patterns in the
gross hematuria; if the color persists in the supernatant after centrifu- rise and fall of SCr. Prerenal azotemia typically leads to modest rises
gation, then pigment nephropathy from rhabdomyolysis or hemolysis in SCr that return to baseline with improvement in hemodynamic
should be suspected. status. Contrast nephropathy leads to a rise in SCr within 24–48 h,
The urinalysis and urine sediment examination are invaluable peak within 3–5 days, and resolution within 5–7 days. In comparison,
tools, but they require clinical correlation because of generally limited atheroembolic disease usually manifests with more subacute rises in

SCr, although severe AKI with rapid increases in SCr can occur in this The ability of the kidney to produce a concentrated urine is depen- 2107
setting. With many of the epithelial cell toxins such as aminoglycoside dent upon many factors and reliant on good tubular function in
antibiotics and cisplatin, the rise in SCr is characteristically delayed for multiple regions of the kidney. In the patient not taking diuretics and
3–5 days to 2 weeks after initial exposure. with good baseline kidney function, urine osmolality may be >500
A complete blood count may provide diagnostic clues. Anemia is mOsm/kg in prerenal azotemia, consistent with an intact medullary
common in AKI and is usually multifactorial in origin. It is not related to concentration gradient and elevated serum vasopressin levels causing
an effect of AKI solely on production of red blood cells because this effect water reabsorption resulting in concentrated urine. In elderly patients
in isolation takes longer to manifest. Peripheral eosinophilia can accom- and those with CKD, however, baseline concentrating defects may
pany interstitial nephritis, atheroembolic disease, polyarteritis nodosa, exist, making urinary osmolality unreliable in many instances. Loss of
and Churg-Strauss vasculitis. Severe anemia in the absence of bleeding concentrating ability is common in most forms of AKI that affect the
may reflect hemolysis, multiple myeloma, or thrombotic microangio- tubules and interstitium, resulting in urine osmolality <350 mOsm/kg,
pathy (e.g., hemolytic uremic syndrome [HUS] or TTP). Other labora- but the finding is not specific.
tory findings of thrombotic microangiopathy include thrombocytopenia,
schistocytes on peripheral blood smear, elevated lactate dehydrogenase ■■RADIOLOGIC EVALUATION
level, and low haptoglobin content. Evaluation of patients suspected Postrenal AKI should always be considered in the differential diagnosis
of having TTP or HUS includes measurement of levels of the von of AKI because treatment is usually successful if instituted early. Sim-
Willebrand factor cleaving protease (ADAMTS13) and testing for ple bladder catheterization can rule out urethral obstruction. Imaging
Shiga toxin–producing Escherichia coli. “Atypical HUS” constitutes the of the urinary tract with renal ultrasound or CT should be undertaken
majority of adult cases of HUS; genetic testing is important because it is to investigate obstruction in individuals with AKI unless an alternate
estimated that 60–70% of atypical HUS patients have mutations in genes diagnosis is apparent. Findings of obstruction include dilation of
encoding proteins that regulate the alternative complement pathway. the collecting system and hydroureteronephrosis. Obstruction can
AKI often leads to hyperkalemia, hyperphosphatemia, and hypocal- be present without radiologic abnormalities in the setting of volume

cemia. Marked hyperphosphatemia with accompanying hypocalcemia, depletion, retroperitoneal fibrosis, encasement with tumor, and also
however, suggests rhabdomyolysis or the tumor lysis syndrome. Serum early in the course of obstruction. If a high-clinical index of suspicion
creatine kinase and uric acid levels are often elevated in rhabdomyoly- for obstruction persists despite normal imaging, antegrade or retro-
sis, while tumor lysis syndrome shows normal or marginally elevated grade pyelography should be performed. Imaging may also provide
creatine kinase and markedly elevated serum uric acid. The anion gap additional helpful information about kidney size and echogenicity
may be increased with any cause of uremia due to retention of anions to assist in the distinction between acute versus CKD. In CKD, kid-
such as phosphate, hippurate, sulfate, and urate. The co-occurrence neys are usually smaller unless the patient has diabetic nephropathy,
of an increased anion gap and an osmolal gap may suggest ethylene HIV-associated nephropathy, or infiltrative diseases. Normal sized
glycol poisoning, which may also cause oxalate crystalluria and oxalate kidneys are expected in AKI. Enlarged kidneys in a patient with AKI
deposition in kidney tissue. Low anion gap may provide a clue to suggests the possibility of acute interstitial nephritis or infiltrative dis-
the diagnosis of multiple myeloma due to the presence of unmeasured eases. Vascular imaging may be useful if venous or arterial obstruction
cationic proteins. Laboratory blood tests helpful for the diagnosis of is suspected, but the risks of contrast administration should be kept in
glomerulonephritis and vasculitis include depressed complement mind. MRI with gadolinium-based contrast agents should be avoided
levels and high titers of antinuclear antibodies (ANAs), antineutrophil if possible in severe AKI due to the possibility of inducing nephrogenic
cytoplasmic antibodies (ANCAs), antiglomerular basement membrane system fibrosis, a rare but serious complication seen most commonly in
(Anti-GBM) antibodies, and cryoglobulins. patients with end-stage renal disease.
■■RENAL FAILURE INDICES ■■KIDNEY BIOPSY

Several indices have been used to help differentiate prerenal azotemia If the cause of AKI is not apparent based on the clinical context, physi-
from intrinsic AKI when the tubules are malfunctioning. The low cal examination, laboratory studies, and radiologic evaluation, kidney
tubular flow rate and increased renal medullary recycling of urea seen biopsy should be considered. The kidney biopsy can provide definitive
in prerenal azotemia may cause a disproportionate elevation of the diagnostic and prognostic information about acute kidney disease
BUN compared to creatinine. Other causes of disproportionate BUN and CKD. The procedure is most often used in AKI when prerenal
elevation need to be kept in mind, however, including upper gastroin- azotemia, postrenal AKI, and ischemic or nephrotoxic AKI have been
testinal bleeding, hyperalimentation, increased tissue catabolism, and deemed unlikely, and other possible diagnoses are being considered
glucocorticoid use. such as glomerulonephritis, vasculitis, interstitial nephritis, myeloma
The FeNa is the fraction of the filtered sodium load that is reab- kidney, HUS and TTP, and allograft dysfunction. Kidney biopsy is
sorbed by the tubules, and is a measure of both the kidney’s ability to associated with a risk of bleeding, which can be severe and organ- or
reabsorb sodium as well as endogenously and exogenously adminis- life-threatening in patients with thrombocytopenia or coagulopathy.
tered factors that affect tubular reabsorption. As such, it depends on
sodium intake, effective intravascular volume, GFR, diuretic intake, ■■NOVEL BIOMARKERS
and intact tubular reabsorptive mechanisms. With prerenal azotemia, BUN and creatinine are functional biomarkers of glomerular filtration
the FeNa may be <1%, suggesting avid tubular sodium reabsorption. rather than tissue injury biomarkers and, therefore, may be suboptimal
In patients with CKD, a FeNa significantly >1% can be present despite for the diagnosis of actual parenchymal kidney damage. BUN and cre-
a superimposed prerenal state. The FeNa may also be >1% despite atinine are also relatively slow to rise after kidney injury. Several novel
hypovolemia due to treatment with diuretics. Low FeNa is often seen biomarkers have been investigated and show promise for earlier and
early in glomerulonephritis and other disorders and, hence, should not accurate diagnosis of AKI and for predicting AKI prognosis. In cases
be taken as prima facie evidence of prerenal azotemia. Low FeNa is of oliguric AKI, the urinary flow rate in response to bolus intravenous
therefore suggestive, but not synonymous, with effective intravascular furosemide 1.0–1.5 mg/kg can be used a prognostic test: urine output
volume depletion, and should not be used as the sole guide for volume of less than 200 mL over 2 h after intravenous furosemide may identify
management. The response of urine output to crystalloid or colloid patients at higher risk of progression to more severe AKI, and the need
fluid administration may be both diagnostic and therapeutic in pre- for renal replacement therapy. The severity or risk of progressive AKI
renal azotemia. In ischemic AKI, the FeNa is frequently >1% because may also be reflected in findings on urine microscopy. In one study
of tubular injury and resultant inability to reabsorb sodium. Several involving review of fresh urine sediments by board-certified nephrolo-
causes of ischemia-associated and nephrotoxin-associated AKI can gists, a greater number of renal tubular epithelial cells and/or granular
present with FeNa <1%, however, including sepsis (often early in the casts in the urine sediment was associated with both the severity and
course), rhabdomyolysis, and contrast nephropathy. worsening of AKI. Novel protein biomarkers of kidney injury have also

2108 been identified in animal models of AKI and further tested in humans. ■■HYPERKALEMIA
Kidney injury molecule-1 (KIM-1) is a type 1 transmembrane protein that An important complication of AKI is hyperkalemia. Marked hyperka-
is abundantly expressed in proximal tubular cells injured by ischemia lemia is particularly common in rhabdomyolysis, hemolysis, and tumor
or nephrotoxins such as cisplatin. KIM-1 is not expressed in apprecia- lysis syndrome due to release of intracellular potassium from damaged
ble quantities in the absence of tubular injury or in extrarenal tissues. cells. Muscle weakness may be a symptom of hyperkalemia. Potassium
KIM-1’s functional role may be to confer phagocytic properties to affects the cellular membrane potential of cardiac and neuromuscular
tubular cells, enabling them to clear debris from the tubular lumen after tissues. The more serious complication of hyperkalemia is due to effects
kidney injury and also may reduce the inflammatory response to acute on cardiac conduction, leading to potentially fatal arrhythmias.
injury. KIM-1 can be detected shortly after ischemic or nephrotoxic
injury in the urine and, therefore, may be an easily tested biomarker ■■ACIDOSIS
in the clinical setting. Neutrophil gelatinase associated lipocalin (NGAL, Metabolic acidosis, usually accompanied by an elevation in the anion
also known as lipocalin-2 or siderocalin) is another novel biomarker gap, is common in AKI, and can further complicate acid-base and
of AKI. NGAL was first discovered as a protein in granules of human potassium balance in individuals with other causes of acidosis, includ-
neutrophils. NGAL can bind to iron siderophore complexes and may ing sepsis, diabetic ketoacidosis, or respiratory acidosis.
have tissue-protective effects in the proximal tubule. NGAL is highly
upregulated after inflammation and kidney injury and can be detected
■■HYPERPHOSPHATEMIA AND HYPOCALCEMIA
AKI can lead to hyperphosphatemia, particularly in highly catabolic
in the plasma and urine within 2 h of cardiopulmonary bypass–
patients or those with AKI from rhabdomyolysis, hemolysis, and
associated AKI. In 2014, the U.S. Food and Drug Administration
tumor lysis syndrome. Metastatic deposition of calcium phosphate
approved the marketing of a test based on the combination of the
can lead to hypocalcemia. AKI-associated hypocalcemia may also arise
urinary concentrations of two cell-cycle arrest biomarkers, insulin-
from derangements in the vitamin D–parathyroid hormone–fibroblast
like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of
growth factor-23 axis. Hypocalcemia is often asymptomatic but can
metalloproteinase-2 (TIMP-2) as predictive biomarkers for higher risk
lead to perioral paresthesias, muscle cramps, seizures, carpopedal
of the development of moderate to severe AKI in critically ill patients.
spasms, and prolongation of the QT interval on electrocardiography.
PART 9
A number of other biomarkers are under investigation for early and

Calcium levels should be corrected for the degree of hypoalbuminemia,
accurate identification of AKI and for risk stratification to identify
if present, or ionized calcium levels should be followed. Mild, asymp-
individuals at increased risk. The optimal use of novel AKI biomarkers
tomatic hypocalcemia does not require treatment.
in clinical settings is an area of ongoing investigation.
■■BLEEDING
COMPLICATIONS OF AKI Hematologic complications of AKI include anemia and bleeding, both
The kidney plays a central role in homeostatic control of volume status, of which are exacerbated by coexisting disease processes such as sepsis,
blood pressure, plasma electrolyte composition, and acid-base balance, liver disease, and disseminated intravascular coagulation. Direct hema-
and for excretion of nitrogenous and other waste products. Complica- tologic effects from AKI-related uremia include decreased erythropoie-
tions associated with AKI are, therefore, protean, and depend on the sis and platelet dysfunction.
severity of AKI and other associated conditions. Mild to moderate AKI ■■INFECTIONS
may be entirely asymptomatic, particularly early in the course. Infections are a common precipitant of AKI and also a dreaded compli-
cation of AKI. Impaired host immunity has been described in end-stage
■■UREMIA renal disease and may be operative in severe AKI.
Buildup of nitrogenous waste products, manifested as an elevated
BUN concentration, is a hallmark of AKI. BUN itself poses little direct ■■CARDIAC COMPLICATIONS
toxicity at levels <100 mg/dL. At higher concentrations, mental status The major cardiac complications of AKI are arrhythmias, pericarditis,
changes and bleeding complications can arise. Other toxins normally and pericardial effusion. In addition, volume overload and uremia
cleared by the kidney may be responsible for the symptom complex may lead to cardiac injury and impaired cardiac function. In animal
known as uremia. Few of the many possible uremic toxins have been studies cellular apoptosis and capillary vascular congestion as well as
definitively identified. The correlation of BUN and SCr concentrations mitochondrial dysfunction have been described in the heart after renal
with uremic symptoms is extremely variable, due in part to differences ischemia reperfusion.
in urea and creatinine generation rates across individuals.
■■MALNUTRITION
■■HYPERVOLEMIA AND HYPOVOLEMIA AKI is often a severely hypercatabolic state, and therefore, malnutrition
Expansion of extracellular fluid volume is a major complication of is a major complication.
oliguric and anuric AKI, due to impaired salt and water excretion. The
■■PREVENTION AND TREATMENT OF AKI
result can be weight gain, dependent edema, increased jugular venous
The management of individuals with and at risk for AKI varies accord-
pressure, and pulmonary edema; the latter can be life threatening.
ing to the underlying cause (Table 304-2). Common to all are several
Pulmonary edema can also occur from volume overload and hemor-
principles. Optimization of hemodynamics, correction of fluid and elec-
rhage in pulmonary renal syndromes. AKI may also induce or exacer-
trolyte imbalances, discontinuation of nephrotoxic medications, and
bate acute lung injury characterized by increased vascular permeability
dose adjustment of administered medications are all critical. Common
and inflammatory cell infiltration in lung parenchyma. Recovery from
causes of AKI such as sepsis and ischemic ATN do not yet have specific
AKI can sometimes be accompanied by polyuria, which, if untreated,
therapies once injury is established, but meticulous clinical attention
can lead to significant volume depletion. The polyuric phase of recovery
is needed to support the patient until (if) AKI resolves. The kidney
may be due to an osmotic diuresis from retained urea and other waste
possesses remarkable capacity to repair itself after even severe, dialy-
products as well as delayed recovery of tubular reabsorptive functions.
sis-requiring AKI, when baseline renal function was intact. However,
many patients with AKI, particularly when superimposed on preexist-
■■HYPONATREMIA ing CKD, do not recover fully and may remain dialysis dependent. It
Abnormalities in plasma electrolyte composition can be mild or life
has become increasingly apparent that AKI predisposes to accelerated
threatening. The dysfunctional kidney has limited ability to regulate
progression of CKD, and CKD is an important risk factor for AKI.
electrolyte balance. Administration of excessive hypotonic crystal-
loid or isotonic dextrose solutions can result in hypoosmolality and Prerenal Azotemia Prevention and treatment of prerenal
hyponatremia, which, if severe, can cause neurologic abnormalities, azotemia require optimization of renal perfusion. The composition
including seizures. of replacement fluids should be targeted to the type of fluid lost.

TABLE 304-2 Management of Acute Kidney Injury severe AKI and are contraindicated. Crystalloid has been reported to be 2109
preferable to albumin in the setting of traumatic brain injury. Isotonic
General Issues
crystalloid (e.g., 0.9% saline) or colloid should be used for volume
1. Optimization of systemic and renal hemodynamics through volume resuscitation in severe hypovolemia, whereas hypotonic crystalloids
resuscitation and judicious use of vasopressors
(e.g., 0.45% saline) suffice for less severe hypovolemia and can also be
2. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs,
aminoglycosides) if possible
used in the setting of hypernatremia. Excessive chloride administra-
tion from 0.9% saline may lead to hyperchloremic metabolic acidosis
3. Initiation of renal replacement therapy when indicated
and may impair GFR. Bicarbonate-containing solutions (e.g., dextrose
Specific Issues water with 150 mEq sodium bicarbonate) can be used if metabolic aci-
1. Nephrotoxin-specific dosis is a concern. Whether buffered crystalloid solutions containing
a. Rhabdomyolysis: aggressive intravenous fluids; consider forced bicarbonate or lactate offer advantages over normal saline for volume
alkaline diuresis repletion in most critically ill patients is not yet established.
b. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or Optimization of cardiac function in AKI may require use of inotropic
rasburicase agents, preload- and afterload-reducing agents, antiarrhythmic drugs,
2. Volume overload and mechanical aids such as ventricular assist devices. Invasive hemo-
a. Salt and water restriction dynamic monitoring to guide therapy may be necessary.
b. Diuretics
c. Ultrafiltration
Cirrhosis and Hepatorenal Syndrome Fluid management
in individuals with cirrhosis, ascites, and AKI is challenging because
3. Hyponatremia
of the frequent difficulty in ascertaining intravascular volume status.
a. Restriction of enteral free water intake, minimization of hypotonic Administration of intravenous fluids as a volume challenge may be
intravenous solutions including those containing dextrose
required diagnostically as well as therapeutically. Excessive volume
b. Hypertonic saline is rarely necessary in AKI. Vasopressin antagonists
administration may, however, result in worsening ascites and pulmo-

are generally not needed.
nary compromise in the setting of hepatorenal syndrome or AKI due
4. Hyperkalemia
to superimposed spontaneous bacterial peritonitis. Peritonitis should
a. Restriction of dietary potassium intake
be ruled out by culture of ascitic fluid. Albumin may prevent AKI in
b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, those treated with antibiotics for spontaneous bacterial peritonitis. The
NSAIDs
definitive treatment of the hepatorenal syndrome is orthotopic liver
c. Loop diuretics to promote urinary potassium loss
transplantation. Bridge therapies that have shown promise include ter-
d. Potassium binding ion-exchange resin (sodium polystyrene sulfonate) lipressin (a vasopressin analog), combination therapy with octreotide
e. Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to (a somatostatin analog) and midodrine (an α1-adrenergic agonist), and
promote entry of potassium intracellularly norepinephrine, in combination with intravenous albumin (25–50 g,
f. Inhaled beta-agonist therapy to promote entry of potassium maximum 100 g/d).
intracellularly
g. Calcium gluconate or calcium chloride (1 g) to stabilize the Intrinsic AKI Several agents have been tested and have failed to
myocardium show benefit in the treatment of acute tubular injury. These include
5. Metabolic acidosis atrial natriuretic peptide, low-dose dopamine, endothelin antagonists,
a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L) erythropoietin, loop diuretics, calcium channel blockers, α-adrenergic
b. Administration of other bases, e.g., THAM receptor blockers, prostaglandin analogs, antioxidants, antibodies
c. Renal replacement therapy against leukocyte adhesion molecules, and insulin-like growth factor,
6. Hyperphosphatemia among many others. Most studies have enrolled patients with severe
a. Restriction of dietary phosphate intake
and well-established AKI, and treatment may have been initiated too
late. Novel kidney injury biomarkers may provide an opportunity to
b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride,
aluminum hydroxide—taken with meals) test agents earlier in the course of AKI.
7. Hypocalcemia
AKI due to acute glomerulonephritis or vasculitis may respond to
immunosuppressive agents and/or plasmapheresis (Chap. 303). Allergic
a. Calcium carbonate or calcium gluconate if symptomatic
interstitial nephritis due to medications requires discontinuation of
8. Hypermagnesemia
the offending agent. Glucocorticoids have been used, but not tested
a. Discontinue Mg2+ containing antacids in randomized trials, in cases where AKI persists or worsens despite
9. Hyperuricemia discontinuation of the suspected medication. AKI due to scleroderma
a. Acute treatment is usually not required except in the setting of tumor (scleroderma renal crisis) should be treated with ACE inhibitors.
lysis syndrome (see above) Idiopathic TTP-HUS is a medical emergency and should be treated
10. Nutrition promptly with plasma exchange. Pharmacologic blockade of comple-
a. Sufficient protein and calorie intake (20–30 kcal/kg per day) to avoid ment activation may be effective in atypical HUS.
negative nitrogen balance. Nutrition should be provided via the enteral Early and aggressive volume repletion is mandatory in patients with
route if possible.
rhabdomyolysis, who may initially require 10 L of fluid per day. Alkaline
11. Drug dosing fluids (e.g., 75 mmol/L sodium bicarbonate added to 0.45% saline)
a. Careful attention to dosages and frequency of administration of drugs, may be beneficial in preventing tubular injury and cast formation, but
adjustment for degree of renal failure
carry the risk of worsening hypocalcemia. Diuretics may be used if
b. Note that serum creatinine concentration may overestimate renal fluid repletion is adequate but unsuccessful in achieving urinary flow
function in the non–steady state characteristic of patients with AKI
rates of 200–300 mL/h. There is no specific therapy for established
Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor AKI in rhabdomyolysis, other than dialysis in severe cases or general
blocker; NSAIDs, nonsteroidal anti-inflammatory drug; THAM, tris (hydroxymethyl)
aminomethane.
supportive care to maintain fluid and electrolyte balance and tissue
perfusion. Careful attention must be focused on calcium and phosphate
status because of precipitation in damaged tissue and release when the
Severe acute blood loss should be treated with packed red blood cells. tissue heals.
Isotonic crystalloid and/or colloid should be used for less severe acute
hemorrhage or plasma loss in the case of burns and pancreatitis. Crys- Postrenal AKI Prompt recognition and relief of urinary tract
talloid solutions are less expensive and probably equally efficacious obstruction can forestall the development of permanent structural
as colloid solutions. Hydroxyethyl starch solutions increase the risk of damage induced by urinary stasis. The site of obstruction defines

2110 the treatment approach. Transurethral or suprapubic bladder cathe- prophylaxis is important and should be tailored to the clinical setting;
terization may be all that is needed initially for urethral strictures or low-molecular-weight heparins and factor Xa inhibitors have unpre-
functional bladder impairment. Ureteric obstruction may be treated by dictable pharmacokinetics in severe AKI and should be avoided.
percutaneous nephrostomy tube placement or ureteral stent placement.
Relief of obstruction is usually followed by an appropriate diuresis Dialysis Indications and Modalities (See also Chap. 306)
for several days. In rare cases, severe polyuria persists due to tubular Dialysis is indicated when medical management fails to control vol-
dysfunction and may require continued administration of intravenous ume overload, hyperkalemia, or acidosis; in some toxic ingestions; and
fluids and electrolytes for a period of time. when there are severe complications of uremia (asterixis, pericardial
rub or effusion, encephalopathy, uremic bleeding). The timing of
■■SUPPORTIVE MEASURES FOR AKI dialysis is still a matter of debate. Late initiation of dialysis carries the
risk of avoidable volume, electrolyte, and metabolic complications of
Volume Management Hypervolemia in oliguric or anuric AKI AKI. On the other hand, initiating dialysis too early may unnecessarily
may be life threatening due to acute pulmonary edema, especially expose individuals to intravenous lines and invasive procedures, with
because many patients have coexisting pulmonary disease, and AKI the attendant risks of infection, bleeding, procedural complications,
likely increases pulmonary vascular permeability. Fluid and sodium and hypotension. The initiation of dialysis should not await the devel-
should be restricted, and diuretics may be used to increase the uri- opment of a life-threatening complication of renal failure. Many neph-
nary flow rate. There is no evidence that increasing urine output itself rologists initiate dialysis for AKI empirically when the BUN exceeds
improves the natural history of AKI, but diuretics may help to avoid a certain value (e.g., 100 mg/dL) in patients without clinical signs of
the need for dialysis in some cases. In severe cases of volume over- recovery of kidney function. The available modes for renal replace-
load, furosemide may be given as a bolus (200 mg) followed by an ment therapy in AKI require either access to the peritoneal cavity (for
intravenous drip (10–40 mg/h), with or without a thiazide diuretic. In peritoneal dialysis) or the large blood vessels (for hemodialysis, hemo-
decompensated heart failure, stepped diuretic therapy was found to be filtration, and other hybrid procedures). Small solutes are removed
superior to ultrafiltration in preserving renal function. Diuretic therapy across a semipermeable membrane down their concentration gradient
should be stopped if there is no response. Dopamine in low doses may
PART 9
(“diffusive” clearance) and/or along with the movement of plasma

transiently increase salt and water excretion by the kidney in prerenal water (“convective” clearance). The choice of modality is often dic-
states, but clinical trials have failed to show any benefit in patients with tated by the immediate availability of technology and the expertise of
intrinsic AKI. Because of the risk of arrhythmias and potential bowel medical staff.
ischemia, the risks of dopamine outweigh the benefits if used specifi- Hemodialysis can be used intermittently or continuously and can be
cally for the treatment or prevention of AKI. done through convective clearance, diffusive clearance, or a combina-
tion of the two. Vascular access is through the femoral, internal jugular,
Electrolyte and Acid-Base Abnormalities The treatment of
or subclavian veins. Hemodialysis is an intermittent procedure that
dysnatremias and hyperkalemia is described in Chap. 49. Metabolic
removes solutes through diffusive and convective clearance. Hemo-
acidosis is generally not treated unless severe (pH <7.20 and serum
dialysis is typically performed 3–4 h per day, three to four times per
bicarbonate <15 mmol/L). Acidosis can be treated with oral or intra-
week, and is the most common form of renal replacement therapy for
venous sodium bicarbonate (Chap. 51), but overcorrection should be
AKI. One of the major complications of hemodialysis is hypotension,
avoided because of the possibility of metabolic alkalosis, hypocalcemia,
particularly in the critically ill, which can perpetuate AKI by causing
hypokalemia, and volume overload. Hyperphosphatemia is common
ischemic injury to the recovering organ.
in AKI and can usually be treated by limiting intestinal absorption of
Continuous intravascular procedures were developed in the early
phosphate using phosphate binders (calcium carbonate, calcium ace-
1980s to treat hemodynamically unstable patients without inducing
tate, lanthanum, sevelamer, or aluminum hydroxide). Hypocalcemia
the rapid shifts of volume, osmolarity, and electrolytes characteristic
does not usually require therapy unless symptoms are present. Ionized
of intermittent hemodialysis. Continuous renal replacement therapy
calcium should be monitored rather than total calcium when hypoal-
(CRRT) can be performed by convective clearance (continuous ven-
buminemia is present.
ovenous hemofiltration [CVVH]), in which large volumes of plasma
Malnutrition Protein energy wasting is common in AKI, particu- water (and accompanying solutes) are forced across the semipermeable
larly in the setting of multisystem organ failure. Inadequate nutrition membrane by means of hydrostatic pressure; the plasma water is then
may lead to starvation ketoacidosis and protein catabolism. Excessive replaced by a physiologic crystalloid solution. CRRT can also be per-
nutrition may increase the generation of nitrogenous waste and lead formed by diffusive clearance (continuous venovenous hemodialysis
to worsening azotemia. Total parenteral nutrition requires large vol- [CVVHD]), a technology similar to hemodialysis except at lower blood
umes of fluid administration and may complicate efforts at volume flow and dialysate flow rates. A hybrid therapy combines both diffu-
control. According to the Kidney Disease Improving Global Outcomes sive and convective clearance (continuous venovenous hemodiafiltra-
(KDIGO) guidelines, patients with AKI should achieve a total energy tion [CVVHDF]). To achieve some of the advantages of CRRT without
intake of 20–30 kcal/kg per day. Protein intake should vary depend- the need for 24-h staffing of the procedure, some physicians favor slow
ing on the severity of AKI: 0.8–1.0 g/kg per day in noncatabolic AKI low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this
without the need for dialysis; 1.0–1.5 g/kg per day in patients on dial- therapy, blood flow and dialysate flow are higher than in CVVHD, but
ysis; and up to a maximum of 1.7 g/kg per day if hypercatabolic and the treatment time is reduced to ≤12 h.
receiving continuous renal replacement therapy. Trace elements and The optimal dose of dialysis for AKI is not clear. Daily intermittent
water-soluble vitamins should also be supplemented in AKI patients hemodialysis and high-dose CRRT do not confer a demonstrable sur-
treated with dialysis and continuous renal replacement therapy. vival or renal recovery advantage, but care should be taken to avoid
undertreatment. Studies have failed to show that continuous therapies
Anemia The anemia seen in AKI is usually multifactorial and are superior to intermittent therapies. If available, CRRT is often pre-
is not improved by erythropoiesis-stimulating agents, due to their ferred in patients with severe hemodynamic instability, cerebral edema,
delayed onset of action and the presence of bone marrow resistance in or significant volume overload.
critically ill patients. Uremic bleeding may respond to desmopressin Peritoneal dialysis can be performed through a temporary intraperi-
or estrogens, but may require dialysis for treatment in the case of toneal catheter, although it is rarely used in the United States for AKI in
long-standing or severe uremia. Gastrointestinal prophylaxis with adults. Peritoneal dialysis has enjoyed widespread use internationally,
proton pump inhibitors or histamine (H2) receptor blockers is required. particularly when hemodialysis technology is not as readily available.
It is important to recognize, however, that protein pump inhibitors Dialysate solution is instilled into and removed from the peritoneal
have been associated with AKI from interstitial nephritis, a relation- cavity at regular intervals in order to achieve diffusive and convective
ship that is increasingly being recognized. Venous thromboembolism clearance of solutes across the peritoneal membrane; ultrafiltration of

water is achieved by the presence of an osmotic gradient across the glomerular architecture, abnormal podocyte function, and disrup- 2111
peritoneal membrane achieved by high concentrations of dextrose in tion of the filtration barrier leading to sclerosis and dropout of the
the dialysate solution. Because of its continuous nature, it is often better remaining nephrons (Fig. 305-2). Increased intrarenal activity of the
tolerated than intermittent procedures like hemodialysis in hypoten- renin-angiotensin system (RAS) appears to contribute both to the ini-
sive patients. Peritoneal dialysis may not be sufficient for hypercata- tial compensatory hyperfiltration and to the subsequent maladaptive
bolic patients due to inherent limitations in dialysis efficacy. hypertrophy and sclerosis. This process explains why a reduction in
renal mass from an isolated insult may lead to a progressive decline in
OUTCOME AND PROGNOSIS renal function over many years (Fig. 305-3).
The development of AKI is associated with a significantly increased
risk of in-hospital and long-term mortality, longer length of stay, and ■ IDENTIFICATION OF RISK FACTORS AND STAGING
increased costs. Prerenal azotemia, with the exception of the cardiore- OF CKD
nal and hepatorenal syndromes, and postrenal azotemia carry a better It is important to identify factors that increase the risk for CKD, even
prognosis than most cases of intrinsic AKI. The kidneys may recover in individuals with normal GFR. Risk factors include small for gesta-
even after severe, dialysis-requiring AKI. Survivors of an episode of tion birth weight, childhood obesity, hypertension, diabetes mellitus,
AKI requiring temporary dialysis, however, are at extremely high risk autoimmune disease, advanced age, African ancestry, a family history
for progressive CKD, and up to 10% may develop end-stage renal of kidney disease, a previous episode of acute kidney injury, and the
disease. Postdischarge care under the supervision of a nephrologist for presence of proteinuria, abnormal urinary sediment, or structural
aggressive secondary prevention of kidney disease is prudent. Patients abnormalities of the urinary tract. It has been increasingly recognized
with AKI are more likely to die prematurely after they leave the hospi- that one or more episodes of acute kidney injury are associated with an
tal even if their kidney function has recovered. increased risk of developing CKD.
Many rare inherited forms of CKD follow a Mendelian inheritance
■ FURTHER READING pattern, often as part of a systemic syndrome, with the most common
Bonventre JV, Yang L: Cellular pathophysiology of ischemic acute
CHAPTER 305 Chronic Kidney Disease

in this category being autosomal dominant polycystic kidney disease.
kidney injury. J Clin Invest 121:4210, 2011. In addition, recent research in the genetics of predisposition to common
Gaudry S et al: Initiation strategies for renal-replacement therapy in complex diseases (Chap. 456) has revealed DNA sequence variants at a
the intensive care unit. N Engl J Med 375:122, 2016. number of genetic loci that are associated with common forms of CKD.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute A striking example is the finding of allelic versions of the APOL1 gene,
Kidney Injury Work Group. KDIGO Clinical Practice Guidelines for of West African population ancestry, which contributes to the several-
Acute Kidney Injury. Kidney Int. Supp 2:1, 2012. fold higher frequency of certain common etiologies of nondiabetic CKD
Lameire NH et al: Acute kidney injury: An increasing global concern. (e.g., focal segmental glomerulosclerosis) observed among African and
Lancet 382:170, 2013. Hispanic Americans, in major regions of continental Africa and the
Zeng X et al: Incidence, outcomes, and comparisons across definitions global African diaspora. The prevalence in West African populations
of AKI in hospitalized individuals. Clin J Am Soc Nephrol 9:12, 2014. seems to have arisen as an evolutionary adaptation conferring pro-
tection from tropical pathogens. As in other common diseases with a
heritable component, environmental triggers (such as a viral pathogen)
305 Chronic Kidney Disease

transform genetic risk into disease.
To stage CKD, it is necessary to estimate the GFR rather than relying
on serum creatinine concentration (Table 305-1). Many laboratories
Joanne M. Bargman, Karl L. Skorecki now report an estimated GFR, or eGFR, using one of these equations.
These equations are valid only if the patient is in steady state, that is,
the serum creatinine is neither rising nor falling over days.
Chronic kidney disease (CKD) encompasses a spectrum of patho- The normal annual mean decline in GFR with age from the peak
physiologic processes associated with abnormal kidney function and GFR (~120 mL/min per 1.73 m2) attained during the third decade
a progressive decline in glomerular filtration rate (GFR). The risk of of life is ~1 mL/min per year per 1.73 m2, reaching a mean value of
CKD progression is closely linked to both the GFR and the amount of 70 mL/min per 1.73 m2 at age 70, with considerable inter-individual
albuminuria. Figure 305-1 provides a staging of CKD stratified by the variability. Although reduced GFR is expected with aging, the lower
estimates of both of these parameters. GFR signifies a true loss of kidney function with attendant consequences
The dispiriting term end-stage renal disease represents a stage of CKD in terms of risk of CKD complications, and requirement for dose adjust-
where the accumulation of toxins, fluid, and electrolytes normally ment of medications. The mean GFR is lower in women than in men.
excreted by the kidneys leads to death unless the toxins are removed For example, a woman in her eighties with a laboratory report of serum
by renal replacement therapy, using dialysis or kidney transplantation. creatinine in the normal range may have a GFR of <50 mL/min per
These interventions are discussed in Chaps. 306 and 307. End-stage 1.73 m2. Relatedly, even a mild elevation in serum creatinine concentra-
renal disease will be supplanted in this chapter by the term stage 5 CKD. tion often signifies a substantial reduction in GFR in older individuals.
Measurement of albuminuria is also helpful for monitoring nephron
■ PATHOPHYSIOLOGY OF CKD injury and the response to therapy in many forms of CKD, especially
The pathophysiology of CKD involves two broad sets of mechanisms chronic glomerular diseases. The cumbersome 24-h urine collection
of damage: (1) initiating mechanisms specific to the underlying etiol- has been replaced by measurement of urinary albumin to creatinine
ogy (e.g., abnormalities in kidney development or integrity, immune ratio (UACR) in one and preferably several spot first-morning urine
complex deposition and inflammation in certain types of glomeru- samples as a measure pointing to glomerular injury. Even in patients
lonephritis, or toxin exposure in certain diseases of the renal tubules with negative conventional dipstick tests for elevated total protein
and interstitium) and (2) hyperfiltration and hypertrophy of the excretion, UACR above 17 mg albumin/g creatinine in men
remaining viable nephrons, that are a common consequence following and 25 mg albumin/g creatinine in women serves as a marker not
long-term reduction of renal mass, irrespective of underlying etiology only for early detection of primary kidney disease, but for systemic
and lead to further decline in kidney function (Chap. 333e from the microvas-cular disease as well. The presence of albuminuria in
19th edition of Harrison’s). The responses to reduction in nephron general serves as a well-studied screening marker for the presence of
number are mediated by vasoactive hormones, cytokines, and growth systemic microvas-cular disease and endothelial dysfunction.
factors. Eventually, these short-term adaptations of hyperfiltration and A Kidney Failure Risk (KFR) equation has been devised to pre-
hypertrophy to maintain GFR become maladaptive as the increased dict the risk of progression to stage 5 dialysis-dependent kidney
pressure and flow within the nephron predisposes to distortion of disease. The equation is available on many sites online (for example,

2112
Persistent albuminuria categories
description and range
A1 A2 A3
Prognosis of CKD by GFR
Normal to
and albuminuria categories: Moderately Severely
mildly
KDIGO 2012 increased increased
increased
<30 mg/g 30–300 mg/g >300 mg/g

<3 mg/mmol 3–30 mg/mmol >30 mg/mmol
G1 Normal or high ≥90

GFR categories (ml/min/1.73 m2)
G2 Mildly decreased 60–89

description and range
Mildly to moderately
G3a decreased 45–59
Moderately to
G3b 30–44
severely decreased
PART 9
G4 Severely decreased 15–29
G5 Kidney failure <15

FIGURE 305-1 Kidney Disease Improving Global Outcome (KDIGO) classification of chronic kidney disease (CKD). Gradation of color from green to red corresponds
to increasing risk and progression of CKD. GFR, glomerular filtration rate. (Reproduced with permission from Kidney Int Suppl 3:5–14, 2013.)
www.kidneyfailurerisk.com) and uses age, sex, region (North American Virtually all organ systems are affected, but the most evident com-
or non-North American), GFR and the urine albumin/creatinine. It has plications include anemia and associated easy fatigability; decreased
been validated in several cohorts around the world, although the risk appetite with progressive malnutrition; abnormalities in calcium,
for progression appears to be greater in North America, accounting for phosphorus, and mineral-regulating hormones, such as 1,25(OH)2D3
the regional adjustment in the equation. (calcitriol), parathyroid hormone (PTH), and fibroblast growth factor 23
Stages 1 and 2 CKD are usually asymptomatic, such that the rec- (FGF-23); and abnormalities in sodium, potassium, water, and acid-
ognition of CKD occurs more often as a result of laboratory testing base homeostasis. Many patients, especially the elderly, will have eGFR
in clinical settings other than suspicion of kidney disease. Moreover, values compatible with stage 2 or 3 CKD. However, the majority of
in the absence of the risk factors noted above, population-wide these patients will show no further deterioration of renal function. The
screening is not recommended. With progression to CKD stages 3 primary care physician is advised to recheck kidney function, and if it
and 4, clinical and laboratory complications become more prominent. is stable and not associated with proteinuria, the patient can usually be
Normal Glomerulus Hyperfiltering Glomerulus
Distal
Afferent tubule
arteriole
Efferent
arteriole
Normal Damaged
endothelium endothelium
Basement Sclerosis
membrane
Podocytes
Enlarged
arteriole
FIGURE 305-2 Left: Schema of the normal glomerular architecture. Right: Secondary glomerular changes associated with a reduction in nephron number, including
enlargement of capillary lumens and focal adhesions, which are thought to occur consequent to compensatory hyperfiltration and hypertrophy in the remaining
nephrons. (Modified from JR Ingelfinger: N Engl J Med 348:99, 2003.)

2113
TABLE 305-2 Leading Categories of Etiologies of CKDa
• Diabetic nephropathy
• Glomerulonephritis
• Hypertension-associated CKD (includes vascular and ischemic kidney
disease and primary glomerular disease with associated hypertension)
• Autosomal dominant polycystic kidney disease
• Other cystic and tubulointerstitial nephropathy
Relative contribution of each category varies with geographic region and race.
a
CKD often have hypertension. When no overt evidence for a primary

glomerular or tubulointerstitial kidney disease process is present,
CKD is frequently attributed to hypertension. However, it is now
appreciated that such individuals can be considered in two categories.
The first includes patients with a subclinical primary glomerulopathy,
such as focal segmental or global glomerulosclerosis (Chap. 308). The
second includes patients in whom progressive nephrosclerosis and
hypertension is the renal correlate of a systemic vascular disease, often
also involving large- and small-vessel cardiac and cerebral pathology.
This latter combination is especially common in the elderly, in whom
chronic renal ischemia as a cause of CKD may be underdiagnosed. The

increasing incidence of CKD in the elderly has been ascribed, in part,
to decreased mortality rate from the cardiac and cerebral complications
of atherosclerotic vascular disease, enabling a greater segment of the
FIGURE 305-3 Left: Low-power photomicrograph of a normal kidney showing population to progress to more advanced stages of CKD. Nevertheless,
normal glomeruli and healthy tubulointerstitium without fibrosis. Right: Low-power it should be appreciated that the majority of patients with early stages
photomicrograph of chronic kidney disease with sclerosis of many glomeruli and of CKD succumb to cardiovascular and cerebrovascular complications
severe tubulointerstitial fibrosis (Masson trichrome, 40× magnification). (Slides before they progress to the more advanced stages of CKD. Indeed,
courtesy of the late Dr. Andrew Herzenberg.)
even a minor decrement in GFR or the presence of albuminuria is now
recognized as a major risk factor for cardiovascular disease.
followed with interval repeat testing without referral to nephrologist.
However, caution should be exercised in terms of potential exposure ■■PATHOPHYSIOLOGY AND BIOCHEMISTRY OF
to nephrotoxins or interventions that risk acute kidney injury (AKI) UREMIA
and also with respect to medication dose adjustment. If repeat testing Although serum urea and creatinine concentrations are used to mea-
shows declining GFR, albuminuria, or uncontrolled hypertension, sure the excretory capacity of the kidneys, accumulation of these
referral to a nephrologist is appropriate. If the patient progresses to two molecules themselves does not account for the many symptoms
stage 5 CKD, toxins accumulate such that patients usually experience and signs that characterize the uremic syndrome in advanced renal
a marked disturbance in their activities of daily living, well-being, failure. Large numbers of toxins that accumulate when GFR declines
nutritional status, and water and electrolyte homeostasis, eventuating have been implicated in the uremic syndrome. These include water-
in the uremic syndrome. soluble, hydrophobic, protein-bound, charged, and uncharged nitrogen-
containing non-volatile products of metabolism. It is thus evident that
■■ETIOLOGY AND EPIDEMIOLOGY
the serum concentrations of urea and creatinine should be viewed as
It has been estimated from population data that at least 6% of the
being readily measured, but very incomplete surrogate markers for
adult population in the United States has CKD at stages 1 and 2. An
retained toxins, and monitoring the levels of urea and creatinine in the
additional 4.5% of the U.S. population is estimated to have stages 3
patient with impaired kidney function represents a vast oversimplifi-
and 4 CKD. Table 305-2 lists the five most frequent categories of
cation of the uremic state.
causes of CKD, cumulatively accounting for >90% of the CKD disease
The uremic syndrome involves more than renal excretory failure.
burden worldwide. The relative contribution of each category varies
A host of metabolic and endocrine functions normally performed by
among different geographic regions. The most frequent cause of CKD
the kidneys is also impaired, and this results in anemia, malnutrition,
in North America and Europe is diabetic nephropathy, most often
and abnormal metabolism of carbohydrates, fats, and proteins. Fur-
secondary to type 2 diabetes mellitus. Patients with newly diagnosed
thermore, plasma levels of many hormones, including PTH, FGF-23,
insulin, glucagon, steroid hormones including vitamin D and sex
TABLE 305-1 Recommended Equations for Estimation of Glomerular hormones, and prolactin change with CKD as a result of reduced
Filtration Rate (GFR) Using Serum Creatinine Concentration (SCR), excretion, decreased degradation, or abnormal regulation. Finally,
Age, Sex, Race, and Body Weight CKD is associated with increased systemic inflammation. Elevated
1. Equation from the Modification of Diet in Renal Disease Study levels of C-reactive protein are detected along with other acute-phase
Estimated GFR (mL/min per 1.73 m2) = 1.86 × (SCr)−1.154 × (age)−0.203 reactants, whereas levels of so-called negative acute-phase reactants,
Multiply by 0.742 for women such as albumin and fetuin, decline. Thus, the inflammation associated
Multiply by 1.21 for African ancestry with CKD is important in the malnutrition-inflammation-atherosclerosis/
calcification syndrome, which contributes in turn to the acceleration of vas-
2. CKD-EPI Equation
cular disease and comorbidity associated with advanced kidney disease.
GFR = 141 × min(SCr/κ, 1)α × max(SCr/κ, 1)–1.209 × 0.993Age In summary, the pathophysiology of the uremic syndrome can be
Multiply by 1.018 for women divided into manifestations in three spheres of dysfunction: (1) those
Multiply by 1.159 for African ancestry consequent to the accumulation of toxins that normally undergo renal
where SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for excretion; (2) those consequent to the loss of other kidney functions,
males, α is –0.329 for females and –0.411 for males, min indicates the such as fluid and electrolyte homeostasis and hormone regulation; and
minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1. (3) progressive systemic inflammation and its vascular and nutritional
Abbreviation: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. consequences.

2114 CLINICAL AND LABORATORY supplements and potassium-sparing diuretics may be risky in patients
MANIFESTATIONS OF CKD AND UREMIA with impaired renal function, and needs to be monitored closely.
Uremia leads to disturbances in the function of virtually every organ Metabolic Acidosis Metabolic acidosis is a common disturbance
system. Chronic dialysis can reduce the incidence and severity of many in advanced CKD. The majority of patients can still acidify the urine,
of these disturbances, so that the florid manifestations of uremia have but they produce less ammonia and, therefore cannot excrete the nor-
largely disappeared in the modern health setting. However, even optimal quantity of protons. Hyperkalemia, if present, further depresses
mal dialysis therapy is not completely effective as renal replacement ammonia production. The combination of hyperkalemia and hyper-
therapy, because some disturbances resulting from impaired kidney chloremic metabolic acidosis is often present, even at earlier stages of
function fail to respond to dialysis. CKD (stages 1–3), in patients with diabetic nephropathy or in those
with predominant tubulointerstitial disease or obstructive uropathy.
■■FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS With worsening renal function, the total urinary net daily acid
excretion is usually limited to 30–40 mmol, and the anions of retained
Sodium and Water Homeostasis With normal renal function, organic acids can then lead to an anion-gap metabolic acidosis. Thus,
tubular excretion of filtered sodium and water matches intake. Many the non-anion-gap metabolic acidosis seen in earlier stages of CKD may
forms of kidney disease (e.g., glomerulonephritis) disrupt this bal- be complicated by the addition of an anion-gap metabolic acidosis as
ance such that dietary intake of sodium exceeds its urinary excretion, CKD progresses. In most patients, the metabolic acidosis is mild; the
leading to sodium retention and attendant extracellular fluid volume pH is rarely <7.32 and can usually be corrected with oral sodium bicar-
(ECFV) expansion. This expansion may contribute to hypertension, bonate supplementation. Animal and human studies have suggested
which itself can accelerate nephron injury. As long as water intake does that even modest degrees of metabolic acidosis may be associated with
not exceed the capacity for renal water clearance, the ECFV expansion the development of protein catabolism. Alkali supplementation may, in
will be isotonic and the patient will have a normal plasma sodium addition, attenuate the catabolic state and possibly slow CKD progres-
concentration. Hyponatremia is not commonly seen in CKD patients sion and is recommended when the serum bicarbonate concentration
but, when present, often responds to water restriction. The patient with falls below 20–23 mmol/L. The concomitant sodium load mandates
PART 9
ECFV expansion (peripheral edema, sometimes hypertension poorly careful attention to volume status and the need for diuretic agents.
responsive to therapy) should be counseled regarding salt restriction.
Thiazide diuretics have limited utility in stages 3–5 CKD, such that
administration of loop diuretics, including furosemide, bumetanide, TREATMENT
or torsemide, may also be needed. Resistance to loop diuretics in CKD Fluid, Electrolyte, and Acid-Base Disorders
often mandates use of higher doses than those used in patients with
higher GFR. The combination of loop diuretics with metolazone may Dietary salt restriction and the use of loop diuretics, occasion-
be helpful. Diuretic resistance with intractable edema and hypertension ally in combination with metolazone, may be needed to maintain
in advanced CKD may serve as an indication to initiate dialysis. euvolemia. Water restriction is indicated only if there is a problem
In addition to problems with salt and water excretion, some patients with hyponatremia.
with CKD may instead have impaired renal conservation of sodium Hyperkalemia often responds to dietary restriction of potassium,
and water. When an extrarenal cause for fluid loss, such as gastrointes- the use of kaliuretic diuretics, and avoidance of both potassium sup-
tinal (GI) loss, is present, these patients may be prone to ECFV deple- plements (including occult sources, such as dietary salt substitutes)
tion because of the inability of the failing kidney to reclaim filtered and dose reduction or avoidance of potassium-retaining medica-
sodium adequately. Furthermore, depletion of ECFV, whether due tions (especially angiotensin-converting enzyme [ACE] inhibitors or
to GI losses or overzealous diuretic therapy, can further compromise angiotensin receptor blockers [ARBs]). Kaliuretic diuretics promote
kidney function through underperfusion, or a “prerenal” state, leading urinary potassium excretion, whereas potassium-binding resins,
to acute-on-chronic kidney failure. In this setting, holding or adjusting such as calcium resonium, sodium polystyrene or patiromer can
the diuretic dose or even cautious volume repletion with normal saline promote potassium loss through the GI tract and may reduce the
may return the ECFV to normal and restore renal function to baseline. incidence of hyperkalemia. Intractable hyperkalemia is an indica-
tion (although uncommon) to consider institution of dialysis in a
Potassium Homeostasis In CKD, the decline in GFR is not CKD patient. The renal tubular acidosis and subsequent anion-gap
necessarily accompanied by a parallel decline in urinary potassium metabolic acidosis in progressive CKD will respond to alkali sup-
excretion, which is predominantly mediated by aldosterone-dependent plementation, typically with sodium bicarbonate. Recent studies
secretion in the distal nephron. Another defense against potassium suggest that this replacement should be considered when the serum
retention in these patients is augmented potassium excretion in the GI bicarbonate concentration falls below 20–23 mmol/L to avoid the
tract. Notwithstanding these two homeostatic responses, hyperkalemia protein catabolic state seen with even mild degrees of metabolic
may be precipitated in certain settings. These include increased dietary acidosis and to slow the progression of CKD.
potassium intake, hemolysis, hemorrhage, transfusion of stored red
blood cells, and metabolic acidosis. Importantly, a host of medications
■■DISORDERS OF CALCIUM AND PHOSPHATE
can inhibit renal potassium excretion and lead to hyperkalemia. The
METABOLISM
most important medications in this respect include the RAS inhibitors
The principal complications of abnormalities of calcium and phosphate
and spironolactone and other potassium-sparing diuretics such as ami-
metabolism in CKD occur in the skeleton and the vascular bed, with
loride, eplerenone, and triamterene. The benefits of the RAS inhibitors
occasional severe involvement of soft tissues. It is likely that disorders
in ameliorating the progression of CKD and its complications often
of bone turnover and disorders of vascular and soft tissue calcification
favor their cautious and judicious use with very close monitoring of
are related to each other (Fig. 305-3).
plasma potassium concentration.
Certain causes of CKD can be associated with earlier and more Bone Manifestations of CKD The major disorders of bone
severe disruption of potassium-secretory mechanisms in the distal disease can be classified into those associated with high bone turn-
nephron, out of proportion to the decline in GFR. These include condi- over with increased PTH levels (including osteitis fibrosa cystica, the
tions associated with hyporeninemic hypoaldosteronism, such as dia- classic lesion of secondary hyperparathyroidism), osteomalacia due to
betes, and renal diseases that preferentially affect the distal nephron, reduced action of the active forms of vitamin D, and low bone turnover
such as obstructive uropathy and sickle cell nephropathy. with low or normal PTH levels (adynamic bone disease) or most often
Hypokalemia is not common in CKD and usually reflects markedly combinations of the foregoing.
reduced dietary potassium intake, especially in association with exces- The pathophysiology of secondary hyperparathyroidism and the
sive diuretic therapy or concurrent GI losses. The use of potassium consequent high-turnover bone disease is related to abnormal mineral

metabolism through the following events: (1) declining GFR leads to often experience the most severe symptoms of musculoskeletal pain, 2115
reduced excretion of phosphate and, thus, phosphate retention; (2) the owing to the inability to repair the microfractures that occur properly
retained phosphate stimulates increased synthesis of both FGF-23 by as a part of healthy skeletal homeostasis with regular physical activity.
osteocytes and PTH and stimulates growth of parathyroid gland mass; Osteomalacia is a distinct process, consequent to reduced production
and (3) decreased levels of ionized calcium, resulting from suppression and action of 1,25(OH)2D3, leading to non-mineralized osteoid.
of calcitriol production by FGF-23 and by the failing kidney, as well
as phosphate retention, also stimulate PTH production. Low calcitriol Calcium, Phosphorus, and the Cardiovascular System
levels contribute to hyperparathyroidism, both by leading to hypoc- Recent epidemiologic evidence has shown a strong association between
alcemia and also by a direct effect on PTH gene transcription. These hyperphosphatemia and increased cardiovascular mortality in patients
changes start to occur when the GFR falls below 60 mL/min. with stage 5 and earlier stages of CKD. Hyperphosphatemia and
FGF-23 is part of a family of phosphatonins that promotes renal hypercalcemia are associated with increased vascular calcification, but
phosphate excretion. Recent studies have shown that levels of this it is unclear whether the excessive mortality is mediated by this mech-
hormone, secreted by osteocytes, increase early in the course of CKD, anism. Studies using computed tomography (CT) and electron-beam
even before phosphate retention and hyperphosphatemia. FGF-23 may CT scanning show that CKD patients have calcification of the media
defend normal serum phosphorus in at least three ways: (1) increased in coronary arteries and even heart valves that appear to be orders
renal phosphate excretion; (2) stimulation of PTH, which also increases of magnitude greater than that in patients without renal disease. The
renal phosphate excretion; and (3) suppression of the formation of magnitude of the calcification is proportional to age and hyperphos-
1,25(OH)2D3, leading to diminished phosphorus absorption from the GI phatemia and is also associated with low PTH levels and low bone
tract. Interestingly, high levels of FGF-23 are also an independent risk turnover. It is possible that in CKD patients ingested calcium cannot be
factor for left ventricular hypertrophy and mortality in CKD, dialysis, incorporated into bones with low turnover and, therefore, is deposited
and kidney transplant patients. Moreover, elevated levels of FGF-23 at extraosseous sites, such as the vascular bed and soft tissues. It is
may indicate the need for therapeutic intervention (e.g., phosphate interesting in this regard that there is also an association between oste-
oporosis and vascular calcification in the general population. Finally,

restriction), even when serum phosphate levels are within the normal
range. hyperphosphatemia can induce a change in gene expression in vascu-
Hyperparathyroidism stimulates bone turnover and leads to osteitis lar cells to an osteoblast-like profile, leading to vascular calcification
fibrosa cystica. Bone histology shows abnormal osteoid, bone and bone and even ossification.
marrow fibrosis, and in advanced stages, the formation of bone cysts, Other Complications of Abnormal Mineral Metabolism
sometimes with hemorrhagic elements so that they appear brown in Calciphylaxis is a devastating condition seen almost exclusively in
color, hence the term brown tumor. Clinical manifestations of severe patients with advanced CKD. It is heralded by livedo reticularis and
hyperparathyroidism include bone pain and fragility, brown tumors, advances to patches of ischemic necrosis, especially on the legs, thighs,
compression syndromes, and erythropoietin (EPO) resistance in part abdomen, and breasts (Fig. 305-5). Pathologically, there is evidence of
related to the bone marrow fibrosis. Furthermore, PTH itself is con- vascular occlusion in association with extensive vascular and soft tissue
sidered a uremic toxin, and high levels are associated with muscle calcification. It appears that this condition is increasing in incidence.
weakness, fibrosis of cardiac muscle, and nonspecific constitutional Originally it was ascribed to severe abnormalities in calcium and phos-
symptoms. phorus control in dialysis patients, usually associated with advanced
Adynamic bone disease is increasing in prevalence, especially among hyperparathyroidism. However, more recently, calciphylaxis has been
diabetics and the elderly. It is characterized by reduced bone volume seen with increasing frequency in the absence of severe hyperparathy-
and mineralization and may result from excessive suppression of PTH roidism. Other etiologies have been suggested, including the increased
production, chronic inflammation, or both. Suppression of PTH can use of oral calcium as a phosphate binder. Warfarin is commonly used
result from the use of vitamin D preparations or from excessive calcium in hemodialysis patients in whom most direct oral anticoagulants
exposure in the form of calcium-containing phosphate binders or high- (DOACs) are contraindicated, and one of the effects of warfarin ther-
calcium dialysis solutions. Complications of adynamic bone disease apy is to decrease the vitamin K–dependent regeneration of matrix
include an increased incidence of fracture and bone pain and an associ- GLA protein. This latter protein is important in preventing vascular
ation with increased vascular and cardiac calcification. Occasionally the
calcium will precipitate in the soft tissues into large concretions termed
“tumoral calcinosis” (Fig. 305-4). Patients with adynamic bone disease Calciphylaxis
Tumoral Calcinosis in a Dialysis Patient
FIGURE 305-5 Calciphylaxis. This peritoneal dialysis patient was on chronic

FIGURE 305-4 Tumoral calcinosis. This patient was on hemodialysis for many warfarin therapy for atrial fibrillation. She noticed a small painful nodule on the
years and was nonadherent to dietary phosphorus restriction or the use abdomen that was followed by progressive skin necrosis and ulceration of the
of phosphate binders. He was chronically severely hyperphosphatemic. He anterior abdominal wall. She was treated with hyperbaric oxygen, intravenous
developed an enlarging painful mass on his arm that was extensively calcified. thiosulfate, and discontinuation of warfarin, with slow resolution of the ulceration.

2116 calcification. Thus, warfarin treatment is considered a risk factor for and 45% of those patients who do reach stage 5 CKD have advanced
calciphylaxis, and if a patient develops this syndrome, this medication cardiovascular complications. Thus, the focus of patient care in ear-
should be discontinued and replaced with another anticoagulant. lier CKD stages should be directed to prevention of cardiovascular
complications.
TREATMENT Ischemic Vascular Disease The increased prevalence of vas-
Disorders of Calcium and Phosphate Metabolism cular disease in CKD patients derives from both traditional (“classic”)
and nontraditional (CKD-related) risk factors. Traditional risk fac-
The optimal management of secondary hyperparathyroidism and tors include hypertension, hypervolemia, dyslipidemia, sympathetic
osteitis fibrosa is prevention. Once the parathyroid gland mass is very overactivity, and hyperhomocysteinemia. The CKD-related risk fac-
large, it is difficult to control the disease. Careful attention should be tors comprise anemia, hyperphosphatemia, hyperparathyroidism,
paid to the plasma phosphate concentration in CKD patients, who increased FGF-23, sleep apnea, and generalized inflammation. The
should be counseled on a low-phosphate diet as well as the appro- inflammatory state appears to accelerate vascular occlusive disease,
priate use of phosphate-binding agents. These are agents that are and low levels of fetuin may permit more rapid vascular calcification,
taken with meals and complex the dietary phosphate to limit its GI especially in the face of hyperphosphatemia. Other abnormalities seen
absorption. Examples of phosphate binders are calcium acetate and in CKD may augment myocardial ischemia, including left ventricular
calcium carbonate. A major side effect of calcium-based phosphate hypertrophy and microvascular disease. In addition, hemodialysis,
binders is calcium accumulation and hypercalcemia, especially in with its attendant episodes of hypotension and hypovolemia, may
patients with low-turnover bone disease. Sevelamer and lanthanum further aggravate coronary ischemia and repeatedly stun the myocar-
are non-calcium-containing polymers that also function as phos- dium. Interestingly, however, the largest increment in cardiovascular
phate binders; they do not predispose CKD patients to hypercalce- mortality rate in dialysis patients is not necessarily directly associated
mia and may attenuate calcium deposition in the vascular bed. with documented acute myocardial infarction but, instead, is the result
Calcitriol exerts a direct suppressive effect on PTH secretion and of congestive heart failure and sudden death.
also indirectly suppresses PTH secretion by raising the concentra- Cardiac troponin levels are frequently elevated in CKD without
PART 9
tion of ionized calcium. However, calcitriol therapy may result in evidence of acute ischemia. The elevation complicates the diagnosis
hypercalcemia and/or hyperphosphatemia through increased GI of acute myocardial infarction in this population. Serial measurements
absorption of these minerals. Certain analogues of calcitriol are may be needed. Therefore, the trend in levels over the hours after pre-
available (e.g., paricalcitol) that suppress PTH secretion with less sentation may be more informative than a single, elevated level. Inter-
attendant hypercalcemia. estingly, consistently elevated levels are an independent prognostic

Recognition of the role of the extracellular calcium-sensing recep- factor for adverse cardiovascular events in this population.
tor has led to the development of calcimimetic agents that enhance
the sensitivity of the parathyroid cell to the suppressive effect of
Heart Failure Abnormal cardiac function secondary to myocardial
ischemia, left ventricular hypertrophy, diastolic dysfunction, and frank
calcium. This class of drug, which includes cinacalcet, produces a
cardiomyopathy, in combination with the salt and water retention often
dose-dependent reduction in PTH and plasma calcium concentra-
results in heart failure or even pulmonary edema. Heart failure can be
tion in some patients.
a consequence of diastolic or systolic dysfunction, or both. A form of
Current National Kidney Foundation Kidney Disease Outcomes
“low-pressure” pulmonary edema can also occur in advanced CKD,
Quality Initiative guidelines recommend a target PTH level between
manifesting as shortness of breath and a “bat wing” distribution of
150 and 300 pg/mL, recognizing that very low PTH levels are asso-
alveolar edema fluid on the chest x-ray. This finding can occur even in
ciated with adynamic bone disease and possible consequences of
the absence of ECFV overload and is associated with normal or mildly
fracture and ectopic calcification.
elevated pulmonary capillary wedge pressure. This process has been
ascribed to increased permeability of alveolar capillary membranes as
■■CARDIOVASCULAR ABNORMALITIES a manifestation of the uremic state, and it responds to dialysis. Other
Cardiovascular disease is the leading cause of morbidity and mortality CKD-related risk factors, including anemia and sleep apnea, may con-
in patients at every stage of CKD. The incremental risk of cardiovascu- tribute to the risk of heart failure.
lar disease in those with CKD compared to the age- and sex-matched Hypertension and Left Ventricular Hypertrophy Hyperten-
general population ranges from 10- to 200-fold, depending on the stage sion is one of the most common complications of CKD. It usually devel-
of CKD. As a result, most patients with CKD succumb to cardiovascu- ops early during the course of CKD and is associated with adverse
lar disease (Fig. 305-6) before ever reaching stage 5 CKD. Between 30 outcomes, including the development of ventricular hypertrophy
and a more rapid loss of renal function. Left ventricular hypertrophy
100 and dilated cardiomyopathy are among the strongest risk factors for
9% cardiovascular morbidity and mortality in patients with CKD and
Medicare Cohort, 1998–99, %
90 15%
80 25% are thought to be related primarily, but not exclusively, to prolonged
30% hypertension and ECFV overload. In addition, anemia and the place-
70
40% ment of an arteriovenous fistula for hemodialysis can generate a high
60
cardiac output state and consequent heart failure.
50
The absence of hypertension may signify poor left ventricular
40
function. Indeed, in epidemiologic studies of dialysis patients, low
30
blood pressure actually carries a worse prognosis than does high blood
20
pressure. This mechanism, in part, accounts for the “reverse causation”
10 seen in dialysis patients, wherein the presence of traditional risk
0 factors, such as hypertension, hyperlipidemia, and obesity, appear to
KD
sis
DM
KD
portend a better prognosis. Importantly, these observations derive from

CK
aly
+C
/C
no
cross-sectional studies of late-stage CKD patients and should not be

Di
DM
no
DM
D
interpreted to discourage appropriate management of these risk factors

DM
CK
No
in CKD patients, especially at early stages. In contrast to the general

FIGURE 305-6 U.S. Renal Data System showing increased likelihood of dying
rather than starting dialysis or reaching stage 5 chronic kidney disease (CKD).
population, it is possible that in late-stage CKD, low blood pressure,
1, Death; 2, ESRD; 3, event-free. DM; diabetes mellitus. (Data from RN Foley reduced body mass index, and hypolipidemia indicate the presence
et al: J Am Soc Nephrol 16:489–495, 2005.) of an advanced malnutrition-inflammation state, with poor prognosis.

The use of exogenous erythropoiesis-stimulating agents can increase Pericardial Disease Chest pain with respiratory accentuation, 2117
blood pressure and the requirement for antihypertensive drugs. accompanied by a friction rub, is diagnostic of pericarditis. Classic
Chronic ECFV overload is also a contributor to hypertension, and electrocardiographic abnormalities include PR-interval depression and
improvement in blood pressure can often be seen with the use of diffuse ST-segment elevation. Pericarditis can be accompanied by peri-
dietary sodium restriction, diuretics, and fluid removal with dialysis. cardial effusion that is seen on echocardiography and can rarely lead
Nevertheless, because of activation of the RAS and other disturbances to tamponade. However, the pericardial effusion can be asymptomatic,
in the balance of vasoconstrictors and vasodilators, some patients and pericarditis can be seen without significant effusion.
remain hypertensive despite careful attention to ECFV status. Pericarditis is observed in advanced uremia, and with the advent of
timely initiation of dialysis, is not as common as it once was. It is now
TREATMENT more often observed in underdialyzed, non-adherent patients than in
those starting dialysis.
Cardiovascular Abnormalities
MANAGEMENT OF HYPERTENSION TREATMENT
The overarching goal of hypertension therapy in CKD is to prevent
the extrarenal complications of high blood pressure, such as car- Pericardial Disease
diovascular disease and stroke. Although a clear-cut generalizable Uremic pericarditis is an absolute indication for the urgent initiation
benefit in slowing progression of CKD remains as yet unproven, the of dialysis or for intensification of the dialysis prescription in those
benefit for cardiac and cerebrovascular health is compelling. In all already receiving dialysis. Because of the propensity to hemorrhage
patients with CKD, blood pressure should be controlled to levels rec- in pericardial fluid, hemodialysis should be performed without
ommended by national guideline panels. In CKD patients with dia- heparin. A pericardial drainage procedure should be considered in
betes or proteinuria >1 g per 24 h, blood pressure should be reduced patients with recurrent pericardial effusion, especially with echoc-

to <130/80 mmHg, if achievable without prohibitive adverse effects. ardiographic signs of impending tamponade. Non-uremic causes of
Salt restriction should be the first line of therapy. When volume pericarditis and effusion include viral, malignant, tuberculous, and
management alone is not sufficient, the choice of antihypertensive autoimmune etiologies. It may also be seen after myocardial infarc-
agent is similar to that in the general population. ACE inhibitors tion and as a complication of treatment with the antihypertensive
and ARBs appear to slow the rate of decline of kidney function in a drug minoxidil.
manner that extends beyond reduction of systemic arterial pressure
and that involves correction of the intraglomerular hyperfiltration
and hypertension. Occasionally, introduction of ACE inhibitors and ■■HEMATOLOGIC ABNORMALITIES
ARBs can actually precipitate an episode of acute kidney injury,
especially when used in combination in patients with ischemic ren- Anemia A normocytic, normochromic anemia is observed as early
ovascular disease. Slight reduction of GFR (<30% of baseline) may as stage 3 CKD and is almost universal by stage 4. The primary cause
signify a salutary reduction in intra-glomerular hypertension and is insufficient production of EPO by the diseased kidneys. Additional
hyperfiltration, and, if stable over time, can be tolerated with contin- factors are reviewed in Table 305-3.
ued monitoring. Progressive decline in GFR should prompt discon- The anemia of CKD is associated with a number of adverse patho-
tinuation of these agents. The use of ACE inhibitors and ARBs may physiologic consequences, including decreased tissue oxygen delivery
also be complicated by the development of hyperkalemia. Often the and utilization, increased cardiac output, ventricular dilation, and
concomitant use of a combination of kaliuretic diuretics (e.g., furo- ventricular hypertrophy. Clinical manifestations include fatigue and
semide with metolazone), or a potassium-lowering GI tract binder, diminished exercise tolerance, angina, heart failure, decreased cogni-
such as patrimer, can improve potassium excretion in addition tion and mental acuity, and impaired host defense against infection. In
to improving blood pressure control. Potassium-sparing diuretics addition, anemia may play a role in growth restriction in children with
should be used with caution or avoided altogether in most patients. CKD. Although many studies in CKD patients have found that anemia
The recent movement to even lower blood pressure targets in and resistance to exogenous erythropoietic-stimulating agents (ESA)
the general population may not be applicable to patients with CKD, are associated with a poor prognosis, the relative contribution to a poor
who often lack autoregulation to maintain GFR in the face of low outcome of the low hematocrit itself, versus inflammation as a cause of
perfusion pressure. If a patient experiences sudden decline in kidney the anemia and ESA resistance, remains unclear.
function with intensification of antihypertensive therapy, consider-
ation should be given to reducing therapy.
TREATMENT
MANAGEMENT OF CARDIOVASCULAR DISEASE
There are many strategies available to treat the traditional and
Anemia
nontraditional risk factors in CKD patients. Although these have The availability of recombinant human ESA has been one of the
proved effective in the general population, there is little evidence most significant advances in the care of renal patients since the
for their benefit in patients with advanced CKD, especially those on introduction of dialysis and renal transplantation. Its routine use
dialysis. Certainly hypertension, and dyslipidemia promote athero-
sclerotic disease and are treatable complications of CKD. Renal dis-
ease complicated by nephrotic syndrome is associated with a very TABLE 305-3 Causes of Anemia in CKD
atherogenic lipid profile and hypercoagulability, which increases
Relative deficiency of erythropoietin
the risk of occlusive vascular disease. Because diabetes mellitus and
Diminished red blood cell survival
hypertension are the two most frequent causes of advanced CKD,
it is not surprising that cardiovascular disease is the most frequent Bleeding diathesis
cause of death in dialysis patients. The role of “inflammation” may Iron deficiency due to poor dietary absorption and gastrointestinal blood loss
be quantitatively more important in patients with kidney disease, Hyperparathyroidism/bone marrow fibrosis
and the treatment of more traditional risk factors may result in only Chronic inflammation
modest success. However, modulation of traditional risk factors may Folate or vitamin B12 deficiency
be the only weapon in the therapeutic armamentarium for these Hemoglobinopathy
patients until the nature of inflammation in CKD and its treatment Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated
are better understood. disease, autoimmune disease, immunosuppressive drugs

2118 has obviated the need for regular blood transfusions in severely Certain anticoagulants, such as fractionated low-molecular-
anemic CKD patients, thus dramatically reducing the incidence of weight heparin, may need to be avoided or dose-adjusted in these
transfusion-associated infections and iron overload. Frequent blood patients, with monitoring of factor Xa activity where available. It
transfusions in dialysis patients also lead to the development of is often more prudent to use conventional unfractionated heparin,
alloantibodies that can sensitize the patient to donor kidney antigens titrated to the measured partial thromboplastin time, in hospitalized
and make renal transplantation more problematic. patients requiring an alternative to warfarin anticoagulation. The
Adequate bone marrow iron stores should be available before new classes of oral anticoagulants are all, in part, renally eliminated
treatment with ESA is initiated. Iron supplementation is usually and need to be avoided or dose adjusted in the face of decreased
essential to ensure an optimal response to ESA in patients with CKD GFR (Chap. 114).
because the demand for iron by the marrow frequently exceeds
the amount of iron that is immediately available for erythropoiesis
(measured by percent transferrin saturation), as well as the amount ■■NEUROMUSCULAR ABNORMALITIES
in iron stores (measured by serum ferritin). For the CKD patient not Central nervous system (CNS), peripheral, and autonomic neuropa-
yet on dialysis or the patient treated with peritoneal dialysis, oral thy as well as abnormalities in muscle structure and function are all
iron supplementation should be attempted. If there is GI intolerance well-recognized complications of CKD. Subtle clinical manifestations of
or poor GI absorption, the patient may have to undergo IV iron uremic neuromuscular disease usually become evident at stage 3 CKD.
infusion. For patients on hemodialysis, IV iron can be administered Early manifestations of CNS complications include mild disturbances
during dialysis, keeping in mind that iron therapy can increase the in memory and concentration and sleep disturbance. Neuromuscular
susceptibility to bacterial infections, and that the adverse effects irritability, including hiccups, cramps, and twitching, becomes evident
of free serum iron are still under investigation. In addition to iron, at later stages. In advanced untreated kidney failure, asterixis, myoclo-
an adequate supply of other major substrates and cofactors for red nus, seizures, and coma can be seen.
cell production must be ensured, including vitamin B12 and folate. Peripheral neuropathy usually becomes clinically evident after the
Anemia resistant to recommended doses of ESA in the face of ade- patient reaches stage 4 CKD, although electrophysiologic and histo-
logic evidence occurs earlier. Initially, sensory nerves are involved
PART 9
quate iron stores may be due to some combination of the following:

acute or chronic inflammation, inadequate dialysis, severe hyper- more than motor, lower extremities more than upper, and distal parts
parathyroidism, chronic blood loss or hemolysis, chronic infection, of the extremities more than proximal. The “restless leg syndrome”
or malignancy. is characterized by ill-defined sensations of sometimes debilitating
Randomized, controlled trials of ESA in CKD have failed to show discomfort in the legs and feet relieved by frequent leg movement.
an improvement in cardiovascular outcomes with this therapy. Evidence of peripheral neuropathy without another cause (e.g., dia-
Indeed, there has been an indication that the use of ESA in CKD betes mellitus) is an indication for starting renal replacement therapy.
may be associated with an increased risk of stroke in those with type Many of the complications described above will resolve with dialysis,
2 diabetes, an increase in thromboembolic events, and perhaps a although subtle nonspecific abnormalities may persist.
faster progression of renal decline. Therefore, any benefit in terms of
improvement of anemic symptoms needs to be balanced against the ■■GASTROINTESTINAL AND NUTRITIONAL
potential cardiovascular risk. Although further studies are needed, ABNORMALITIES
it is quite clear that complete normalization of the hemoglobin con- Uremic fetor, a urine-like odor on the breath, derives from the break-
centration has not been demonstrated to be of incremental benefit to down of urea to ammonia in saliva and is often associated with an
CKD patients. Current practice is to target a hemoglobin concentra- unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and
tion of 100–115 g/L. mucosal ulcerations at any level of the GI tract occur in uremic patients
and can lead to abdominal pain, nausea, vomiting, and GI bleeding.
These patients are also prone to constipation, which can be worsened
Abnormal Hemostasis Patients with later stages of CKD may by the administration of calcium and iron supplements. The retention
have a prolonged bleeding time, decreased activity of platelet factor III, of uremic toxins also leads to anorexia, nausea, and vomiting.
abnormal platelet aggregation and adhesiveness, and impaired proth- Protein restriction may be useful to decrease nausea and vomiting;
rombin consumption. Clinical manifestations include an increased however, it may put the patient at risk for malnutrition and should
tendency to bleeding and bruising, prolonged bleeding from surgical be carried out, if possible, in consultation with a registered dietitian
incisions, menorrhagia, and GI bleeding. Interestingly, CKD patients specializing in the management of CKD patients. Weight loss and
also have a greater susceptibility to thromboembolism, especially if protein-energy malnutrition, a consequence of low protein and caloric
they have renal disease that includes nephrotic-range proteinuria. The intake, is common in advanced CKD and is often an indication for
latter condition results in hypoalbuminemia and renal loss of anticoag- initiation of renal replacement therapy. Metabolic acidosis and the
ulant factors, which can lead to a thrombophilic state. activation of inflammatory cytokines can promote protein catabolism.
A number of indices are useful in nutritional assessment and include
dietary history, including food diary and subjective global assessment;
TREATMENT edema-free body weight; and measurement of urinary protein nitrogen
Abnormal Hemostasis appearance. Dual-energy x-ray absorptiometry is now widely used to
estimate lean body mass versus fluid weight. Nutritional guidelines for
Abnormal bleeding time and coagulopathy in patients with renal patients with CKD are summarized in the “Treatment” section.
failure may be reversed temporarily with desmopressin (DDAVP),
cryoprecipitate, IV conjugated estrogens, blood transfusions, and ■■ENDOCRINE-METABOLIC DISTURBANCES
ESA therapy. Optimal dialysis will usually correct a prolonged Glucose metabolism is impaired in CKD. However, fasting blood
bleeding time. glucose is usually normal or only slightly elevated, and mild glucose
Given the coexistence of bleeding disorders and a propensity to intolerance does not require specific therapy. Because the kidney
thrombosis that is unique in the CKD patient, decisions about anti- contributes to insulin removal from the circulation, plasma levels of
coagulation that have a favorable risk-benefit profile in the general insulin are slightly to moderately elevated in most uremic patients,
population may not be applicable to the patient with advanced both in the fasting and postprandial states. Because of this diminished
CKD. One example is warfarin anticoagulation for atrial fibrillation; renal degradation of insulin, patients on insulin therapy may need
the decision to anticoagulate should be made on an individual basis progressive reduction in dose as their renal function worsens. Many
in the CKD patient because there appears to be a greater risk of anti-hyperglycemic agents, including the gliptins, require dose reduc-
bleeding complications. tion in renal failure, and some, such as metformin and sulfonylureas

are contraindicated when the GFR is less than half of normal. A recent restless legs are especially helpful. A family history of kidney disease, 2119
exception is the class of drugs that inhibit sodium-glucose transport together with assessment of manifestations in other organ systems
in the proximal tubule, resulting in glucose lowering, accompanied by such as auditory, visual, and integumentary, may lead to the diagnosis
striking reductions in kidney function decline and in cardiovascular of a heritable form of CKD (e.g., Alport or Fabry disease, cystinosis)
events. The stabilization of GFR in many patients with this therapeutic or shared environmental exposure to nephrotoxic agents (e.g., heavy
intervention represents a major, important added beneficial effect of metals, aristolochic acid). It should be noted that clustering of CKD,
these drugs. Their long-term stabilizing effect on GFR and urine albu- sometimes of different etiologies, is often observed within families.
min excretion appears to result from correction of hyperfiltration early The physical examination should focus on blood pressure and target
in type 2 diabetes mellitus via re-activation of the tubuloglomerular organ damage from hypertension. Thus, funduscopy and precordial
feedback loop. This represents a fortunate convergence of pathophys- examination should be carried out. Funduscopy is important in the
iology of glomerular hyperfiltration in diabetes with drug discovery. diabetic patient, because it may show evidence of diabetic retinopathy,
In women with CKD, estrogen levels are low, and menstrual which is associated with nephropathy. Other physical examination
abnormalities, infertility, and inability to carry pregnancies to term are manifestations of CKD include edema and sensory polyneuropathy.
common. When the GFR has declined to ~40 mL/min, pregnancy is The finding of asterixis or a pericardial friction rub not attributable to
associated with a high rate of spontaneous abortion, with only ~20% other causes usually signifies the presence of the uremic syndrome.
of pregnancies leading to live births, and pregnancy may hasten the
progression of the kidney disease itself. Women with CKD who are Laboratory Investigation Laboratory studies should focus on a
contemplating pregnancy should consult first with a nephrologist in search for clues to an underlying causative or aggravating disease pro-
conjunction with an obstetrician specializing in high-risk pregnancy. cess and on the degree of renal damage and its consequences. Serum
Men with CKD have reduced plasma testosterone levels, and sexual and urine protein electrophoresis, looking for multiple myeloma,
dysfunction and oligospermia may supervene. Sexual maturation may should be obtained in all patients >35 years with unexplained CKD,
be delayed or impaired in adolescent children with CKD, even among especially if there is associated anemia and elevated, or even inappro-

those treated with dialysis. Many of these abnormalities improve or priately normal, serum calcium concentration in the face of renal insuf-
reverse with intensive dialysis or with successful renal transplantation. ficiency. In the presence of glomerulonephritis, autoimmune diseases
such as lupus and underlying infectious etiologies such as hepatitis B
■■DERMATOLOGIC ABNORMALITIES and C and HIV should be tested. Serial measurements of renal function
Abnormalities of the skin are prevalent in progressive CKD. Pruritus should be obtained to determine the pace of renal deterioration and
is quite common and one of the most vexing manifestations of the ensure that the disease is truly chronic rather than acute or subacute
uremic state. In advanced CKD, even on dialysis, patients may become and hence potentially reversible. Serum concentrations of calcium,
more pigmented, and this is felt to reflect the deposition of retained phosphorus, vitamin D, and PTH should be measured to evaluate met-
pigmented metabolites, or urochromes. Although many of the cutaneous abolic bone disease. Hemoglobin concentration, iron, vitamin B12, and
abnormalities improve with dialysis, pruritus is often tenacious. The folate should also be evaluated. A 24-h urine collection may be helpful,
first lines of management are to rule out unrelated skin disorders, such because protein excretion >300 mg may be an indication for therapy
as scabies, and to treat hyperphosphatemia, which can cause itch. Local with ACE inhibitors or ARBs.
moisturizers, mild topical glucocorticoids, oral antihistamines, and
ultraviolet radiation have been reported to be helpful. Imaging Studies The most useful imaging study is a renal ultra-
A skin condition unique to CKD patients called nephrogenic fibrosing sound, which can verify the presence of two kidneys, determine if they
dermopathy consists of progressive subcutaneous induration, especially are symmetric, provide an estimate of kidney size, and rule out renal
on the arms and legs. The condition is seen very rarely in patients with masses and evidence of obstruction. Because it takes time for kidneys
CKD who have been exposed to the magnetic resonance contrast agent to shrink as a result of chronic disease, the finding of bilaterally small
gadolinium. Current recommendations are that patients with CKD kidneys supports the diagnosis of CKD of long-standing duration. If
stage 3 (GFR 30–59 mL/min) should minimize exposure to gadolinium, the kidney size is normal, it is possible that the renal disease is acute
and those with CKD stages 4–5 (GFR <30 mL/min) should avoid the or subacute. The exceptions are diabetic nephropathy (where kidney
use of gadolinium agents unless it is medically necessary. However, size is increased at the onset of diabetic nephropathy before CKD
no patient should be denied an imaging investigation that is critical to supervenes), amyloidosis, and HIV nephropathy, where kidney size
management, and under such circumstances, rapid removal of gadolin- may be normal in the face of CKD. Polycystic kidney disease that has
ium by hemodialysis (even in patient’s not yet receiving renal replace- reached some degree of renal failure will almost always present with
ment therapy) shortly after the procedure may mitigate this sometimes enlarged kidneys with multiple cysts (Chap. 309). A discrepancy >1 cm
devastating complication. in kidney length suggests either a unilateral developmental abnormal-
ity or disease process or renovascular disease with arterial insufficiency
affecting one kidney more than the other. The diagnosis of renovascular
EVALUATION AND MANAGEMENT OF disease can be undertaken with different techniques, including Doppler
PATIENTS WITH CKD sonography, nuclear medicine studies, or CT or magnetic resonance
■■INITIAL APPROACH imaging (MRI) studies. If there is a suspicion of reflux nephropathy
(recurrent childhood urinary tract infection, asymmetric renal size
History and Physical Examination Symptoms and overt signs with scars on the renal poles), a voiding cystogram may be indicated.
of kidney disease are often subtle or absent until renal failure super- However, in most cases, by the time the patient has CKD, the reflux has
venes. Thus, the diagnosis of kidney disease often surprises patients resolved, and even if still present, repair does not improve renal func-
and may be a cause of skepticism and denial. Particular aspects of the tion. Radiographic contrast imaging studies are not particularly helpful
history that are germane to renal disease include a history of hyper- in the investigation of CKD. Intravenous or intraarterial dye should be
tension (which can cause CKD or more commonly be a consequence avoided where possible in the CKD patient, especially with diabetic
of CKD), diabetes mellitus, abnormal urinalyses, and problems with nephropathy, because of the risk of radiographic contrast dye–induced
pregnancy such as preeclampsia or early pregnancy loss. A careful renal failure. When unavoidable, appropriate precautionary measures
drug history should be elicited. Drugs to consider include nonsteroi- include avoidance of hypovolemia at the time of contrast exposure,
dal anti-inflammatory agents, cyclooxygenase-2 (COX-2) inhibitors, minimization of the dye load, and choice of radiographic contrast
antimicrobials, chemotherapeutic agents, antiretroviral agents, proton preparations with the least nephrotoxic potential. Additional measures
pump inhibitors, phosphate-containing bowel cathartics, and lithium. thought to attenuate contrast-induced worsening of renal function
In evaluating the uremic syndrome, questions about appetite, weight include judicious administration of sodium bicarbonate–containing
loss, nausea, hiccups, peripheral edema, muscle cramps, pruritus, and solutions and N acetylcysteine.

2120 Kidney Biopsy In the patient with bilaterally small kidneys, radiographic dye), and reactivation or flare of the original disease,
renal biopsy is not advised because (1) it is technically difficult and such as lupus or vasculitis.
has a greater likelihood of causing bleeding and other adverse con-
SLOWING THE PROGRESSION OF CKD
sequences, (2) there is usually so much scarring that the underlying
disease may not be apparent, and (3) the window of opportunity to There is variation in the rate of decline of GFR among patients with
render disease-specific therapy has passed. Other contraindications to CKD. However, the following interventions should be considered in
renal biopsy include uncontrolled hypertension, active urinary tract an effort to stabilize or slow the decline of renal function.
infection, bleeding diathesis (including ongoing anticoagulation), and Reducing Intraglomerular Hypertension and Proteinuria Increased
severe obesity. Ultrasound-guided percutaneous biopsy is the favored intraglomerular filtration pressures and glomerular hypertrophy
approach, but a surgical or laparoscopic approach can be considered, develop as a response to loss of nephron number. This response is
especially in the patient with a single kidney where direct visualiza- maladaptive, as it promotes the ongoing decline of kidney func-
tion and control of bleeding are crucial. In the CKD patient in whom a tion even if the inciting process has been treated or spontaneously
kidney biopsy is indicated (e.g., suspicion of a concomitant or super- resolved. Control of glomerular hypertension is important in slow-
imposed active process such as interstitial nephritis or in the face of ing the progression of CKD. Moreover, elevated blood pressure
accelerated loss of GFR), the bleeding time should be measured, and increases proteinuria by increasing its flux across the glomerular
if increased, desmopressin should be administered immediately prior capillaries. Conversely, the renoprotective effect of antihypertensive
to the procedure. medications is gauged through the consequent reduction of pro-
A brief run of hemodialysis (without heparin) may also be consid- teinuria. Thus, the more effective a given treatment is in lowering
ered prior to renal biopsy to normalize the bleeding time. protein excretion, the greater the subsequent impact on protection
from decline in GFR. This observation is the basis for the treatment
■■ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF
guideline establishing 130/80 mmHg as a target blood pressure in
CKD
proteinuric CKD patients.
The most important initial diagnostic step is to distinguish newly diag-
Several controlled studies have shown that ACE inhibitors and
nosed CKD from acute or subacute renal failure, because the latter two
PART 9
ARBs are effective in slowing the progression of renal failure in

conditions may respond to targeted therapy. Previous measurements of
patients with advanced stages of both diabetic and nondiabetic
serum creatinine concentration are particularly helpful in this regard.
CKD, in large part through effects on efferent vasodilatation and
Normal values from recent months or even years suggest that the cur-
the subsequent decline in glomerular hypertension. In the absence
rent extent of renal dysfunction could be more acute, and hence revers-
of an anti-proteinuric response with either agent alone, combined
ible, than might otherwise be appreciated. In contrast, elevated serum

treatment with both ACE inhibitors and ARBs has been consid-
creatinine concentration in the past suggests that the renal disease rep-
resents a chronic process. Even if there is evidence of chronicity, there is ered. The combination is associated with a greater reduction in
the possibility of a superimposed acute process (e.g., ECFV depletion, proteinuria compared to either agent alone. Insofar as reduction in
urinary infection or obstruction, or nephrotoxin exposure) superven- proteinuria is a surrogate for improved renal outcome, the combina-
ing on the chronic condition. If the history suggests multiple systemic tion would appear to be advantageous. However, there is a greater
manifestations of recent onset (e.g., fever, polyarthritis, rash), it should incidence of acute kidney injury and adverse cardiac events from
be assumed that renal insufficiency is part of an acute systemic illness. such combination therapy. On balance, therefore, ACE inhibitor
Although kidney biopsy can usually be performed in early CKD plus ARB therapy should be avoided. A progressive increase in
(stages 1–3), it is not always indicated. For example, in a patient with serum creatinine concentration with these agents may suggest the
a history of type 1 diabetes mellitus for 15–20 years with retinopathy, presence of renovascular disease within the large or small arteries.
nephrotic-range proteinuria, and absence of hematuria, the diagnosis Development of side effects may mandate the use of second-line
of diabetic nephropathy is very likely and biopsy is usually not neces- antihypertensive agents instead of ACE inhibitors or ARBs. Among
sary. However, if there were some other finding not typical of diabetic the calcium channel blockers, diltiazem and verapamil may exhibit
nephropathy, such as hematuria or white blood cell casts, or absence of superior antiproteinuric and renoprotective effects compared to the
diabetic retinopathy, some other disease may be present and a biopsy dihydropyridines. At least two different categories of response can
may be indicated. be considered: one in which progression is strongly associated with
In the absence of a clinical diagnosis, kidney biopsy may be the systemic and intraglomerular hypertension and proteinuria (e.g.,
only recourse to establish an etiology in early-stage CKD. However, diabetic nephropathy, glomerular diseases) and in which ACE inhib-
as noted above, once the CKD is advanced and the kidneys are small itors and ARBs are likely to be the first choice; and another in which
and scarred, there is little utility and significant risk in attempting to proteinuria is mild or absent initially (e.g., adult polycystic kidney
arrive at a specific diagnosis. Genetic testing is increasingly entering disease and other tubulointerstitial diseases), where the contribution
the repertoire of diagnostic tests, since the patterns of injury and of intraglomerular hypertension is less prominent and other antihy-
kidney morphologic abnormalities often reflect overlapping causal pertensive agents can be useful for control of systemic hypertension.
mechanisms, whose origins can sometimes be attributed to a genetic SLOWING THE PROGRESSION OF DIABETIC NEPHROPATHY
predisposition or cause.
See Chap. 397
TREATMENT MANAGING OTHER COMPLICATIONS OF CKD
Chronic Kidney Disease Medication Dose Adjustment Although the loading dose of most
drugs is not affected by CKD because renal elimination is not
Treatments aimed at specific causes of CKD are discussed else- used in the calculation, the maintenance doses of many drugs will
where. The optimal timing of both specific and nonspecific therapy need to be adjusted. For those agents in which >70% excretion is
is usually well before there has been a measurable decline in GFR by a nonrenal route, such as hepatic elimination, dose adjustment
and certainly before CKD is established. It is helpful to measure may not be needed. Some drugs that should be avoided include
sequentially and plot the rate of decline of GFR in all patients. metformin, meperidine, and oral anti-hyperglycemics that are
Any acceleration in the rate of decline should prompt a search for eliminated by the kidney. NSAIDs should be avoided because of
superimposed acute or subacute processes that may be reversible. the risk of further worsening of kidney function. Many antibiotics,
These include ECFV depletion, uncontrolled hypertension, urinary antihypertensives, and antiarrhythmics may require a reduction in
tract infection, new obstructive uropathy, exposure to nephrotoxic dosage or change in the dose interval. Several online Web-based
agents (such as nonsteroidal anti-inflammatory drugs [NSAIDs] or databases for dose adjustment of medications according to stage of

CKD or estimated GFR are available (e.g., http://www.globalrph.com/ Kidney transplantation (Chap. 307) offers the best potential for 2121
index_renal.htm). Nephrotoxic radiocontrast agents and gadolinium complete rehabilitation, because dialysis replaces only a small fraction
should be avoided or used according to strict guidelines when med- of the kidneys’ filtration function and none of the other renal functions,
ically necessary as discussed above. including endocrine and anti-inflammatory effects. Generally, kidney
transplantation follows a period of dialysis treatment, although pre-
PREPARATION FOR RENAL REPLACEMENT THERAPY
emptive kidney transplantation (usually from a living donor) can be
(See also Chap. 307) Temporary relief of symptoms and signs of carried out if it is certain that the renal failure is irreversible.
impending uremia, such as anorexia, nausea, vomiting, lassitude,
and pruritus, may sometimes be achieved with dietary protein
restriction. However, this carries a risk of malnutrition, and thus ■■IMPLICATIONS FOR GLOBAL HEALTH
plans for more long-term management should be in place. In contrast to the natural decline and successful eradication of
Maintenance dialysis and kidney transplantation have extended many devastating infectious diseases, there is rapid growth in
the lives of hundreds of thousands of patients with CKD world- the prevalence of metabolic and vascular disease in develop-
wide. Clear indications for initiation of renal replacement therapy ing countries. Diabetes mellitus is becoming increasingly prevalent in
for patients with CKD include uremic pericarditis, encephalopathy, these countries, perhaps due in part to change in dietary habits, dimin-
intractable muscle cramping, anorexia, and nausea not attributable ished physical activity, and weight gain. Therefore, it follows that there
to reversible causes such as peptic ulcer disease, evidence of malnu- will be a proportionate increase in vascular and renal disease. Health
trition, and fluid and electrolyte abnormalities, principally hyperka- care agencies must plan for improved screening of high-risk individu-
lemia or ECFV overload, that are refractory to other measures. als for early detection, prevention, and treatment plans in these nations
and must start considering options for improved availability of renal
Recommendations for the Optimal Time for Initiation of Renal replacement therapies.
Replacement Therapy Because of the individual variability in the There is also increasing recognition of endemic nephropathies in
severity of uremic symptoms and renal function, it is ill-advised developing countries that particularly target young males working
CHAPTER 306 Dialysis in the Treatment of Renal Failure

to assign an arbitrary urea nitrogen or creatinine level to the need in agriculture. The extent of morbidity and mortality associated with
to start dialysis. Moreover, patients may become accustomed to these nephropathies is only starting to be appreciated. It is unclear
chronic uremia and deny symptoms, only to find that they feel what the cause is, but a combination of population genetic risk with
better with dialysis and realize in retrospect how poorly they were endemic nephrotoxins, exposure to pesticides, NSAID use, and chronic
feeling before its initiation. volume depletion have all been suggested to contribute.
Previous studies suggested that starting dialysis before the onset
of severe symptoms and signs of uremia was associated with pro- ■■FURTHER READING
longation of survival. This led to the concept of “healthy” start and Coca SG et al: Chronic kidney disease after acute kidney injury: A
is congruent with the philosophy that it is better to keep patients systematic review and meta-analysis. Kidney Int 81:442, 2012.
feeling well rather than allowing them to become ill with uremia Coresh J et al: Decline in estimated glomerular filtration rate and sub-
and then attempting to return them to better health with dialysis sequent risk of end-stage renal disease and mortality. JAMA 311:2518,
or transplantation. Although recent studies have not confirmed 2014.
an association of early-start dialysis with improved patient sur- Correa-Rotter R et al: CKD of unknown origin in Central America:
vival, there may be merit in this approach for some patients. On a The case for a Mesoamerican nephropathy. Am J Kidney Dis 63:506,
practical level, advanced preparation may help to avoid problems 2014.
with the dialysis process itself (e.g., a poorly functioning fistula Tangri N et al: Multinational assessment of accuracy of equations for
for hemodialysis or malfunctioning peritoneal dialysis catheter) predicting risk of kidney failure: A meta-analysis. JAMA 315:164,
and, thus, preempt the morbidity associated with resorting to the 2016.
insertion of temporary hemodialysis access with its attendant risks Wanner C et al: Empagliflozin and progression of kidney disease in
of sepsis, bleeding, thrombosis, and association with accelerated type 2 diabetes. N Engl J Med 375:323, 2016.
mortality.
Patient Education Social, psychological, and physical prepa-
306
ration for the transition to renal replacement therapy and the
choice of the optimal initial modality are best accomplished with Dialysis in the Treatment
a gradual approach involving a multidisciplinary team. Along
with conservative measures discussed in the sections above, it is of Renal Failure
important to prepare patients with an intensive educational pro-
gram, explaining the likelihood and timing of initiation of renal Kathleen D. Liu, Glenn M. Chertow
replacement therapy and the various forms of therapy available,
and the option of nondialytic conservative care. The more knowl-
edgeable that patients are about hemodialysis (both in-center and Dialysis may be required for the treatment of either acute or chronic
home-based), peritoneal dialysis, and kidney transplantation, the kidney disease (CKD). The use of continuous renal replacement ther-
easier and more appropriate will be their decisions. Patients who apies (CRRT) and prolonged intermittent renal replacement therapy
are provided with education are more likely to choose home- (PIRRT)/slow low-efficiency dialysis (SLED) is specific to the manage-
based dialysis therapy. This approach is of societal benefit because ment of acute renal failure and is discussed in Chap. 304. These modal-
home-based therapy is less expensive and is associated with ities are performed continuously (CRRT) or over 6–12 h per session
improved quality of life. The educational programs should be (PIRRT/SLED), in contrast to the 3–4 h of an intermittent hemodialysis
commenced no later than stage 4 CKD so that the patient has suffi- session. Advantages and disadvantages of CRRT and PIRRT/SLED
cient time and cognitive function to learn the important concepts, are discussed in Chap. 304.
make informed choices, and implement preparatory measures for Peritoneal dialysis is rarely used in developed countries for the treat-
renal replacement therapy. ment of acute renal failure because of the increased risk of infection and
Exploration of social support is also important. Early education (as will be discussed in more detail below) less efficient clearance per
of family members for selection and preparation of a home dialy- unit of time. The focus of this chapter will be on the use of peritoneal
sis helper or a biologically or emotionally related potential living and hemodialysis for end-stage renal disease (ESRD).
kidney donor should occur long before the onset of symptomatic With the widespread availability of dialysis, the lives of hundreds
renal failure. of thousands of patients with ESRD have been prolonged. In the

2122 United States alone, there are now ~675,000 patients with treated ESRD on the two sides of the membrane. According to laws of diffusion, the
(kidney failure requiring dialysis or transplantation), the vast majority larger the molecule, the slower its rate of transfer across the membrane.
of whom require dialysis. Since 2000, the prevalence of treated ESRD A small molecule, such as urea (60 Da), undergoes substantial clear-
has increased 74%, which reflects both a small increase in the incidence ance, whereas a larger molecule, such as creatinine (113 Da), is cleared
rate and marginally enhanced survival of patients receiving dialysis. less efficiently. In addition to diffusive clearance, movement of waste
The incidence rate for treated ESRD in the United States is 370 cases products from the circulation into the dialysate may occur as a result
per million population per year; ESRD is disproportionately higher in of ultrafiltration. Convective clearance occurs because of solvent drag,
African Americans (875 per million population per year) as compared with solutes being swept along with water across the semipermeable
with white Americans (285 per million population per year). In the dialysis membrane.
United States, the leading cause of ESRD is diabetes mellitus, currently
accounting for almost 45% of newly diagnosed cases of ESRD. Approxi- ■■THE DIALYZER
mately 30% of patients have ESRD that has been attributed to hyperten- There are three essential components to hemodialysis: the dialyzer,
sion, although it is unclear whether in these cases hypertension is the the composition and delivery of the dialysate, and the blood delivery
cause or a consequence of vascular disease or other unknown causes of system (Fig. 306-1). The dialyzer is a plastic chamber with the ability
kidney failure. Other prevalent causes of ESRD include glomerulone- to perfuse blood and dialysate compartments simultaneously at very
phritis, polycystic kidney disease, and obstructive uropathy. A fraction high flow rates. The hollow-fiber dialyzer is the most common in
of the excess incidence of ESRD in African Americans is likely related use in the United States. These dialyzers are composed of bundles of
to transmission of high-risk alleles for the APOL1 gene. capillary tubes through which blood circulates while dialysate travels
Globally, mortality rates for patients with ESRD are lowest in Europe on the outside of the fiber bundle. Virtually all dialyzers now manu-
and Japan but very high in the developing world because of the lim- factured in the United States are “biocompatible” synthetic membranes
ited availability of dialysis. In the United States, the mortality rate derived from polysulfone or related compounds (versus older cellulose
of patients on dialysis has decreased slightly but remains extremely “bioincompatible” membranes that activated the complement cas-
high, with a 5-year survival rate of ~40% for patients receiving dial- cade). The frequency of reprocessing and reuse of hemodialyzers and
PART 9
ysis. Deaths are due mainly to cardiovascular diseases and infections blood lines varies across the world. In general as the cost of disposable
(~40 and 10% of deaths, respectively). Older age, male sex, nonblack supplies has decreased, their use has increased. In the United States,
race, diabetes mellitus, malnutrition, and underlying heart disease are reprocessing of dialyzers is now extremely rare. Formaldehyde, perace-
important predictors of death. tic acid–hydrogen peroxide, glutaraldehyde, and bleach have all been
used as reprocessing agents.
TREATMENT OPTIONS FOR PATIENTS WITH

ESRD ■■DIALYSATE
Commonly accepted criteria for initiating patients on maintenance The potassium concentration of dialysate may be varied from 0 to
dialysis include the presence of uremic symptoms, the presence of 4 mmol/L depending on the predialysis serum potassium concen-
hyperkalemia unresponsive to conservative measures, persistent extra- tration. The use of 0 or 1 mmol/L potassium dialysate is becoming
cellular volume expansion despite diuretic therapy, acidosis refractory less common owing to data suggesting that patients who undergo
to medical therapy, a bleeding diathesis, and a creatinine clearance or treatments with very low potassium dialysate have an increased risk
estimated glomerular filtration rate (GFR) <10 mL/min per 1.73 m2 (see of sudden death, perhaps due to arrhythmias in the setting of potas-
Chap. 305 for estimating equations). Timely referral to a nephrologist sium shifts. The usual dialysate calcium concentration is 1.25 mmol/L
for advanced planning and creation of a dialysis access, education (2.5 mEq/L), although modification may be required in selected set-
about ESRD treatment options, and management of the complications tings (e.g., higher dialysate calcium concentrations may be used in
of advanced CKD, including hypertension, anemia, acidosis, and sec- patients with hypocalcemia associated with secondary hyperparathy-
ondary hyperparathyroidism, is advisable. Recent data have suggested roidism or with “hungry bone syndrome” following parathyroidec-
that a sizable fraction of ESRD cases result following episodes of tomy). The usual dialysate sodium concentration is 136–140 mmol/L.
acute renal failure, particularly among persons with underlying CKD. In patients who frequently develop hypotension during their dialysis
Furthermore, there is no benefit to initiating dialysis preemptively at a run, “sodium modeling” to counterbalance urea-related osmolar gradi-
GFR of 10–14 mL/min per 1.73 m2 compared to initiating dialysis for ents may be employed. With sodium modeling, the dialysate sodium
symptoms of uremia. concentration is gradually lowered from the range of 145–155 mmol/L
In ESRD, treatment options include hemodialysis (in center or at to isotonic concentrations (136–140 mmol/L) near the end of the dialy-
home); peritoneal dialysis, as either continuous ambulatory peritoneal sis treatment, typically declining either in steps or in a linear or expo-
dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD); or nential fashion. However, higher dialysate sodium concentrations and
transplantation (Chap. 307). Although there are significant geographic sodium modeling may predispose patients to positive sodium balance
variations and differences in practice patterns, in-center hemodialysis and increased thirst; thus, these strategies to ameliorate intradialytic
remains the most common therapeutic modality for ESRD (>90% of hypotension may be undesirable in patients with hypertension or in
patients) in the United States. In contrast to hemodialysis, peritoneal patients with large interdialytic weight gains. Because patients are
dialysis is continuous, but much less efficient, in terms of solute clear- exposed to ~120 L of water during each dialysis treatment, water used
ance. While no large-scale clinical trials have been completed compar- for the dialysate is subjected to filtration, softening, deionization, and,
ing outcomes among patients randomized to either hemodialysis or ultimately, reverse osmosis to remove microbiologic contaminants and
peritoneal dialysis, outcomes associated with both therapies are similar dissolved ions.
in most reports, and the decision of which modality to select is often
based on personal preferences and quality-of-life considerations. ■■BLOOD DELIVERY SYSTEM
The blood delivery system is composed of the extracorporeal circuit
HEMODIALYSIS and the dialysis access. The dialysis machine consists of a blood pump,
Hemodialysis relies on the principles of solute diffusion across a dialysis solution delivery system, and various safety monitors. The
semipermeable membrane. Movement of metabolic waste products blood pump moves blood from the access site, through the dialyzer,
takes place down a concentration gradient from the circulation into and back to the patient. The blood flow rate typically ranges from
the dialysate. The rate of diffusive transport increases in response to 250 to 450 mL/min, depending on the type and integrity of the vas-
several factors, including the magnitude of the concentration gradient, cular access. Negative hydrostatic pressure on the dialysate side can
the membrane surface area, and the mass transfer coefficient of the be manipulated to achieve desirable fluid removal or ultrafiltration.
membrane. The latter is a function of the porosity and thickness of the Dialysis membranes have different ultrafiltration coefficients (i.e., mL
membrane, the size of the solute molecule, and the conditions of flow removed/min per mmHg) so that along with hydrostatic changes,

Acid 2123
Venous
Water treatment concentrate
Arterial (deionization Na+ Cl–
and reverse K+ Acetate – NaBicarb
Dialysate osmosis) Ca2+ Mg2+ NaCl
V
Arteriovenous
fistula
Dialysate
A
Venous line
Dialysate
Arterial line Hollow fiber
flow rate
dialyzer
Dialysate
pressure
Dialysate

Arterial pressure
Venous pressure conductivity
Blood flow rate Blood (leak)
Air (leak) detection detection
Dialysate drain “Delivery” system
FIGURE 306-1 Schema for hemodialysis.
fluid removal can be varied. The dialysis solution delivery system have failed or are not feasible due to anatomic considerations. These
dilutes the concentrated dialysate with water and monitors the temper- catheters are tunneled under the skin; the tunnel reduces bacterial
ature, conductivity, and flow of dialysate. translocation from the skin, resulting in a lower infection rate than with
nontunneled temporary catheters. Most tunneled catheters are placed
■■DIALYSIS ACCESS in the internal jugular veins; the external jugular, femoral, and subcla-
The fistula, graft, or catheter through which blood is obtained for vian veins may also be used.
hemodialysis is often referred to as a hemodialysis (or vascular) access. Nephrologists, interventional radiologists, and vascular surgeons
A native fistula created by the anastomosis of an artery to a vein (e.g., generally prefer to avoid placement of catheters into the subclavian
the Brescia-Cimino fistula, in which the cephalic vein is anastomosed veins; while flow rates are usually excellent, subclavian stenosis is a
end-to-side to the radial artery) results in arterialization of the vein. frequent complication and, if present, will likely prohibit permanent
This facilitates its subsequent use in the placement of large needles vascular access (i.e., a fistula or graft) in the ipsilateral extremity.
(typically 15 gauge) to access the circulation. Fistulas have the highest Infection rates may be higher with femoral catheters. For patients with
long-term patency rate of all hemodialysis access options. For patients multiple vascular access complications and no other options for perma-
in whom fistulas fail to mature, or in patients whose vasculature does nent vascular access, tunneled catheters may be the last “lifeline” for
not allow creation of a successful fistula (i.e., poor arterial inflow or hemodialysis. Translumbar or transhepatic approaches into the inferior
recipient veins of inadequate caliber), patients undergo placement of vena cava may be required if the superior vena cava or other central
an arteriovenous graft (i.e., the interposition of prosthetic material, veins draining the upper extremities are stenosed or thrombosed.
usually polytetrafluoroethylene, between an artery and a vein) or a
tunneled hemodialysis catheter. In recent years, nephrologists, vas- ■■GOALS OF DIALYSIS
cular surgeons, and health care policy makers in the United States The hemodialysis procedure consists of pumping heparinized blood
have encouraged creation of arteriovenous fistulas in a larger fraction through the dialyzer at a flow rate of 250–450 mL/min, while dialy-
of patients (the “fistula first” initiative). Unfortunately, even when sate flows in an opposite counter-current direction at 500–800 mL/min.
created, arteriovenous fistulas may not mature sufficiently to provide The efficiency of dialysis is determined by blood and dialysate flow
reliable access to the circulation, or they may thrombose early in their through the dialyzer as well as dialyzer characteristics (i.e., its effi-
development. ciency in removing solute). The dose of dialysis, which is currently
The most important complication of arteriovenous grafts is thrombo- defined as a derivation of the fractional urea clearance during a single
sis of the graft and graft failure, due principally to intimal hyperplasia treatment, is further governed by patient size, residual kidney function,
at the anastomosis between the graft and recipient vein. When grafts dietary protein intake, the degree of anabolism or catabolism, and the
(or fistulas) fail, catheter-guided angioplasty can be used to dilate ste- presence of comorbid conditions.
noses; monitoring of venous pressures on dialysis and of access flow, Since the landmark studies of Sargent and Gotch relating the mea-
although not routinely performed, may assist in the early recognition surement of the dose of dialysis using urea concentrations with mor-
of impending vascular access failure. In addition to increased rates of bidity in the National Cooperative Dialysis Study, the delivered dose of
access failure, grafts and (in particular) catheters are associated with dialysis has been measured and considered as a quality assurance and
much higher rates of infection than fistulas. improvement tool. While the fractional removal of urea nitrogen and
Intravenous large-bore catheters are often used in patients with derivations thereof are considered to be the standard methods by which
acute renal failure and CKD. For persons on maintenance hemodialy- “adequacy of dialysis” is measured, a large multicenter randomized
sis, tunneled catheters (either two separate catheters or a single catheter clinical trial (the HEMO Study) failed to show a difference in mor-
with two lumens) are often used when arteriovenous fistulas and grafts tality associated with a large difference in per-session urea clearance.

2124 Current targets include a urea reduction ratio (the fractional reduction discontinued. Treatment with steroids or epinephrine may be needed if
in blood urea nitrogen per hemodialysis session) of >65–70% and a symptoms are severe. The type B reaction consists of a symptom com-
body water–indexed clearance × time product (Kt/V) >1.2 or 1.05, plex of nonspecific chest and back pain, which appears to result from
depending on whether urea concentrations are “equilibrated.” For complement activation and cytokine release. These symptoms typically
the majority of patients with ESRD, between 9 and 12 h of dialysis are occur several minutes into the dialysis run and typically resolve over
required each week, usually divided into three equal sessions. Several time with continued dialysis.
studies have suggested that longer hemodialysis session lengths may
be beneficial (independent of urea clearance), although these studies PERITONEAL DIALYSIS
are confounded by a variety of patient characteristics, including body In peritoneal dialysis, 1.5–3 L of a dextrose-containing solution is
size and nutritional status. Hemodialysis “dose” should be individu- infused into the peritoneal cavity and allowed to dwell for a set period
alized, and factors other than the urea nitrogen should be considered, of time, usually 2–4 h. As with hemodialysis, metabolic byproducts
including the adequacy of ultrafiltration or fluid removal and control of are removed through a combination of convective clearance generated
hyperkalemia, hyperphosphatemia, and metabolic acidosis. A random- through ultrafiltration and diffusive clearance down a concentration
ized clinical trial comparing 6 versus 3 times per week hemodialysis gradient. The clearance of solutes and water during a peritoneal dialy-
(the “Frequent Hemodialysis Network Daily Trial”) demonstrated sis exchange depends on the balance between the movement of solute
improved control of hypertension and hyperphosphatemia, reduced and water into the peritoneal cavity versus absorption from the perito-
left ventricular mass, and improved self-reported physical health with neal cavity. The rate of diffusion diminishes with time and eventually
more frequent hemodialysis. Secondary analyses also demonstrated stops when equilibration between plasma and dialysate is reached.
improvements in other metrics of health-related quality of life, includ- Absorption of solutes and water from the peritoneal cavity occurs
ing improved self-reported general health and a reduced “time to across the peritoneal membrane into the peritoneal capillary circulation
recovery” (time until usual activities can be resumed) among patients and via peritoneal lymphatics into the lymphatic circulation. The rate
randomized to more frequent hemodialysis. A companion trial in of peritoneal solute transport varies from patient to patient and may be
which frequent nocturnal hemodialysis was compared to conventional altered by the presence of infection (peritonitis), drugs, and physical
factors such as position and exercise.
PART 9
hemodialysis at home showed no significant effect on left ventricular

mass or self-reported physical health. Finally, an evaluation of the U.S.
Renal Data System registry showed a significant increase in mortality ■■FORMS OF PERITONEAL DIALYSIS
and hospitalization for heart failure after the longer interdialytic inter- Peritoneal dialysis may be carried out as CAPD, CCPD, or a combina-
val that occurs over the dialysis “weekend.” tion of both. In CAPD, dialysate is manually infused into the peritoneal
cavity and exchanged three to five times during the day. A nighttime
■■COMPLICATIONS DURING HEMODIALYSIS dwell is frequently instilled at bedtime and remains in the peritoneal
Hypotension is the most common acute complication of hemodialysis, cavity through the night. In CCPD, exchanges are performed in an
particularly among patients with diabetes mellitus. Numerous factors automated fashion, usually at night; the patient is connected to an auto-
appear to increase the risk of hypotension, including excessive ultra- mated cycler that performs a series of exchange cycles while the patient
filtration with inadequate compensatory vascular filling, impaired sleeps. The number of exchange cycles required to optimize peritoneal
vasoactive or autonomic responses, osmolar shifts, overzealous use of solute clearance varies by the peritoneal membrane characteristics; as
antihypertensive agents, and reduced cardiac reserve. Patients with with hemodialysis, solute clearance should be tracked to ensure dial-
arteriovenous fistulas and grafts may develop high-output cardiac ysis “adequacy.”
failure due to shunting of blood through the dialysis access; on rare Peritoneal dialysis solutions are available in volumes typically rang-
occasions, this may necessitate ligation of the fistula or graft. The ing from 1.5 to 3 L. The major difference between the dialysate used for
management of hypotension during dialysis consists of discontinuing peritoneal rather than hemodialysis is that the hypertonicity of perito-
ultrafiltration, the administration of 100–250 mL of isotonic saline, or neal dialysis solutions drives solute and fluid removal, whereas solute
administration of salt-poor albumin. Hypotension during dialysis can removal in hemodialysis depends on concentration gradients, and fluid
frequently be prevented by careful evaluation of the dry weight and removal requires transmembrane pressure. Typically, dextrose at vary-
by ultrafiltration modeling, such that more fluid is removed at the ing concentrations contributes to the hypertonicity of peritoneal dial-
beginning rather than the end of the dialysis procedure. Excessively ysate. Icodextrin is a nonabsorbable carbohydrate that can be used in
rapid fluid removal (>13 mL/kg per h) should be avoided, as rapid place of dextrose. Studies have demonstrated more efficient ultrafiltra-
fluid removal has been associated with adverse outcomes, including tion with icodextrin than with dextrose-containing solutions. Icodextrin
cardiovascular deaths. Additional maneuvers to prevent intradialytic is typically used as the “last fill” for patients on CCPD or for the longest
hypotension include the performance of sequential ultrafiltration fol- dwell in patients on CAPD. The most common additives to peritoneal
lowed by dialysis, cooling of the dialysate during dialysis treatment, dialysis solutions are heparin to prevent obstruction of the dialysis
and avoiding heavy meals during dialysis. Midodrine, an oral selec- catheter lumen with fibrin and antibiotics during an episode of acute
tive α1 adrenergic agent, has been advocated by some practitioners, peritonitis. Insulin may also be added in patients with diabetes mellitus.
although there is insufficient evidence of its safety and efficacy to
support its routine use. ■■ACCESS TO THE PERITONEAL CAVITY
Muscle cramps during dialysis are also a common complication. Access to the peritoneal cavity is obtained through a peritoneal cath-
The etiology of dialysis-associated cramps remains obscure. Changes eter. Catheters used for maintenance peritoneal dialysis are flexible,
in muscle perfusion because of excessively rapid volume removal being made of silicone rubber with numerous side holes at the distal
or targeted removal below the patient’s estimated dry weight often end. These catheters usually have two Dacron cuffs. The scarring that
precipitate dialysis-associated cramps. Strategies that may be used occurs around the cuffs anchors the catheter and seals it from bacteria
to prevent cramps include reducing volume removal during dialysis, tracking from the skin surface into the peritoneal cavity; it also pre-
ultrafiltration profiling, and the use of sodium modeling (see above). vents the external leakage of fluid from the peritoneal cavity. The cuffs
Anaphylactoid reactions to the dialyzer, particularly on its first are placed in the preperitoneal plane and ~2 cm from the skin surface.
use, have been reported most frequently with the bioincompatible The peritoneal equilibrium test is a formal evaluation of peritoneal
cellulosic-containing membranes. Dialyzer reactions can be divided membrane characteristics that measures the transfer rates of creatinine
into two types, A and B. Type A reactions are attributed to an IgE- and glucose across the peritoneal membrane. Patients are classified
mediated intermediate hypersensitivity reaction to ethylene oxide used as low, low–average, high–average, and high transporters. Patients
in the sterilization of new dialyzers. This reaction typically occurs soon with rapid equilibration (i.e., high transporters) tend to absorb more
after the initiation of a treatment (within the first few minutes) and glucose and lose efficiency of ultrafiltration with long daytime dwells.
can progress to full-blown anaphylaxis if the therapy is not promptly High transporters also tend to lose larger quantities of albumin and

other proteins across the peritoneal membrane. In general, patients LONG-TERM OUTCOMES IN ESRD 2125
with rapid transporting characteristics require more frequent, shorter Cardiovascular disease constitutes the major cause of death in patients
dwell time exchanges, nearly always obligating use of a cycler. with ESRD. Cardiovascular mortality and event rates are higher
Slower (low and low–average) transporters tend to do well with fewer in patients receiving dialysis than in patients posttransplantation,
exchanges. The efficiency of solute clearance also depends on the vol- although rates are extraordinarily high in both populations. The under-
ume of dialysate infused. Larger volumes allow for greater solute clear- lying cause of cardiovascular disease is unclear but may be related to
ance, particularly with CAPD in patients with low and low–average shared risk factors (e.g., diabetes mellitus, hypertension, atherosclerotic
transport characteristics. and arteriosclerotic vascular disease), chronic inflammation, massive
As with hemodialysis, the optimal dose of peritoneal dialysis is changes in extracellular volume (especially with high interdialytic
unknown. Several observational studies have suggested that higher weight gains), inadequate treatment of hypertension, dyslipidemia,
rates of urea and creatinine clearance (the latter generally measured in anemia, dystrophic (vascular) calcification, and, perhaps, alterations
L/week) are associated with lower mortality rates and fewer uremic in cardiovascular dynamics during the dialysis treatment. Few studies
complications. However, a randomized clinical trial (Adequacy of have targeted cardiovascular risk reduction in ESRD patients; none
Peritoneal Dialysis in Mexico [ADEMEX]) failed to show a significant have demonstrated consistent benefit. Two clinical trials of statin
reduction in mortality or complications with a relatively large incre- agents in ESRD demonstrated significant reductions in low-density
ment in urea clearance. In general, patients on peritoneal dialysis do lipoprotein (LDL) cholesterol concentrations but no significant reduc-
well when they retain residual kidney function. Rates of technique tions in death or cardiovascular events (Die Deutsche Diabetes Dialyse
failure increase with years on dialysis and have been correlated with Studie [4D] and AURORA studies). The Study of Heart and Renal
loss of residual function to a greater extent than loss of peritoneal mem- Protection (SHARP) which included patients on dialysis and others
brane capacity. For some patients in whom CCPD does not provide suf- with nondialysis-requiring CKD showed a 17% reduction in the rate of
ficient solute clearance, a hybrid approach can be adopted where one major cardiovascular events or cardiovascular death with simvastatin-
or more daytime exchanges are added to the CCPD regimen. While this ezatamide treatment. Most experts recommend conventional cardio-

approach can enhance solute clearance and prolong a patient’s capacity protective strategies (e.g., lipid-lowering agents, aspirin, inhibitors of
to remain on peritoneal dialysis, the burden of the hybrid approach can the renin-angiotensin-aldosterone system, and β-adrenergic antago-
be overwhelming. nists) in patients receiving dialysis based on the patients’ cardiovascu-
lar risk profile, which appears to be increased by more than an order
■■COMPLICATIONS DURING PERITONEAL DIALYSIS of magnitude relative to persons unaffected by kidney disease. Other
The major complications of peritoneal dialysis are peritonitis, catheter- complications of ESRD include a high incidence of infection, progres-
associated nonperitonitis infections, weight gain and other metabolic sive debility and frailty, protein-energy malnutrition, and impaired
disturbances, and residual uremia (especially among patients with cognitive function.
little or no residual kidney function).
Peritonitis typically develops when there has been a break in sterile
technique during one or more of the exchange procedures. Peritonitis GLOBAL PERSPECTIVE
is usually defined by an elevated peritoneal fluid leukocyte count The incidence of ESRD is increasing worldwide with longer
(100/mm3, of which at least 50% are polymorphonuclear neutrophils); life expectancies and improved care of infectious and cardio-
these cutoffs are lower than in spontaneous bacterial peritonitis vascular diseases. The management of ESRD varies widely by
because of the presence of dextrose in peritoneal dialysis solutions country and within country by region, and it is influenced by economic
and rapid bacterial proliferation in this environment without antibiotic and other major factors. In general, peritoneal dialysis is more com-
therapy. The clinical presentation typically consists of pain and cloudy monly performed in poorer countries owing to its lower expense and
dialysate, often with fever and other constitutional symptoms. The the high cost of establishing in-center hemodialysis units.
most common culprit organisms are gram-positive cocci, including
Staphylococcus, reflecting the origin from the skin. Gram-negative rod
infections are less common; fungal and mycobacterial infections can ■■FURTHER READING
be seen in selected patients, particularly after antibacterial therapy. Cooper BA et al: A randomized, controlled trial of early versus late
Most cases of peritonitis can be managed either with intraperitoneal initiation of dialysis. N Engl J Med 363:609, 2010.
or oral antibiotics, depending on the organism; many patients with Correa-Rotter R et al: Peritoneal dialysis, in Brenner and Rector’s The
peritonitis do not require hospitalization. In cases where peritonitis is Kidney, 9th ed, MW Taal, GM Chertow, PA Marsden, K Skorecki, and
due to hydrophilic gram-negative rods (e.g., Pseudomonas sp.) or yeast, ASL Yu (eds). Philadelphia, Elsevier, 2011.
antimicrobial therapy is usually not sufficient, and catheter removal is Fellstrom BC et al: Rosuvastatin and cardiovascular events in patients
required to ensure complete eradication of infection. Nonperitonitis undergoing hemodialysis. N Engl J Med 360:1395, 2009.
catheter-associated infections (often termed tunnel infections) vary Flythe JE et al: Rapid fluid removal during dialysis is associated with
widely in severity. Some cases can be managed with local antibiotic or cardiovascular morbidity and mortality. Kidney Int 79:250, 2011.
silver nitrate administration, while others are severe enough to require Foley RN et al: Long interdialytic interval and mortality among
parenteral antibiotic therapy and catheter removal. patients receiving hemodialysis. N Engl J Med 365:1099, 2011.
Peritoneal dialysis is associated with a variety of metabolic compli- Frequent Hemodialysis Network Trial Group: In-center hemodial-
cations. Albumin and other proteins can be lost across the peritoneal ysis six times per week versus three times per week. N Engl J Med
membrane in concert with the loss of metabolic wastes. Hypopro- 363:2287, 2010.
teinemia obligates a higher dietary protein intake in order to maintain National Kidney Foundation: Kidney disease quality initiative
nitrogen balance. Hyperglycemia and weight gain are also common clinical practice guidelines: Hemodialysis and peritoneal dialysis
complications of peritoneal dialysis. Several hundred calories in the adequacy, 2006. Available online: http://www.kidney.org/professionals/
form of dextrose are absorbed each day, depending on the concentra- kdoqi/guidelines.cfm.
tion of dextrose employed. Patients receiving peritoneal dialysis, par- Rocco MV et al: The effects of frequent nocturnal home hemodialy-
ticularly those with diabetes mellitus, are prone to other complications sis: The frequent hemodialysis network nocturnal trial. Kidney Int
of insulin resistance, including hypertriglyceridemia. On the positive 80:1080, 2011.
side, the continuous nature of peritoneal dialysis usually allows for U.S. Renal Data System: USRDS 2016 Annual Data Report: Atlas of
a more liberal diet, due to continuous removal of potassium and End-Stage Renal Disease in the United States. Bethesda, National
phosphorus—two major dietary components whose accumulation can Institutes of Health, National Institute of Diabetes and Digestive and
be hazardous in ESRD. Kidney Disease, 2016.

2126 TABLE 307-1 Definition of a Non-Heart-Beating Donor
307 Transplantation in the

Treatment of Renal Failure
(Donation After Cardiac Deatha [DCD])
I: Brought in dead
II: Unsuccessful resuscitation
III: Awaiting cardiac arrest
Jamil Azzi, Edgar L. Milford, IV: Cardiac arrest after brainstem death
Mohamed H. Sayegh, Anil Chandraker V: Cardiac arrest in a hospital patient
a
Kidneys can be used for transplantation from categories II–V but are commonly
only used from categories III and IV. The survival of these kidneys has not been
Transplantation of the human kidney is the treatment of choice for shown to be inferior to that of deceased-donor kidneys.
advanced chronic renal failure. Worldwide, tens of thousands of these Note: Kidneys can both have a KDPI >85 % and be DCD. High KDPI kidneys have
been shown to have a poorer survival, and there is a separate shorter waiting list
procedures have been performed with >180,000 patients bearing func- for those kidneys. They are generally utilized for patients for whom the benefits of
tioning kidney transplants in the United States today. When azathio- being transplanted earlier outweigh the associated risks of using a lower quality
prine and prednisone initially were used as immunosuppressive drugs kidney.
in the 1960s, the results with properly matched familial donors were
superior to those with organs from deceased donors: 75–90% compared
with 50–60% graft survival rates at 1 year. During the 1970s and 1980s, however, there has been a steeper decline in survival of those with
the success rate at the 1-year mark for deceased-donor transplants deceased-donor kidneys.
rose progressively. Currently, deceased-donor grafts have a 92% 1-year
survival and living-donor grafts have a 97% 1-year survival. Although ■■RECIPIENT SELECTION
there has been improvement in long-term survival, it has not been as There are few absolute contraindications to renal transplantation. The
impressive as the short-term survival, and currently the “average” transplant procedure is relatively noninvasive, as the organ is generally
(t1/2) life expectancy of a living-donor graft is around 14 years and that placed in the inguinal fossa without entering the peritoneal cavity.
PART 9
of a deceased-donor graft is close to 10 years. Recipients without perioperative complications often can be discharged
Mortality rates after transplantation are highest in the first year and from the hospital in excellent condition within 5 days of the operation.
are age-related: 2% for ages 18–34 years, 3% for ages 35–49 years, and Virtually all patients with ESRD who receive a transplant have a
6.8% for ages ≥50–60 years. These rates compare favorably with those higher life expectancy than do risk-matched patients who remain on
dialysis. Even though diabetic patients and older candidates have a
in the chronic dialysis population even after risk adjustments for age,
diabetes, and cardiovascular status. While the loss of kidney trans- higher mortality rate than other transplant recipients, their survival is
plant due to acute rejection is currently rare, most allografts succumb improved with transplantation compared with those remaining on dial-
at varying rates to a chronic process consisting of interstitial fibrosis, ysis. This global benefit of transplantation as a treatment modality poses
tubular atrophy, vasculopathy, and glomerulopathy, the pathogenesis substantial ethical issues for policy makers, as the number of deceased
of which is incompletely understood. Overall, transplantation returns donor kidneys available is far from sufficient to meet the current needs
most patients to an improved lifestyle and an improved life expectancy of the candidates. The current standard of care is that the candidate
compared with patients on dialysis. should have a life expectancy of >5 years to be put on a deceased organ
wait list. Even for living donation, the candidate should have >5 years
of life expectancy. This standard has been established because the
RECENT ACTIVITY AND RESULTS benefits of kidney transplantation over dialysis are realized only after
In 2014 there were more than 12,328 deceased-donor kidney trans- a perioperative period in which the mortality rate is higher in trans-
plants and 5574 living-donor transplants in the United States, with the planted patients than in dialysis patients with comparable risk profiles.
ratio of deceased to living donors remaining stable over the last few All candidates must have a thorough risk-versus-benefit evaluation
years. The backlog of patients with end-stage renal disease (ESRD) before being approved for transplantation. In particular, an aggressive
has been increasing every year, and it always lags behind the number approach to diagnosis of correctable coronary artery disease, presence
of available donors. As the number of patients with end-stage kidney of latent or indolent infection (HIV, hepatitis B or C, tuberculosis), and
disease increases, the demand for kidney transplants continues to neoplasm should be a routine part of the candidate workup. Most
increase. As of 2015, there were 50,692 active adult candidates on the transplant centers consider overt AIDS and active hepatitis absolute
waiting list, and <18,000 patients were transplanted. This imbalance is contraindications to transplantation because of the high risk of oppor-
set to worsen over the coming years with the predicted increased rates tunistic infection. Some centers are now transplanting individuals with
of obesity and diabetes worldwide. In an attempt to increase utilization hepatitis and even HIV infection under strict protocols to determine
of marginal kidneys while insuring longevity-matching, a new alloca- whether the risks and benefits favor transplantation over dialysis. Over
tion system was developed and recently implemented. The main rule the last few years, new direct acting hepatitis C antiviral medications
is that patients expected to survive the longest receive the allografts have been introduced and have been shown to be very effective thera-
expected to last the longest. For this purpose, the Kidney Donor Profile pies both pre- and posttransplant. Those medications are reshaping our
Index (KDPI) score from 0 to 100% has been introduced to quantify the approach to patients with hepatitis C.
potential risk of graft failure after kidney transplant based on 10 donor Among the few absolute “immunologic” contraindications to trans-
factors. The lower KDPI values are associated with higher expected plantation is the presence of antibodies against the donor kidney at the
post-transplant survival. Hence, kidneys with KDPI <20% are allocated time of the anticipated transplant that can cause hyperacute rejection.
to the 20% of the potential recipients with the highest expected pos- Those harmful antibodies include natural antibodies against the ABO
transplant survival. The kidneys with KDPI >85% (previously called blood group antigens and antibodies against human leukocyte antigen
expanded criteria donor or ECD kidneys) are usually used for older (HLA) class I (A, B, C) or class II (DR, DQ, DP) antigens. These antibod-
patients who are expected to fare less well on dialysis. Kidneys from ies are routinely excluded by proper screening of the candidate’s ABO
donors after cardiac death (DCD) are also been used to overcome the compatibility and direct cytotoxic cross-matching of candidate serum
increasing demand on the waiting list (Table 307-1). with lymphocytes of the donor.
The overall results of transplantation are presented in Table 307-2
as the survival of grafts and of patients. At the 1-year mark, graft sur- TISSUE TYPING AND CLINICAL
vival is higher for living-donor recipients, most likely because those IMMUNOGENETICS
grafts are not subject to as much ischemic injury. The more effective Matching for antigens of the HLA major histocompatibility gene com-
drugs now in use for immunosuppression have almost equalized the plex (Chap. 343) is an important criterion for selection of donors for
risk of graft rejection in all patients for the first year. At 5 and 10 years, renal allografts. Each mammalian species has a single chromosomal

2127
TABLE 307-2 Mean Rates of Graft and Patient Survival for Kidneys Transplanted in the United States from 1998 to 2008a
1-YEAR FOLLOW-UP 5-YEAR FOLLOW-UP 10-YEAR FOLLOW-UP
GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, %
Deceased donor 92 96 72 84 46 64
Living donor 96 99 81 91 59 77
a
All patients transplanted are included, and the follow-up unadjusted survival data from the 1-, 5- , and 10-year periods are presented to show the attrition rates over
time within the two types of organ donors.
Source: Data from Summary Tables, 2009 Annual Reports, Scientific Registry of Transplant Recipients.
region that encodes the strong, or major, transplantation antigens, In the United States, there is a coordinated national system of
and this region on the human sixth chromosome is called HLA. HLA regulations, allocation support, and outcomes analysis for kidney
antigens have been classically defined by serologic techniques, but transplantation called the Organ Procurement Transplant Network. It
methods to define specific nucleotide sequences in genomic DNA are is now possible to remove deceased-donor kidneys and maintain them
increasingly being used. Other “minor” antigens may play crucial for up to 48 h on cold pulsatile perfusion or with simple flushing and
roles, in addition to the ABH(O) blood groups and endothelial antigens cooling. Although generally an ischemic time of <24 h is preferred, this
that are not shared with lymphocytes. The Rh system is not expressed approach permits adequate time for typing, cross-matching, transpor-
on graft tissue. Evidence for designation of HLA as the genetic region tation, and selection problems to be solved.
that encodes major transplantation antigens comes from the success
rate in living related donor renal and bone marrow transplantation,
■■PRESENSITIZATION
A positive cytotoxic cross-match of recipient serum with donor T lym-
with superior results in HLA-identical sibling pairs. Nevertheless, 5%
phocytes indicates the presence of pre-formed donor specific anti-HLA
of HLA-identical renal allografts are rejected, often within the first
class I antibodies and is usually predictive of an acute vasculitic event
CHAPTER 307 Transplantation in the Treatment of Renal Failure

weeks after transplantation. These failures represent states of prior sen-
termed hyperacute rejection. This finding, along with ABO incompat-
sitization to non-HLA antigens. Non-HLA minor antigens are relatively
ibility, represents the only absolute immunologic contraindication
weak when initially encountered and are, therefore, suppressible by
for kidney transplantation. Recently, an increasing number of tissue
conventional immunosuppressive therapy. Once priming has occurred,
typing laboratories have shifted to a flow cytometric-based crossmatch
however, secondary responses are much more refractory to treatment.
assay, which detects the presence of anti HLA antibodies that are not
necessarily detected on a cytotoxic crossmatch assay and may not be
DONOR SELECTION an absolute contraindication to transplantation. The known sources
Donors can be deceased or volunteer living donors. When first-degree rel- of such sensitization are blood transfusion, a prior transplant, preg-
atives are donors, graft survival rates at 1 year are 5–7% greater than those nancy, and vaccination/infection. Patients sustained by dialysis often
for deceased-donor grafts. The 5-year survival rates still favor a partially show fluctuating antibody titers and specificity patterns. At the time
matched (3/6 HLA mismatched) family donor over a randomly selected of assignment of a cadaveric kidney, cross-matches are performed
cadaver donor. In addition, living donors provide the advantage of imme- with at least a current serum. Previously analyzed antibody specific-
diate availability. For both living and deceased donors, the 5-year out- ities and additional cross-matches are performed accordingly. Flow
comes are somewhat poorer if there is a complete (6/6) HLA mismatch. cytometry detects binding of anti-HLA antibodies of candidate serum
The survival rate of living unrelated renal allografts is as high as that by recipient’s lymphocytes. This highly sensitive test can be useful for
of perfectly HLA-matched cadaver renal transplants and comparable avoidance of accelerated, and often untreatable, early graft rejection in
to that of kidneys from living relatives. This outcome is probably a patients receiving second or third transplants.
consequence of both short cold ischemia time and the extra care taken For the purposes of crossmatching, donor T lymphocytes, which
to document that the condition and renal function of the donor are express class I but not class II antigens, are used as targets for detection
optimal before proceeding with a living unrelated donation. It is illegal of anti–class I (HLA-A and -B) antibodies that are expressed on all
in the United States to purchase organs for transplantation. nucleated cells. Preformed anti–class II (HLA-DR and -DQ) antibodies
Living volunteer donors should be cleared of any medical conditions against the donor also carry a higher risk of graft loss, particularly in
that may cause morbidity and mortality after kidney transplantation. recipients who have suffered early loss of a prior kidney transplant. B
Concern has been expressed about the potential risk to a volunteer lymphocytes, which express both class I and class II antigens, are used
kidney donor of premature renal failure after several years of increased as targets in these assays. Furthermore, donor-specific HLA antibodies
blood flow and hyperfiltration per nephron in the remaining kidney. that fix complements have been shown to strongly correlate with anti-
There are a few reports of the development of hypertension, proteinuria, body mediated rejection and worse long-term outcome.
and even lesions of focal segmental sclerosis in donors over long-term Some non-HLA antigens restricted in expression to endothelium
follow-up. It is also desirable to consider the risk of development of and monocytes have been described, but their clinical relevance is not
type 1 diabetes mellitus in a family member who is a potential donor to well established. A series of minor histocompatibility antigens do not
a diabetic renal failure patient. Anti-insulin and anti-islet cell antibodies elicit antibodies, and sensitization to these antigens is detectable only
should be measured, and glucose tolerance tests should be performed in by cytotoxic T cells, an assay too cumbersome for routine use.
such donors to exclude a prediabetic state. Selective renal arteriography Desensitization before transplantation by reducing the level of
should be performed on donors to rule out the presence of multiple or anti-donor antibodies utilizing plasmapheresis and administration of
abnormal renal arteries, because the surgical procedure is difficult, and pooled immunoglobulin, or both, has been useful in reducing the risk
the ischemic time of the transplanted kidney is long when there are vas- of hyperacute rejection following transplantation.
cular abnormalities. Transplant surgeons commonly use a laparoscopic
approach to isolate and remove the living donor’s kidney. This operation IMMUNOLOGY OF REJECTION
has the advantage of less evident surgical scars, and, as there is less Both cellular and humoral (antibody-mediated) effector mechanisms
tissue trauma, laparoscopic donors have a substantially shorter hospital can play roles in kidney transplant rejection.
stay and less discomfort than those who undergo an open nephrectomy. Cellular rejection is mediated by lymphocytes that respond to HLA
Deceased donors should be free of malignant neoplastic disease, antigens expressed within the organ. The CD4+ lymphocyte responds
hepatitis, and HIV owing to possible transmission to the recipient, to class II (HLA-DR) incompatibility by proliferating and releasing
although under certain circumstances hepatitis C- and HIV-positive proinflammatory cytokines that augment the proliferative response of
organs may be used in previously infected recipients. Increased risk of the immune system. CD8+ cytotoxic lymphocyte precursors respond
graft failure exists when the donor is elderly or has acute renal failure primarily to class I (HLA-A, -B) antigens and mature into cytotoxic
or when the kidney has a prolonged period of ischemia. effector cells that cause organ damage through direct contact and

2128 Direct Pathway Indirect Pathway through both of these pathways induces activation of the kinase activ-
ity of calcineurin which, in turn, activates transcription factors leading
to upregulation of multiple genes, including interleukin-2 (IL-2) and
Allogeneic APC Allogeneic APC Self APC interferon gamma. IL-2 signals through the target of rapamycin (TOR)
to induce cell proliferation in an autocrine fashion. There is evidence
MHC molecule that non-HLA antigens can also play a role in renal transplant rejection
Allogeneic peptide episodes. Recipients who receive a kidney from an HLA-identical
CD8 CD4 CD4 sibling can have rejection episodes and require maintenance immu-
nosuppression, whereas identical twin transplants require no immu-
Tc TH TH nosuppression. There are documented non-HLA antigens, such as an
endothelial-specific antigen system with limited polymorphism and a
tubular antigen, which can act as targets of humoral or cellular rejection
responses, respectively.
Cytokines
IMMUNOSUPPRESSIVE TREATMENT
Immunosuppressive therapy, as currently available, generally sup-
presses all immune responses, including those to bacteria, fungi, and
Tc B cell Macrophage even malignant tumors. In general, all clinically useful drugs are more
selective to primary than to memory immune responses. Agents to sup-
press the immune response are classically divided into induction and
Activated Delayed-type
cytotoxic T cell hypersensitivity maintenance agents, and will be discussed in the following paragraphs.
Those currently in clinical use are listed in Table 307-3.
Alloantibodies
PART 9
■■INDUCTION THERAPY
Cellular Antibody mediated Transplant
Induction therapy is currently given to most kidney transplant recipi-
rejection rejection arteriosclerosis ents in the United States at the time of transplant to reduce the risk of
early acute rejection and to minimize or eliminate the use of either ste-
FIGURE 307-1 Recognition pathways for major histocompatibility complex
roids or calcineurin inhibitors and their associated toxicities. Induction
(MHC) antigens. Graft rejection is initiated by CD4 helper T lymphocytes (TH)

having antigen receptors that bind to specific complexes of peptides and MHC therapy consists of antibodies that could be monoclonal or polyclonal,
class II molecules on antigen-presenting cells (APC). In transplantation, in contrast depletional or nondepletional.
to other immunologic responses, there are two sets of T cell clones involved in
rejection. In the direct pathway the class II MHC of donor allogeneic APCs is Depleting Agents Anti-thymocyte globulin (ATG): peripheral
recognized by CD4 TH cells that bind to the intact MHC molecule, and class I human lymphocytes, thymocytes, or lymphocytes from spleens or tho-
MHC allogeneic cells are recognized by CD8 T cells. The latter generally proliferate racic duct fistulas are injected into horses, rabbits, or goats to produce
into cytotoxic cells (TC). In the indirect pathway, the incompatible MHC molecules anti-lymphocyte serum, from which the globulin fraction is then sepa-
are processed into peptides that are presented by the self-APCs of the recipient.
The indirect, but not the direct, pathway is the normal physiologic process in rated. Those polyclonal antibodies induce lymphocyte depletion, and
T cell recognition of foreign antigens. Once TH cells are activated, they proliferate the immune system may take several months to recover.
and, by secretion of cytokines and direct contact, exert strong helper effects on Monoclonal antibodies against defined lymphocyte subsets offer
macrophages, TC, and B cells. (From MH Sayegh, LH Turka: N Engl J Med, 338:1813, a more precise and standardized form of therapy. Alemtuzumab is
1998. Copyright 1998, Massachusetts Medical Society. All rights reserved.) directed to the CD52 protein, widely distributed on immune cells such as
B and T cells, natural killer cells, macrophages, and some granulocytes.
lysis of donor target cells. Full T cell activation requires not only
T cell receptor binding to the allo-antigens presented by self or donor Nondepleting Agents Another approach to more selective ther-
HLA molecules (indirect and direct presentation respectively), but also apy is to target the 55-kDa alpha chain of the IL-2 receptor, which
engaging costimulatory molecules such as CD28 on T cells and CD80 is expressed only on T cells that have been recently activated. This
and CD86 ligands on antigen presenting cells (Fig. 307-1). Signaling approach is used as prophylaxis for acute rejection in the immediate
TABLE 307-3 Maintenance Immunosuppressive Drugs

AGENT PHARMACOLOGY MECHANISMS SIDE EFFECTS
Glucocorticoids Increased bioavailability with Binds cytosolic receptors and heat shock proteins. Hypertension, glucose intolerance,
hypoalbuminemia and liver disease; Blocks transcription of IL-1, -2, -3, -6, TNF-α, and dyslipidemia, osteoporosis
prednisone/prednisolone generally IFN-γ
used
Cyclosporine (CsA) Lipid-soluble polypeptide, variable Trimolecular complex with cyclophilin and Nephrotoxicity, hypertension, dyslipidemia,
absorption, microemulsion more calcineurin → block in cytokine (e.g., IL-2) glucose intolerance, hirsutism/hyperplasia
predictable production; however, stimulates TGF-β production of gums
Tacrolimus Macrolide, well absorbed Trimolecular complex with FKBP-12 and calcineurin Similar to CsA, but hirsutism/hyperplasia of
→ block in cytokine (e.g., IL-2) production; may gums unusual, and diabetes more likely
stimulate TGF-β production
Azathioprine Mercaptopurine analogue Hepatic metabolites inhibit purine synthesis Marrow suppression (WBC > RBC >
platelets)
Mycophenolate Metabolized to mycophenolic acid Inhibits purine synthesis via inosine Diarrhea/cramps; dose-related liver and
mofetil/sodium monophosphate dehydrogenase marrow suppression is uncommon
Sirolimus/Everolimus Macrolide, poor oral bioavailability Complexes with FKBP-12 and then blocks p70 S6 Hyperlipidemia, thrombocytopenia
kinase in the IL-2 receptor pathway for proliferation
Belatacept Fusion protein, intravenous injections Binds CD80 and CD86, prevents CD28 binding Posttransplant Lymphoproliferative Disease
and T cell activation (PTLD)
Abbreviations: FKBP-12, FK506 binding protein 12; IFN, interferon; IL, interleukin; RBC, red blood cells; TGF, transforming growth factor; TNF, tumor necrosis factor;
WBC, white blood cells.

posttransplant period, and is effective at decreasing the early acute T cell growth factor signaling pathways, preventing the response to 2129
rejection rate with few adverse side effects. IL-2 and other cytokines. Sirolimus can be used in conjunction with
The next step in the evolution of this therapeutic strategy, which has cyclosporine or tacrolimus, or with mycophenolic acid, to avoid the use
already been achieved in the short term in small numbers of immuno- of calcineurin inhibitors.
logically well-matched patients, is the elimination of all maintenance Everolimus is another mTOR inhibitor with similar mechanism of
immunosuppression therapy. action as Sirolimus but with better bioavailability.
■■MAINTENANCE THERAPY Belatacept Belatacept is a fusion protein that binds costimulatory
All kidney transplant recipients should receive maintenance immuno- ligands (CD80 and CD86) present on antigen presenting cells, inter-
suppressive therapies except identical twins. The most frequently used rupting their binding to CD28 on T cells. This inhibition leads to T cell
combination is triple therapy with prednisone, a calcineurin inhibitor, anergy and apoptosis. Belatacept is FDA-approved for kidney trans-
and an antimetabolite; mTOR inhibitors can replace one of the last two plant recipients and is given monthly as an intravenous infusion. The
agents. More recently, the FDA approved a new costimulatory blocking 7 years follow-up of the Belatacept Evaluation of Nephroprotection
antibody, belatacept, as a new strategy to prevent long-term CNI toxicity. and Efficacy as First-line Immunosuppression Trial (BENEFIT) showed
higher patient and graft survival for the belatacept treated group com-
Antimetabolites Azathioprine, an analogue of mercaptopurine, pared to cyclosporine.
was for two decades the keystone to immunosuppressive therapy in
humans, but has given way to more effective agents. This agent can
inhibit synthesis of DNA, RNA, or both. Azathioprine is administered
CLINICAL COURSE AND MANAGEMENT OF
in doses of 1.5–2 mg/kg per day. Reduction in the dose is required THE RECIPIENT
because of leukopenia and occasionally thrombocytopenia. Excessive Adequate hemodialysis should be performed within 48 h of surgery as
amounts of azathioprine may also cause jaundice, anemia, and alope- necessary, and care should be taken that the serum potassium level is
cia. If it is essential to administer allopurinol concurrently, the azathi- not markedly elevated so that intraoperative cardiac arrhythmias can

oprine dose must be reduced. As inhibition of xanthine oxidase delays be averted. The diuresis that commonly occurs postoperatively must
degradation, this combination is best avoided. be carefully monitored. In some instances, it may be massive, reflecting
Mycophenolate mofetil or mycophenolate sodium, both of which are the inability of ischemic tubules to regulate sodium and water excre-
metabolized to mycophenolic acid, is now used in place of azathioprine tion; with large diureses, large amounts of potassium may be lost. Most
in most centers. It has a similar mode of action and a mild degree of chronically uremic patients have some excess of extracellular fluid, and
gastrointestinal toxicity but produces less bone marrow suppression. Its it is useful to maintain an expanded fluid volume in the immediate
advantage is its increased potency in preventing or reversing rejection. postoperative period. Acute tubular necrosis (ATN) due to ischemia
may cause immediate oliguria or may follow an initial short period of
Steroids Glucocorticoids are important adjuncts to immunosuppres- graft function. Recovery usually occurs within 3 weeks, although peri-
sive therapy. Among all the agents employed, prednisone has effects ods as long as 6 weeks have been reported. Superimposition of rejec-
that are easiest to assess, and in large doses it is usually effective for tion on ATN is common, and the differential diagnosis may be difficult
the reversal of rejection. In general, 200–300 mg prednisone is given without a graft biopsy. Cyclosporine therapy prolongs ATN, and some
immediately before or at the time of transplantation, and the dose is patients do not diurese until the dose is reduced drastically. Many cen-
reduced to 30 mg within a week. The side effects of the glucocorti- ters avoid starting calcinenrins for the first several days, using ALG or
coids, particularly impairment of wound healing and predisposition to a monoclonal antibody along with mycophenolic acid and prednisone
infection, make it desirable to taper the dose as rapidly as possible in until renal function is established. Figure 307-2 illustrates an algorithm
the immediate postoperative period. Many centers now have protocols followed by many transplant centers for early posttransplant manage-
for early discontinuance or avoidance of steroids because of long-term ment of recipients at high or low risk of early renal dysfunction.
adverse effects on bone, skin, and glucose metabolism. For treatment
of acute rejection, methylprednisolone, 0.5–1 g IV, is administered ■■THE REJECTION EPISODE
immediately upon diagnosis of beginning rejection and continued Early diagnosis of rejection allows prompt institution of therapy to pre-
once daily for 3 days. Such “pulse” doses are not effective in chronic serve renal function and prevent irreversible damage. Clinical evidence
rejection. Most patients whose renal function is stable after 6 months or of rejection is rarely characterized by fever, swelling, and tenderness
a year do not require large doses of prednisone; maintenance doses of over the allograft. Rejection may present only with a rise in serum cre-
5–10 mg/d are the rule. A major effect of steroids is preventing the atinine, with or without a reduction in urine volume. The focus should
release of interleukin (IL) 6 and IL-1 by monocytes-macrophages. be on ruling out other causes of functional deterioration.
Calcineurin Inhibitors Cyclosporine is a fungal peptide with Doppler ultrasonography may be useful in ascertaining changes in the
potent immunosuppressive activity. It acts on the calcineurin pathway renal vasculature and in renal blood flow. Thrombosis of the renal vein
to block transcription of mRNA for IL-2 and other proinflammatory occurs rarely; it may be reversible if it is caused by technical factors and
cytokines, thereby inhibiting T cell proliferation. Although it works intervention is prompt. Diagnostic ultrasound is the procedure of choice
alone, cyclosporine is more effective in conjunction with glucocorti- to rule out urinary obstruction or to confirm the presence of perirenal
coids and mycophenolate. Clinical results with tens of thousands of collections of urine, blood, or lymph. A rise in the serum creatinine level
renal transplants have been impressive. Among its toxic effects (neph- is a late marker of rejection, but it may be the only sign. Novel biomarkers
rotoxicity, hepatotoxicity, hirsutism, tremor, gingival hyperplasia, and are needed for early noninvasive detection of allograft rejection.
diabetes), only nephrotoxicity presents a serious management problem Calcineurin inhibitors (cyclosporine and tacrolimus) have an affer-
and is further discussed below. ent arteriolar constrictor effect on the kidney, and may produce perma-
Tacrolimus (previously called FK506) is a fungal macrolide that has nent vascular and interstitial injury after sustained high-dose therapy.
the same mode of action as cyclosporine as well as a similar side-effect This action will lead to a deterioration in renal function difficult to
profile; it does not, however, produce hirsutism or gingival hyper- distinguish from rejection without a renal biopsy. Interstitial fibrosis,
plasia. De novo diabetes mellitus is more common with tacrolimus. isometric tubular vacuolization, and thickening of arteriolar walls are
The drug was first used in liver transplantation and may substitute suggestive of this side effect, but not diagnostic. Hence, if no rejection
for cyclosporine entirely or as an alternative in renal patients whose is detected on the biopsy, serum creatinine may respond to a reduction
rejections are poorly controlled by cyclosporine. An extended release in dose. However, if cellular rejection activity is present in the biopsy,
formulation of tacrolimus is now available and is given once daily. appropriate therapy is indicated. The first rejection episode is usually
treated with IV administration of methylprednisolone, 500–1000 mg
TOR Inhibitors Sirolimus (previously called rapamycin) is another daily for 3 days. Failure to respond is an indication for antibody ther-
fungal macrolide but has a different mode of action; i.e., it inhibits apy, usually with antithymocyte globulin.

2130 infections are most common during the first
ALGORITHM FOR KIDNEY RECIPIENT CARE
month after transplantation. The impor-
Recipient High % PRA (sensitization level) Recipient PRA <10%, and tance of blood cultures in such patients can-
not be overemphasized because systemic
Recipient Prior Transplant (lost in <3 months) Recipient First Transplant and infection without obvious foci is common.
Particularly ominous are rapidly occurring
Donor cold ischemia time >24 h, or Donor cold ischemia time <12 h, and
Donor age >60 years, or Donor physiology ideal, and
pulmonary lesions, which may result in
Donor age >50 years with hypertension, or Donor 15–35 years old death within 5 days of onset. When these
Donor kidney biopsy >20% glomerulosclerosis lesions become apparent, immunosuppres-
sive agents should be discontinued, except
for maintenance doses of prednisone.
“High risk” “Low risk” Aggressive diagnostic procedures,
including transbronchial and open-lung
biopsy, are frequently indicated. In the
Antilymphocyte globulin Steroids
case of Pneumocystis carinii (Chap. 215)
“induction” therapy Calcineurin inhibitor
Mycophenolic acid mofetil infection, trimethoprim-sulfamethoxazole
Avoid calcineurin inhibitor
(TMP-SMX) is the treatment of choice;
until kidney function
is established amphotericin B has been used effectively
in systemic fungal infections. Prophylaxis
Persistent renal dysfunction against P. jirovecci with daily or alternate-
or day low-dose TMP-SMX is very effec-
Steroids De novo transplant dysfunction* with
Calcineurin inhibitor tive. Involvement of the oropharynx with
adequate calcineurin inhibitor levels
Mycophenolic acid mofetil Candida (Chap. 211) may be treated with
PART 9
local nystatin. Tissue-invasive fungal infec-

tions require treatment with systemic agents
Empirical IV steroid “pulse”
Transplant dysfunction* therapy (methylprednisolone such as fluconazole. Small doses (a total of
0.2–1 g/d x 3 days) 300 mg) of amphotericin given over a period
of 2 weeks may be effective in fungal infec-
tions refractory to fluconazole. Macrolide

Low calcineurin Adequate calcineurin antibiotics, especially ketoconazole and ery-
inhibitor level inhibitor level No response
thromycin, and some calcium channel block-
ers (diltiazem, verapamil) compete with
calcineurin inhibitors for P450 catabolism
Empirical IV steroid “pulse” and cause elevated levels of these immu-
therapy (methylprednisolone Renal biopsy nosuppressive drugs. Analeptics, such as
0.2–1.0 g/d x 3 days)
phenytoin and carbamazepine, will increase
catabolism to result in low levels. Aspergillus
(Chap. 212), Nocardia (Chap. 169), and espe-
No response Acute rejection cially CMV (Chap. 190) infections also occur.
CMV is a common and dangerous DNA
virus in transplant recipients. It does not
Anti-CD3 monoclonal antibody (OKT3 5 g/d x 7–10 days) generally appear until the end of the first
posttransplant month. Active CMV infec-
FIGURE 307-2 A typical algorithm for early posttransplant care of a kidney recipient. If any of the recipient or
tion is sometimes associated, or occasionally
donor “high-risk” factors exist, more aggressive management is called for. Low-risk patients can be treated with confused, with rejection episodes. Patients at
a standard immunosuppressive regimen. Patients at higher risk of rejection or early ischemic and nephrotoxic highest risk for severe CMV disease are those
transplant dysfunction are often induced with an antilymphocyte globulin to provide more potent early without anti-CMV antibodies who receive a
immunosuppression or to spare calcineurin nephrotoxicity. *When there is early transplant dysfunction, prerenal, graft from a CMV antibody–positive donor
obstructive, and vascular causes must be ruled out by ultrasonographic examination. The panel reactive antibody (15% mortality). Valganciclovir is a cost-
(PRA) is a quantitation of how much antibody is present in a candidate against a panel of cells representing the
distribution of antigens in the donor pool. APC, antigen-presenting cell; MHC, major histocompatibility complex.
effective and bioavailable oral form of ganci-
clovir that has been proved effective in both
prophylaxis and treatment of CMV disease.
Evidence of antibody-mediated injury is present when endothelial
injury and deposition of complement component c4d is detected by TABLE 307-4 The Most Common Opportunistic Infections in Renal
fluorescence labeling. This is usually accompanied by detection of the Transplant Recipients
antibody in the recipient blood. The prognosis is poor, and aggressive Peritransplant (<1 month) Late (>6 months)
use of plasmapheresis, immunoglobulin infusions, anti-CD20 mono- Wound infections Aspergillus
clonal antibody (rituximab) to target B lymphocytes, bortezomib to Herpesvirus Nocardia
target antibody producing plasma cells, and eculizumab to inhibit
Oral candidiasis BK virus (polyoma)
complement is indicated.
Urinary tract infection Herpes zoster
■■MANAGEMENT PROBLEMS Early (1–6 months) Hepatitis B
The typical times after transplantation when the most common opportu- Pneumocystis carinii Hepatitis C
nistic infections occur are shown in Table 307-4. Prophylaxis for cytomeg- Cytomegalovirus
alovirus (CMV) and Pneumocystis Jirovecci pneumonia is given for Legionella
6–12 months after transplantation. Listeria
The signs and symptoms of infection may be masked or distorted. Hepatitis B
Fever without obvious cause is common, and only after days or weeks
Hepatitis C
may it become apparent that it has a viral or fungal origin. Bacterial

Early diagnosis in a febrile patient with clinical suspicion of CMV dis- Hypercalcemia after transplantation may indicate failure of hyper- 2131
ease can be made by determining CMV viral load in the blood. A rise in plastic parathyroid glands to regress. Aseptic necrosis of the head of
IgM antibodies to CMV is also diagnostic. Culture of CMV from blood the femur is probably due to preexisting hyperparathyroidism, with
may be less sensitive. Tissue invasion of CMV is common in the gastro- aggravation by glucocorticoid treatment. With improved manage-
intestinal tract and lungs. CMV retinopathy occurs late in the course, ment of calcium and phosphorus metabolism during chronic dialysis,
if untreated. Treatment of active CMV disease with valganciclovir is the incidence of parathyroid-related complications has fallen dra-
always indicated. In many patients immune to CMV, viral activation matically. Persistent hyperparathyroid activity may require subtotal
can occur with major immunosuppressive regimens. parathyroidectomy.
The polyoma group (BK, JC, SV40) is another class of DNA viruses Although most transplant patients have robust production of ery-
that can become dormant in kidneys and can be activated by immuno- thropoietin and normalization of hemoglobin, anemia is commonly
suppression. When reactivation occurs with BK, if left untreated, there seen in the posttransplant period. Often the anemia is attributable
is a 50% chance of progressive fibrosis and loss of the graft within 1 year to bone marrow–suppressant immunosuppressive medications such
by the activated virus. Risk of infection is associated with the overall as azathioprine, mycophenolic acid, and sirolimus. Gastrointestinal
degree of immunosuppression rather than the individual immunosup- bleeding is a common side effect of high-dose and long-term steroid
pressive drugs used. Renal biopsy is necessary for the diagnosis. There administration. Many transplant patients have creatinine clearances of
have been variable results with leflunomide, cidofovir, and quinolone 30–50 mL/min and can be considered in the same way as other patients
anitibiotics (which are effective against polyoma helicase), but it is most with chronic renal insufficiency for anemia management, including
important to reduce the immunosuppressive load. supplemental erythropoietin.
The complications of glucocorticoid therapy are well known and Chronic hepatitis, particularly when due to hepatitis B virus, can be a
include gastrointestinal bleeding, impairment of wound healing, oste- progressive, fatal disease over a decade or so. Patients who are persis-
oporosis, diabetes mellitus, cataract formation, and hemorrhagic pan- tently hepatitis B surface antigen–positive are at higher risk, according
creatitis. The treatment of unexplained jaundice in transplant patients to some studies, but the presence of hepatitis C virus is also a concern

should include cessation or reduction of immunosuppressive drugs if when one embarks on a course of immunosuppression in a transplant
hepatitis or drug toxicity is suspected. Therapy in such circumstances recipient. However, the introduction of the new highly effective direct
often does not result in rejection of a graft, at least for several weeks. acting hepatitis C antiviral medications promises to reduce this risk
Acyclovir is effective in therapy for herpes simplex virus infections. significantly.
■■CHRONIC LESIONS OF THE TRANSPLANTED KIDNEY ■■FURTHER READING
Although 1-year transplant survival is excellent, most recipients expe- Birnbaum LM et al: Management of chronic allograft nephropathy: A
rience progressive decline in kidney function over time thereafter. systematic review. Clin J Am Soc Nephrol 4:860, 2009.
Chronic renal transplant dysfunction can be caused by recurrent disease, Briganti EM et al: Risk of renal allograft loss from recurrent glomeru-
hypertension, cyclosporine or tacrolimus nephrotoxicity, chronic immu- lonephritis. N Engl J Med 347:103, 2002.
nologic rejection, secondary focal glomerulosclerosis, or a combination Freeman RB Jr: Survival benefit: Quality versus quantity and trade-
of these pathophysiologies. Chronic vascular changes with intimal offs in developing new renal allocation systems. Am J Transplant
proliferation and medial hypertrophy are commonly found. Control of 7:1043, 2007.
systemic and intrarenal hypertension with ACE inhibitors is thought to Hirsch HH et al: Polyomavirus-associated nephropathy in renal
have a beneficial influence on the rate of progression of chronic renal transplantation: Interdisciplinary analyses and recommendations.
transplant dysfunction. Renal biopsy can distinguish subacute cellular Transplantation 79:1277, 2005.
rejection from recurrent disease or secondary focal sclerosis. Hodson EM et al: Antiviral medications for preventing cytomegalovi-
MALIGNANCY rus disease in solid organ transplant recipients. Cochrane Database
The incidence of tumors in patients on immunosuppressive therapy is Syst Rev CD003774, 2008.
5–6%, or ~100 times greater than that in the general population in the Ibrahim HN et al: Long-term consequences of kidney donation. N Engl
same age range. The most common lesions are cancer of the skin and J Med 360:459, 2009.
lips and carcinoma in situ of the cervix, as well as lymphomas such as KDIGO clinical practice guideline for the care of kidney transplant
non-Hodgkin’s lymphoma. The risks are increased in proportion to the recipients. Am J Transplant 9 Suppl 3:S1, 2009.
total immunosuppressive load administered and the time elapsed since Lentine KL et al: Incidence and predictors of myocardial infarction
transplantation. Surveillance for skin and cervical cancers is necessary. after kidney transplantation. J Am Soc Nephrol 16:496, 2005.
Loupy A et al: Complement-binding anti-HLA antibodies and
■■OTHER COMPLICATIONS kidney-allograft survival. N Engl J Med 369:1215, 2013.
Both chronic dialysis and renal transplant patients have a higher inci- Matas AJ et al: OPTN/SRTR 2013 Annual Data Report: Kidney. Am J
dence of death from myocardial infarction and stroke than does the Transplant 15 Suppl 2:1, 2015.
population at large, and this is particularly true in diabetic patients. Riella LV, Sheridan AM: Testing for high-risk APOL1 alleles in poten-
Contributing factors are the use of glucocorticoids and sirolimus, tial living kidney donors. Am J Kidney Dis 66:396, 2015.
as well as hypertension. Recipients of renal transplants have a high Sawinski D et al: Successful treatment of Hepatitis C in renal trans-
prevalence of coronary artery and peripheral vascular diseases. The plant recipients with direct-acting antiviral agents. Am J Transplant
percentage of deaths from these causes has been slowly rising as the 16:1588, 2017.
numbers of transplanted diabetic patients and the average age of Stegall MD: Clinical management of renal transplant patients with
all recipients increase. More than 50% of renal recipient mortality is donor-specific alloantibody: The state of the art. Clin Transpl 307,
attributable to cardiovascular disease. In addition to strict control of 2010.
blood pressure and blood lipid levels, close monitoring of patients for Stewart DE et al: Changes in deceased donor kidney transplantation
indications of further medical or surgical intervention is an important one year after KAS implementation. Am J Transplant 16:1834, 2016.
part of management. Vincenti F et al: Belatacept and long-term outcomes in kidney trans-
Hypertension may be caused by (1) native kidney disease, (2) rejec- plantation. N Engl J Med 374:333, 2016.
tion activity in the transplant, (3) renal artery stenosis if an end-to-end Webster AC et al: Identifying high risk groups and quantifying abso-
anastomosis was constructed with an iliac artery branch, and (4) renal lute risk of cancer after kidney transplantation: a cohort study of
calcineurin inhibitor toxicity, which may improve with reduction in 15,183 recipients. Am J Transplant 7:2140, 2007.
dose. Whereas ACE inhibitors may be useful, calcium channel blockers Wolfe RA et al: Comparison of mortality in all patients on dialysis,
are more frequently used initially. Amelioration of hypertension to the patients on dialysis awaiting transplantation, and recipients of a first
range of 120–130/70–80 mmHg should be the goal in all patients. cadaveric transplant. N Engl J Med 341:1725, 1999.

2132 of albumin in daily voided urine, ~20–60% of total excreted protein.
308 Glomerular Diseases

Julia B. Lewis, Eric G. Neilson
This amount of albumin, and other proteins, can rise to gram quantities
following glomerular injury.
The breadth of diseases affecting the glomerulus is expansive
because the microenvironment supporting the glomerular capillaries
can be injured in a variety of ways, producing many different lesions.
Some order to this vast subject is brought by grouping all of these dis-
Two human kidneys harbor nearly 1.8 million glomerular capillary eases into a smaller number of clinical syndromes.
tufts. Each glomerular tuft resides within Bowman’s space. The cap-
sule circumscribing this space is lined by parietal epithelial cells that PATHOGENESIS OF GLOMERULAR DISEASE
transition into tubular epithelia forming the proximal nephron or There are many forms of glomerular disease with pathogenesis vari-
migrate into the tuft to replenish podocytes. The glomerular capillary ably linked to the presence of genetic mutations, infection, toxin expo-
tuft derives from an afferent arteriole that forms a branching capillary sure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis,
bed embedded in mesangial matrix (Fig. 308-1). This capillary network or diabetes mellitus. Even after careful study, however, the cause often
funnels into an efferent arteriole, which passes filtered blood into cor- remains unknown, and the lesion is called idiopathic. Specific or unique
tical peritubular capillaries or medullary vasa recta that supply and features of pathogenesis are mentioned with the description of each of
exchange with a folded tubular architecture. Hence the glomerular cap- the glomerular diseases later in this chapter.
illary tuft, fed and drained by arterioles, represents an arteriolar portal Some glomerular diseases result from genetic mutations produc-
system. Fenestrated endothelial cells resting on a glomerular basement ing familial disease or a founder effect: congenital nephrotic syn-
membrane (GBM) line glomerular capillaries. Delicate foot processes drome from mutations in NPHS1 (nephrin) and NPHS2 (podocin)
extending from epithelial podocytes shroud the outer surface of these affect the slit-pore membrane at birth, and TRPC6 cation channel muta-
capillaries, and adjacent podocytes interconnect to each other by slit- tions produce focal segmental glomerulosclerosis (FSGS) in adulthood;
pore membranes forming a selective filtration barrier. polymorphisms in the gene encoding apolipoprotein L1, APOL1, are a
The glomerular capillaries filter 120–180 L/d of plasma water con-
PART 9
major risk for nearly 70% of African Americans with nondiabetic end-
taining various solutes for reclamation or discharge by downstream stage renal disease (ESRD), particularly FSGS; mutations in comple-
tubules. Most large proteins and all cells are excluded from filtration ment factor H associate with membranoproliferative glomerulonephritis
by a physicochemical barrier governed by pore size and negative elec- (MPGN), C3 glomerulopathies, or atypical hemolytic uremic syndrome
trostatic charge. The mechanics of filtration and reclamation are quite (aHUS), type II partial lipodystrophy from mutations in genes encod-
complicated for many solutes (Chap. 303). For example, in the case of ing lamin A/C, or PPARγ cause a metabolic syndrome associated with
serum albumin, the glomerulus is an imperfect barrier. Although albu- MPGN, or C3 glomerulopathies, which is sometimes accompanied by
min has a negative charge, which would tend to repel the negatively dense deposits and C3 nephritic factor; Alport’s syndrome, from muta-
charged GBM, it only has a physical radius of 3.6 nm, while pores in the tions in the genes encoding for the α3, α4, or α5 chains of type IV col-
GBM and slit-pore membranes have a radius of 4 nm. Consequently, lagen, produces split-basement membranes with glomerulosclerosis; and
variable amounts of albumin inevitably cross the filtration barrier to be lysosomal storage diseases, such as α-galactosidase A deficiency caus-
reclaimed by megalin and cubilin receptors along the proximal tubule. ing Fabry’s disease and N acetylneuraminic acid hydrolase deficiency
Remarkably, humans with normal nephrons excrete on average 8–10 mg causing nephrosialidosis, produce FSGS.
FIGURE 308-1 Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles, leading to an afferent arteriole,
glomerular capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning electron micrograph of podocytes that
line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular
capillary. D. The various normal regions of the glomerulus on light microscopy. (A–C: Courtesy of Dr. Vincent Gattone, Indiana University; with permission.)

Systemic hypertension and atherosclerosis can produce pressure polyangiitis spread to the kidney, causing secondary glomerular injury. 2133
stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis. Antiglomerular basement membrane disease producing Goodpasture’s
Malignant hypertension can quickly complicate glomerulosclerosis with syndrome primarily injures both the lung and kidney because of the
fibrinoid necrosis of arterioles and glomeruli, thrombotic microan- narrow distribution of the α3 NC1 domain of type IV collagen that is
giopathy, and acute renal failure. Diabetic nephropathy is an acquired the target antigen.
sclerotic injury associated with thickening of the GBM secondary to the Local activation of Toll-like receptors on glomerular cells, deposition
long-standing effects of hyperglycemia, advanced glycosylation end of immune complexes, or complement injury to glomerular structures
products, and reactive oxygen species. induces mononuclear cell infiltration, which subsequently leads to an
Inflammation of the glomerular capillaries is called glomerulone- adaptive immune response attracted to the kidney by local release
phritis. Most glomerular or mesangial antigens involved in immune- of chemokines. Neutrophils, macrophages, and T cells are drawn by
mediated glomerulonephritis are unknown (Fig. 308-2). Glomerular chemokines into the glomerular tuft, where they react with antigens
epithelial or mesangial cells may shed or express epitopes that mimic and epitopes on or near somatic cells or their structures, producing
other immunogenic proteins made elsewhere in the body. Bacteria, more cytokines and proteases that damage the mesangium, capillaries,
fungi, and viruses can directly infect the kidney producing their own and/or the GBM. While the adaptive immune response is similar to
antigens. Autoimmune diseases like idiopathic membranous glomeru- that of other tissues, early T cell activation plays an important role in
lonephritis (MGN) or MPGN are confined to the kidney, whereas sys- the mechanism of glomerulonephritis. Antigens presented by class II
temic inflammatory diseases like lupus nephritis or granulomatosis with major histocompatibility complex (MHC) molecules on macrophages
Basement
membrane
Subepithelial
deposit
CHAPTER 308 Glomerular Diseases

Endothelia
Podocytes
Subendothelial
deposit Linear IgG staining IgG Lumpy-bumpy staining
A B C
N
Mθ
TH1/2 Immune
deposits
Cytokines Cytokines
Chemokines
Chemokines
Basement membrane Endocapillary Extracapillary

damage proliferation proliferation
Oxidants Proteases
C3/C5-9MAC
D
FIGURE 308-2 The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation and collect along the
glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space. B. Immunofluorescent staining of glomeruli
with labeled anti-IgG demonstrating linear staining from a patient with anti-GBM disease or immune deposits from a patient with membranous glomerulonephritis. C.
The mechanisms of glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils
into the glomerulus. T lymphocytes may follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand
this inflammation, and, depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either
endocapillary or extracapillary proliferation.

2134 and dendritic cells in conjunction with associative recognition mole- that efferent arterioles leading from inflamed glomeruli carry forward
cules engage the CD4/8 T cell repertoire. inflammatory mediators, which induces downstream interstitial
Mononuclear cells by themselves can injure the kidney, but auto- nephritis, resulting in fibrosis. Glomerular filtrate from injured glomer-
immune events that damage glomeruli classically produce a humoral ular capillaries adherent to Bowman’s capsule may also be misdirected
immune response. Poststreptococcal glomerulonephritis, lupus nephritis, to the periglomerular interstitium. Most nephrologists believe, how-
and idiopathic membranous nephritis typically are associated with ever, that proteinuric glomerular filtrate forming tubular fluid is the
immune deposits along the GBM, while anti-GBM antibodies produce primary route to downstream tubulointerstitial injury, although none
the linear binding of anti-GBM disease. Preformed circulating immune of these hypotheses are mutually exclusive.
complexes can precipitate along the subendothelial side of the GBM, The simplest explanation for the effect of proteinuria on the develop-
while other immune deposits form in situ on the subepithelial side. ment of interstitial nephritis is that increasingly severe proteinuria, car-
These latter deposits accumulate when circulating autoantibodies rying activated cytokines and lipoproteins producing reactive oxygen
find their antigen trapped along the subepithelial edge of the GBM. species, triggers a downstream inflammatory cascade in and around
Immune deposits in the glomerular mesangium may result from the epithelial cells lining the tubular nephron. These effects induce T lym-
deposition of preformed circulating complexes or in situ antigen- phocyte and macrophage infiltrates in the interstitial spaces along with
antibody interactions. Immune deposits stimulate the release of local fibrosis and tubular atrophy.
proteases and activate the complement cascade, producing C5–9 attack Tubules disaggregate following direct damage to their basement
complexes. In addition, local oxidants damage glomerular structures, membranes, leading to more interstitial fibroblasts and fibrosis at the
producing proteinuria and effacement of the podocytes. Overlapping site of injury; recent comprehensive evidence suggests that renal fibrob-
etiologies or pathophysiologic mechanisms can produce similar glo- lasts increase through several mechanisms: epithelial or endothelial-
merular lesions, suggesting that downstream molecular and cellular mesenchymal transitions (15%), bone marrow-derived fibrocytes
responses often converge toward common patterns of injury. (35%), and the proliferation of resident fibroblasts (50%). Trans-
forming growth factor-β (TGF-β), fibroblast growth factor 2 (FGF-2),
PROGRESSION OF GLOMERULAR DISEASE hypoxemia-inducible factor 1α (HIF-1α), and platelet-derived growth
Persistent glomerulonephritis that worsens renal function is always
PART 9
factor (PDGF) are particularly active in this transition. With persistent

accompanied by interstitial nephritis, renal fibrosis, and tubular atro- nephritis, fibroblasts multiply and lay down tenascin and a fibronectin
phy (see Fig. A3-27). What is not so obvious, however, is that renal scaffold for the polymerization of new interstitial collagen types I/III.
failure in glomerulonephritis best correlates histologically with the These events form scar tissue through a process called fibrogenesis. In
appearance of tubulointerstitial nephritis rather than with the type of experimental studies, bone morphogenetic protein 7 and hepatocyte
inciting glomerular injury. growth factor can reverse early fibrogenesis and preserve tubular archi-
Loss of renal function due to interstitial damage is explained hypo- tecture. When fibroblasts outdistance their survival factors, apoptosis
thetically by several mechanisms. The simplest explanation is that occurs, and the permanent renal scar becomes acellular, leading to
urine flow is impeded by tubular obstruction as a result of interstitial irreversible renal failure.
inflammation and fibrosis. Thus, obstruction of the tubules with debris
or by extrinsic compression functionally results in aglomerular neph-
rons. A second mechanism suggests that interstitial changes, including APPROACH TO THE PATIENT
interstitial edema or fibrosis, alter tubular and vascular architecture Glomerular Disease
and thereby compromise the normal tubular transport of solutes and
water from tubular lumen to vascular space. This failure increases the HEMATURIA, PROTEINURIA, AND PYURIA
solute and water content of the tubule fluid, resulting in isosthenuria Patients with glomerular disease usually have some hematuria with
and polyuria. Adaptive mechanisms related to tubuloglomerular feed- varying degrees of proteinuria. Hematuria is typically asymptom-
back also fail, resulting in a reduction of renin output from the juxtaglo- atic. As few as 3–5 red blood cells in the spun sediment from first-
merular apparatus trapped by interstitial inflammation. Consequently, voided morning urine is suspicious. The diagnosis of glomerular
the local vasoconstrictive influence of angiotensin II on the glomer- injury can be delayed because patients will not realize they have
ular arterioles decreases, and filtration drops owing to a generalized microscopic hematuria, and only rarely with the exception of IgA
decrease in arteriolar tone. A third mechanism involves changes in nephropathy and sickle cell disease is gross hematuria present. When
vascular resistance due to damage of peritubular capillaries. The cross- working up microscopic hematuria, perhaps accompanied by mini-
sectional volume of these capillaries is decreased by interstitial inflam- mal proteinuria (<500 mg/24 h), it is important to exclude anatomic
mation, edema, or fibrosis. These structural alterations in vascular lesions, such as malignancy of the urinary tract, particularly in older
resistance affect renal function through two mechanisms. First, tubular men. Microscopic hematuria may also appear with the onset of
cells are very metabolically active, and, as a result, decreased perfusion benign prostatic hypertrophy, interstitial nephritis, papillary necro-
leads to tubular ischemic injury. Second, impairment of glomerular sis, hypercalciuria, renal stones, cystic kidney diseases, or renal
arteriolar outflow leads to increased intravascular hypertension in vascular injury. However, when red blood cell casts (see Fig. A3-34)
less-involved glomeruli; this selective intraglomerular hypertension or dysmorphic red blood cells are found in the sediment, glomerulo-
aggravates and extends mesangial sclerosis and glomerulosclerosis to nephritis is likely. A mean of 8–10 mg/24 h of albumin appears in the
less-involved glomeruli. Regardless of the exact mechanism, early acute urine in the absence of kidney disease. In early nephropathy, such
tubulointerstitial nephritis (see Fig. A3-27) suggests potentially recov- as in diabetic nephropathy, proteinuria increases to 30–300 mg/24 h
erable renal function, whereas the development of chronic interstitial and is called microalbuminuria and represents the presence of renal
fibrosis prognosticates permanent loss (see Fig. A3-30). disease. Greater than 300 mg/24 h of albuminuria represents frank
Persistent damage to glomerular capillaries spreads to the tubu- proteinuria and more advanced renal disease (Table 308-1).
lointerstitium in association with proteinuria. There is a hypothesis
TABLE 308-1 Urine Assays for Albuminuria/Proteinuria

ALBUMINa/CREATININE 24-h URINE PROTEINb
24-h ALBUMINa (mg/24 h) RATIO (mg/g) DIPSTICK PROTEINURIA (mg/24 h)
Normal 8–10 <30 – <150
Microalbuminuria 30–300 30–300 –/Trace/1+ –
Proteinuria >300 >300 Trace–3+ >150
Albumin detected by radioimmunoassay. bAlbumin represents 20–60% of the total protein excreted in the urine.
a

2135
Sustained proteinuria >1–2 g/24 h is also commonly associated CLINICAL SYNDROMES
with glomerular disease. Patients often will not know they have Various forms of glomerular injury can also be parsed into sev-
proteinuria unless they become edematous or notice foaming urine eral distinct syndromes on clinical grounds (Table 308-2). These
on voiding. Sustained proteinuria has to be distinguished from lesser syndromes, however, are not always mutually exclusive. There is
amounts of so-called benign proteinuria in the normal population. an acute nephritic syndrome producing 1–2 g/24 h of proteinuria,
(Table 308-1). This latter class of proteinuria is nonsustained, gen- hematuria with red blood cell casts, pyuria, hypertension, fluid
erally <1 g/24 h, and is sometimes called functional or transient retention, and a rise in serum creatinine associated with a reduc-
proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, tion in glomerular filtration. If glomerular inflammation develops
and congestive heart failure can explain transient proteinuria. slowly, the serum creatinine will rise gradually over many weeks,
Proteinuria only seen with upright posture is called orthostatic pro- but if the serum creatinine rises quickly, particularly over a few days,
teinuria and has a benign prognosis. Isolated proteinuria sustained acute nephritis is sometimes called rapidly progressive glomerulone-
over multiple clinic visits is found in many glomerular lesions. phritis (RPGN); the histopathologic term crescentic glomerulonephritis
Proteinuria in most adults with glomerular disease is nonselective, is the pathologic equivalent of the clinical presentation of RPGN.
containing albumin and a mixture of other serum proteins, whereas When patients with RPGN present with lung hemorrhage from
in children with minimal change disease (MCD), the proteinuria is Goodpasture’s syndrome, antineutrophil cytoplasmic antibodies
selective and composed largely of albumin. (ANCA)-associated small-vessel vasculitis, lupus erythematosus, or
Some patients with inflammatory glomerular disease, such as cryoglobulinemia, they are often diagnosed as having a pulmonary-renal
acute poststreptococcal glomerulonephritis or MPGN, have pyuria syndrome. Nephrotic syndrome describes the onset of heavy proteinuria
characterized by the presence of considerable numbers of leuko- (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbumine-
cytes. This latter finding has to be distinguished from urine infected mia, edema/anasarca, and microscopic hematuria; if only large
with bacteria. amounts of proteinuria are present without clinical manifestations,

TABLE 308-2 Patterns of Clinical Glomerulonephritis
GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY
Acute Nephritic Syndromes
Poststreptococcal glomerulonephritisa +/++ ++/+++ –
Subacute bacterial endocarditisa +/++ ++ –
Lupus nephritisa +/++ ++/+++ +
Antiglomerular basement membrane diseasea ++ ++/+++ –
IgA nephropathya +/++ +++c –
ANCA small-vessel vasculitisa
Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++
Microscopic polyangiitis +/++ ++/+++ ++++
Churg-Strauss syndrome +/++ ++/+++ ++++
Henoch-Schönlein purpuraa +/++ ++/+++ ++++
Cryoglobulinemiaa +/++ ++/+++ ++++
Membranoproliferative glomerulonephritisa ++ ++/+++ –
C3 Glomerulopathies ++ ++/+++ -
Mesangioproliferative glomerulonephritis + +/++ –
Pulmonary-Renal Syndromes
Goodpasture’s syndromea ++ ++/+++ –
Churg-Strauss syndrome +/++ ++/+++ ++++
Nephrotic Syndromes
Minimal change disease ++++ – –
Focal segmental glomerulosclerosis +++/++++ + –
Membranous glomerulonephritis ++++ + –
Diabetic nephropathy ++/++++ –/+ –
AL and AA amyloidosis +++/++++ + +/++
Light-chain deposition disease +++ + –
Fibrillary-immunotactoid disease +++/++++ + +
Fabry’s disease + + –
Basement Membrane Syndromes
Anti-GBM diseasea ++ ++/+++ –
Alport’s syndrome ++ ++ –
Thin basement membrane disease + ++ –
Nail-patella syndrome ++/+++ ++ –
(Continued)

2136 TABLE 308-2 Patterns of Clinical Glomerulonephritis (Continued)
GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY
Glomerular Vascular Syndromes
Atherosclerotic nephropathy + + +++
Hypertensive nephropathyb +/++ +/++ ++
Cholesterol emboli +/++ ++ +++
Sickle cell disease +/++ +++c +++
Thrombotic microangiopathies ++ ++ +++
Antiphospholipid syndrome ++ ++ +++
Churg-Strauss syndrome +++ ++/+++ ++++
AL and AA amyloidosis +++/++++ + +/++
Infectious Disease–Associated Syndromes
Poststreptococcal glomerulonephritisa +/++ ++/+++ –
Subacute bacterial endocarditisa +/++ ++ –
HIV +++ +/++ –
Hepatitis B and C +++ +/++ –
PART 9
Syphilis +++ + –
Leprosy +++ + –
Malaria +++ +/++ –
Schistosomiasis +++ +/++ –
a
Can present as rapidly progressive glomerulonephritis (RPGN); sometimes called crescentic glomerulonephritis. bCan present as a malignant hypertensive crisis
producing an aggressive fibrinoid necrosis in arterioles and small arteries with microangiopathic hemolytic anemia. cCan present with gross hematuria.
Abbreviations: AA, amyloid A; AL, amyloid L; ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane.
the condition is sometimes called nephrotic-range proteinuria. The to the kidney (primary glomerulonephritis) or is part of a systemic
glomerular filtration rate (GFR) in these patients may initially be disease (secondary glomerulonephritis).
normal or, rarely, higher than normal, but with persistent hyper- When confronted with an abnormal urinalysis and elevated
filtration and continued nephron loss, it typically declines over serum creatinine, with or without edema or congestive heart fail-
months to years. Patients with a basement membrane syndrome either ure, one must consider whether the glomerulonephritis is acute or
have genetically abnormal basement membranes (Alport’s syn- chronic. This assessment is best made by careful history (last known
drome) or an autoimmune response to basement membrane col- urinalysis or serum creatinine during pregnancy or insurance phys-
lagen IV (Goodpasture’s syndrome) associated with microscopic ical, evidence of infection, or use of medication or recreational
hematuria, mild to heavy proteinuria, and hypertension with drugs); the size of the kidneys on renal ultrasound examination; and
variable elevations in serum creatinine. Glomerular–vascular syn- how the patient feels at presentation. Chronic glomerular disease
drome describes patients with vascular injury producing hematuria often presents with decreased kidney size. Patients who quickly
and moderate proteinuria. Affected individuals can have vasculi- develop renal failure are fatigued and weak and often have uremic
tis, thrombotic microangiopathy, antiphospholipid syndrome, or, symptoms associated with nausea, vomiting, fluid retention, and
more commonly, a systemic disease such as atherosclerosis, choles- somnolence. Primary glomerulonephritis presenting with renal fail-
terol emboli, hypertension, sickle cell anemia, and autoimmunity. ure that has progressed slowly, however, can be remarkably asymp-
Infectious disease–associated syndrome is most important if one has a tomatic, as are patients with acute glomerulonephritis without much
global perspective. Save for subacute bacterial endocarditis (SBE) loss in renal function. Once this initial information is collected,
in the Western Hemisphere, malaria, and schistosomiasis may be selected patients who are clinically stable, have adequate blood
the most common causes of glomerulonephritis throughout the clotting parameters, and are willing and able to receive treatment are
world, closely followed by HIV and chronic hepatitis B and C. encouraged to have a renal biopsy.
These infectious diseases produce a variety of inflammatory reac-
tions in glomerular capillaries, ranging from nephrotic syndrome
to acute nephritic injury, and urinalyses that demonstrate a combi- ■■RENAL PATHOLOGY
nation of hematuria and proteinuria. A renal biopsy in the setting of glomerulonephritis quickly identifies
These six general categories of syndromes are usually deter- the type of glomerular injury and often suggests a course of treatment.
mined at the bedside with the help of a history and physical The biopsy is processed for light microscopy using stains for hematoxylin
examination, blood chemistries, renal ultrasound, and urinalysis. and eosin (H&E) to assess cellularity and architecture, periodic acid–Schiff
These initial studies help frame further diagnostic workup that (PAS) to stain carbohydrate moieties in the membranes of the glomerular
typically involves testing of the serum for the presence of various tuft and tubules, Jones-methenamine silver to enhance basement mem-
proteins (HIV and hepatitis B and C antigens), antibodies (anti- brane structure, Congo red for amyloid deposits, and Masson’s trichrome
GBM, antiphospholipid, antistreptolysin O [ASO], anti-DNAse, to identify collagen deposition and assess the degree of glomerulo-
antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and sclerosis and interstitial fibrosis. Biopsies are also processed for direct
anti-hepatitis B and C antibodies) or depletion of complement com- immunofluorescence using conjugated antibodies against IgG, IgM,
ponents (C3 and C4). The bedside history and physical examination and IgA to detect the presence of “lumpy-bumpy” immune deposits
can also help determine whether the glomerulonephritis is isolated or “linear” IgG or IgA antibodies bound to GBM, antibodies against
trapped complement proteins (C3 and C4), or specific antibodies against

a relevant antigen. High-resolution electron microscopy can clarify the Glomerular schematic 1 2137
principal location of immune deposits and the status of the basement Hump
membrane.
Each region of a renal biopsy is assessed separately. By light micros-
copy, glomeruli (ideally 20) are reviewed individually for discrete
lesions; <50% involvement is considered focal, and >50% is diffuse.
Injury in each glomerular tuft can be segmental, involving a portion of
the tuft, or global, involving most of the glomerulus. Glomeruli having
proliferative characteristics show increased cellularity. When cells in the
capillary tuft proliferate, it is called endocapillary, and when cellular
Poly
proliferation extends into Bowman’s space, it is called extracapillary.
Synechiae are formed when epithelial podocytes attach to Bowman’s Subendothelial
capsule in the setting of glomerular injury; crescents, which in some deposits
cases may be the extension of synechiae, develop when fibrocellular/ Mesangial
fibrin collections fill all or part of Bowman’s space; and sclerotic glomer- deposits
uli show acellular, amorphous accumulations of proteinaceous material
throughout the tuft with loss of functional capillaries and normal
mesangium. Since age-related glomerulosclerosis is common in adults,
one can estimate the background percentage of sclerosis by dividing
POST-
the patient’s age in half and subtracting 10. Immunofluorescent and STREPTOCOCCAL
electron microscopy can detect the presence and location of subepithelial, GLOMERULONEPHRITIS
subendothelial, or mesangial immune deposits, or reduplication or splitting

of the basement membrane. In the other regions of the biopsy, the
vasculature surrounding glomeruli and tubules can show angiopathy, The classic presentation is an acute nephritic picture with hematuria,
vasculitis, the presence of fibrils, or thrombi. The tubules can be assessed pyuria, red blood cell casts, edema, hypertension, and oliguric renal
for adjacency to one another; separation can be the result of edema, failure, which may be severe enough to appear as RPGN. Systemic
tubular dropout, or collagen deposition resulting from interstitial symptoms of headache, malaise, anorexia, and flank pain (due to
fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and swelling of the renal capsule) are reported in as many as 50% of cases.
progression to renal failure. Five percent of children and 20% of adults have proteinuria in the
nephrotic range. In the first week of symptoms, 90% of patients will
ACUTE NEPHRITIC SYNDROMES have a depressed CH50 and decreased levels of C3 with normal levels of
Acute nephritic syndromes classically present with hypertension, hema- C4. Positive rheumatoid factor (30–40%), cryoglobulins and circulating
turia, red blood cell casts, pyuria, and mild to moderate proteinuria. immune complexes (60–70%), and ANCA against myeloperoxidase
Extensive inflammatory damage to glomeruli causes a fall in GFR and (10%) are also reported. Positive cultures for streptococcal infection
eventually produces uremic symptoms with salt and water retention, are inconsistently present (10–70%), but increased titers of ASO (30%),
leading to edema and hypertension. anti-DNAse (70%), or antihyaluronidase antibodies (40%) can help
confirm the diagnosis. Consequently, the diagnosis of poststreptococ-
■■POSTSTREPTOCOCCAL GLOMERULONEPHRITIS cal glomerulonephritis rarely requires a renal biopsy. A subclinical
Poststreptococcal glomerulonephritis is prototypical for acute endocap- disease is reported in some series to be 4–5 times as common as clinical
illary proliferative glomerulonephritis. The incidence of poststreptococcal nephritis, and these latter cases are characterized by asymptomatic
glomerulonephritis has dramatically decreased in developed countries microscopic hematuria with low serum C3 complement levels.
and in these locations is typically sporadic. Acute poststreptococcal glo- Treatment is supportive, with control of hypertension, edema, and
merulonephritis in underdeveloped countries is epidemic and usually dialysis as needed. Antibiotic treatment for streptococcal infection
affects children between the ages of 2 and 14 years, but in developed should be given to all patients and their cohabitants. There is no role for
countries is more typical in the elderly, especially in association with immunosuppressive therapy, even in the setting of crescents. Recurrent
debilitating conditions. It is more common in males, and the familial poststreptococcal glomerulonephritis is rare despite repeated strepto-
or cohabitant incidence is as high as 40%. Skin and throat infections coccal infections. Early death is rare in children but does occur in the
with particular M types of streptococci (nephritogenic strains) antedate elderly. Overall, the prognosis is good, with permanent renal failure
glomerular disease; M types 47, 49, 55, 2, 60, and 57 are seen following being reported as very uncommon in the past (<1%) but with recent
impetigo and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis. Post- reports of an increased risk of chronic kidney disease in adulthood.
streptococcal glomerulonephritis due to impetigo develops 2–6 weeks Complete resolution of the hematuria and proteinuria in the majority
after skin infection and 1–3 weeks after streptococcal pharyngitis. of children occurs within 3–6 weeks of the onset of nephritis but 3–10%
The renal biopsy in poststreptococcal glomerulonephritis demonstrates of children may have persistent microscopic hematuria, nonnephrotic
hypercellularity of mesangial and endothelial cells, glomerular infiltrates proteinuria, or hypertension. The prognosis in elderly patients is worse
of polymorphonuclear leukocytes, granular subendothelial immune with a high incidence of azotemia (up to 60%), nephrotic-range pro-
deposits of IgG, IgM, C3, C4, and C5–9, and subepithelial deposits (which teinuria, and ESRD.
appear as “humps”) (see Fig. A3-6). (See Glomerular Schematic 1.)
Poststreptococcal glomerulonephritis is an immune-mediated disease ■■SUBACUTE BACTERIAL ENDOCARDITIS
involving putative streptococcal antigens, circulating immune com- Endocarditis-associated glomerulonephritis is typically a complication of
plexes, and activation of complement in association with cell-mediated SBE, particularly in patients who remain untreated for a long time,
injury. Many candidate antigens have been proposed over the years; have negative blood cultures, or have right-sided endocarditis. Com-
candidates from nephritogenic streptococci of interest at the moment mon comorbidities are valvular heart disease, intravenous drug use,
are: a cationic cysteine proteinase known as streptococcal pyrogenic hepatitis C, and diabetes mellitus. Glomerulonephritis is unusual in
exotoxin B (SPEB) that is generated by proteolysis of a zymogen pre- acute bacterial endocarditis because it takes 10–14 days to develop
cursor (zSPEB), and NAPlr, the nephritis-associated plasmin receptor. immune complex–mediated injury, by which time the patient has been
These two antigens have biochemical affinity for plasmin, bind as treated, often with emergent surgery. Grossly, the kidneys in SBE have
complexes facilitated by this relationship, and activate the alternate subcapsular hemorrhages with a “flea-bitten” appearance, and micros-
complement pathway. The nephritogenic antigen, SPEB, has been copy on renal biopsy reveals focal proliferation around foci of necrosis
demonstrated inside the subepithelial “humps” on biopsy. associated with abundant mesangial, subendothelial, and subepithelial

2138 immune deposits of IgG, IgM, and C . Commonly patients present TABLE 308-3 Classification for Lupus Nephritis
3
with a clinical picture of RPGN and have crescents on biopsy. Embolic Class I Minimal mesangial Normal histology with mesangial
infarcts or septic abscesses may also be present. The pathogenesis deposits
hinges on the renal deposition of circulating immune complexes in Class II Mesangial proliferation Mesangial hypercellularity with
the kidney with complement activation. Patients present with gross expansion of the mesangial matrix
or microscopic hematuria, pyuria, and mild proteinuria, acute kidney Class III Focal nephritis Focal endocapillary ± extracapillary
injury or, RPGN with rapid loss of renal function. A normocytic ane- proliferation with focal subendothelial
mia, elevated erythrocyte sedimentation rate, hypocomplementemia, immune deposits and mild mesangial
high titers of rheumatoid factor, type III cryoglobulins, circulating expansion
immune complexes, and ANCAs may be present. Levels of serum Class IV Diffuse nephritis Diffuse endocapillary ± extracapillary
creatinine may be elevated at diagnosis, but with modern therapy proliferation with diffuse
subendothelial immune deposits and
there is little progression to chronic renal failure. Primary treatment is
mesangial alterations
eradication of the infection with 4–6 weeks of antibiotics, and if accom-
Class V Membranous nephritis Thickened basement membranes
plished expeditiously, the prognosis for renal recovery is good. ANCA- with diffuse subepithelial immune
associated vasculitis sometimes accompanies or is confused with SBE deposits; may occur with class III or
and should be ruled out, as the treatment is different. IV lesions and is sometimes called
As variants of persistent bacterial infection in blood-associated mixed membranous and proliferative
glomerulonephritis, postinfectious glomerulonephritis can occur in nephritis
patients with ventriculoatrial and ventriculoperitoneal shunts; pul- Class VI Sclerotic nephritis Global sclerosis of nearly all
monary, intraabdominal, pelvic, or cutaneous infections; and infected glomerular capillaries
vascular prostheses. In developed countries, a significant proportion Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology
of cases afflict adults, especially the immunocompromised, and the Society Study Group.
predominant organism is Staphylococcus. The clinical presentation of
PART 9
these conditions is variable and includes proteinuria, microscopic the basis for modern treatment recommendations. Class I nephritis
hematuria, acute renal failure, and hypertension. Serum complement describes normal glomerular histology by any technique or normal
levels are low, and there may be elevated levels of C-reactive proteins, light microscopy with minimal mesangial deposits on immunofluo-
rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal rescent or electron microscopy. Class II designates mesangial immune
lesions include MPGN, diffuse proliferative and exudative glomer- complexes with mesangial proliferation. Both class I and II lesions are
ulonephritis (DPGN), or mesangioproliferative glomerulonephritis, typically associated with minimal renal manifestation and normal renal
sometimes leading to RPGN. Treatment focuses on eradicating the function; nephrotic syndrome is rare. Patients with lesions limited to
infection, with most patients treated as if they have endocarditis. The the renal mesangium have an excellent prognosis and generally do not
prognosis is guarded. need therapy for their lupus nephritis.
The subject of lupus nephritis is presented under acute nephritic
■■LUPUS NEPHRITIS syndromes because of the aggressive and important proliferative
Lupus nephritis is a common and serious complication of systemic lesions seen in class III–V renal diseases. Class III describes focal lesions
lupus erythematosus (SLE) and most severe in African-American with proliferation or scarring, often involving only a segment of the glo-
female adolescents. Thirty to 50% of patients will have clinical mani- merulus (see Fig. A3-12). Class III lesions have the most varied course.
festations of renal disease at the time of diagnosis, and 60% of adults Hypertension, an active urinary sediment, and proteinuria are common
and 80% of children develop renal abnormalities at some point in the with nephrotic-range proteinuria in 25–33% of patients. Elevated serum
course of their disease. Lupus nephritis results from the deposition of creatinine is present in 25% of patients. Patients with mild proliferation
circulating immune complexes, which activate the complement cascade involving a small percentage of glomeruli respond well to therapy with
leading to complement-mediated damage, leukocyte infiltration, acti- steroids alone, and fewer than 5% progress to renal failure over 5 years.
vation of procoagulant factors, and release of various cytokines. In situ Patients with more severe proliferation involving a greater percentage
immune complex formation following glomerular binding of nuclear of glomeruli have a far worse prognosis and lower remission rates.
antigens, particularly necrotic nucleosomes, also plays a role in renal Treatment of those patients is the same as that for class IV lesions.
injury. The presence of antiphospholipid antibodies may also trigger a Many nephrologists believe that class III lesions are simply an early
thrombotic microangiopathy in a minority of patients. presentation of class IV disease. Others believe severe class III disease
The clinical manifestations, course of disease, and treatment of lupus is a discrete vasculitic lesion requiring aggressive therapy. Class IV
nephritis are closely linked to renal pathology. The most common clin- describes global, diffuse proliferative lesions involving the vast majority
ical sign of renal disease is proteinuria, but hematuria, hypertension, of glomeruli. Patients with class IV lesions commonly have high anti-
varying degrees of renal failure, and active urine sediment with red DNA antibody titers, low serum complement, hematuria, red blood
blood cell casts can all be present. Although significant renal pathology cell casts, proteinuria, hypertension, and decreased renal function; 50%
can be found on biopsy even in the absence of major abnormalities of patients have nephrotic-range proteinuria. Patients with crescents
in the urinalysis, most nephrologists do not biopsy patients until the on biopsy often have a rapidly progressive decline in renal function
urinalysis is convincingly abnormal. The extrarenal manifestations of (see Fig. A3-12). Without treatment, this aggressive lesion has the
lupus are important in establishing a firm diagnosis of systemic lupus worst renal prognosis. However, if a remission—defined as a return to
because, while serologic abnormalities are common in lupus nephritis, near-normal renal function and proteinuria ≤330 mg/dL per day—is
they are not diagnostic. Anti-dsDNA antibodies that fix complement achieved with treatment, renal outcomes are excellent. Current evi-
correlate best with the presence of renal disease. Hypocomplemen- dence suggests that inducing a remission with administration of high-
temia is common in patients with acute lupus nephritis (70–90%) and dose steroids and either cyclophosphamide or mycophenolate mofetil
declining complement levels may herald a flare. Although urinary for 2–6 months, followed by maintenance therapy with lower doses of
biomarkers of lupus nephritis are being identified to assist in predict- steroids and mycophenolate mofetil or azathioprine, best balances the
ing renal flares, renal biopsy is the only reliable method of identifying likelihood of successful remission with the side effects of therapy. There
the morphologic variants of lupus nephritis. is no consensus on use of high-dose intravenous methylprednisolone
The World Health Organization (WHO) workshop in 1974 first out- versus oral prednisone, monthly intravenous cyclophosphamide ver-
lined several distinct patterns of lupus-related glomerular injury; these sus daily oral cyclophosphamide, or other immunosuppressants such
were modified in 1982. In 2004 the International Society of Nephrology as cyclosporine, tacrolimus, rituximab, or belimumab. Nephrologists
in conjunction with the Renal Pathology Society again updated the classi- tend to avoid prolonged use of cyclophosphamide in patients of child-
fication. This latest version of lesions seen on biopsy (Table 308-3) forms bearing age without first banking eggs or sperm.

The class V lesion describes subepithelial immune deposits produc- This subset of patients has a vasculitis-associated variant, which has a 2139
ing a membranous pattern; a subcategory of class V lesions is associated surprisingly good prognosis with treatment. Prognosis at presentation
with proliferative lesions and is sometimes called mixed membranous is worse if there are >50% crescents on renal biopsy with advanced
and proliferative disease (see Fig. A3-11); this category of injury is treated fibrosis, if serum creatinine is >5–6 mg/dL, if oliguria is present, or
like class IV glomerulonephritis. Sixty percent of patients present if there is a need for acute dialysis. Although frequently attempted,
with nephrotic syndrome or lesser amounts of proteinuria. Patients most of these latter patients will not respond to plasmapheresis and
with lupus nephritis class V, like patients with idiopathic membranous steroids. Patients with advanced renal failure who present with hemop-
nephropathy (IMN), are predisposed to renal-vein thrombosis and other tysis should still be treated for their lung hemorrhage, as it responds
thrombotic complications. A minority of patients with class V will pres- to plasmapheresis and can be lifesaving. Treated patients with less
ent with hypertension and renal dysfunction. There are conflicting data severe disease typically respond to 8–10 treatments of plasmapheresis
on the clinical course, prognosis, and appropriate therapy for patients accompanied by oral prednisone and cyclophosphamide in the first
with class V disease, which may reflect the heterogeneity of this 2 weeks. Kidney transplantation is possible, but because there is risk of
group of patients. Patients with severe nephrotic syndrome, elevated recurrence, experience suggests that patients should wait for 6 months
serum creatinine, and a progressive course will probably benefit from and until serum antibodies are undetectable.
therapy with steroids in combination with other immunosuppressive
agents. Therapy with inhibitors of the renin-angiotensin system also ■■IgA NEPHROPATHY
may attenuate the proteinuria. Antiphospholipid antibodies present in Berger first described the glomerulonephritis now termed IgA nephropa-
lupus may result in glomerular microthromboses and complicate the thy. It is classically characterized by episodic hematuria associated with
course in up to 20% of lupus nephritis patients. The renal prognosis is the deposition of IgA in the mesangium. IgA nephropathy is one of
worse despite anticoagulant therapy. the most common forms of glomerulonephritis worldwide. There is a
Patients with any of the above lesions also can transform to another male preponderance, a peak incidence in the second and third decades
lesion; hence patients often require reevaluation, including repeat renal of life, and rare familial clustering. There are geographic differences

biopsy. Lupus patients with class VI lesions have >90% sclerotic glom- in the prevalence of IgA nephropathy, with 30% prevalence along the
eruli and ESRD with interstitial fibrosis. As a group, ~20% of patients Asian and Pacific Rim and 20% in southern Europe, compared to a
with lupus nephritis will reach end-stage disease, requiring dialysis much lower prevalence in northern Europe and North America. It was
or transplantation. Patients with lupus nephritis have a markedly initially hypothesized that variation in detection, in part, accounted for
increased mortality compared with the general population. Renal regional differences. With clinical care in nephrology becoming more
transplantation in renal failure from lupus, usually performed after uniform, this variation in prevalence more likely reflects true differ-
~6 months of inactive disease, results in allograft survival rates compa- ences among racial and ethnic groups.
rable to patients transplanted for other reasons. IgA nephropathy is predominantly a sporadic disease but suscep-
tibility to it has been shown uncommonly to have a genetic compo-
■■ANTIGLOMERULAR BASEMENT MEMBRANE nent depending on geography and the existence of “founder effects.”
DISEASE Familial forms of IgA nephropathy are more common in northern
Patients who develop autoantibodies directed against glomerular Italy and eastern Kentucky. No single causal gene has been identified.
basement antigens frequently develop a glomerulonephritis termed Clinical and laboratory evidence suggests close similarities between
antiglomerular basement membrane (anti-GBM) disease. When they present Henoch-Schönlein purpura and IgA nephropathy. Henoch-Schönlein
with lung hemorrhage and glomerulonephritis, they have a pulmonary- purpura is distinguished clinically from IgA nephropathy by prominent
renal syndrome called Goodpasture’s syndrome. The target epitopes for systemic symptoms, a younger age (<20 years old), preceding infec-
this autoimmune disease lie in the quaternary structure of α3 NC1 tion, and abdominal complaints. Deposits of IgA are also found in the
domain of collagen IV. Indeed, anti-GBM disease may be considered glomerular mesangium in a variety of systemic diseases, including
an autoimmune “conformeropathy” that involves the perturbation of chronic liver disease, Crohn’s disease, gastrointestinal adenocar-
quaternary structure of the α 345NC1 hexamer. MHC-restricted T cells cinoma, chronic bronchiectasis, idiopathic interstitial pneumonia,
initiate the autoantibody response because humans are not tolerant dermatitis herpetiformis, mycosis fungoides, leprosy, ankylosing spon-
to the epitopes created by this quaternary structure. The epitopes are dylitis, relapsing polychondritis, and Sjögren’s syndrome. IgA deposi-
normally sequestered in the collagen IV hexamer and can be exposed tion in these entities is not usually associated with clinically significant
by infection, smoking, oxidants, or solvents. Goodpasture’s syndrome glomerular inflammation or renal dysfunction and thus is not called
appears in two age groups: in young men in their late twenties and in IgA nephropathy.
men and women in their sixties and seventies. Disease in the younger IgA nephropathy is an immune complex–mediated glomerulone-
age group is usually explosive, with hemoptysis, a sudden fall in hemo- phritis defined by the presence of diffuse mesangial IgA deposits often
globin, fever, dyspnea, and hematuria. Hemoptysis is largely confined associated with mesangial hypercellularity. (See Glomerular Schematic 2.)
to smokers, and those who present with lung hemorrhage as a group IgM, IgG, C3, or immunoglobulin light chains may be codistributed
do better than older populations who have prolonged, asymptomatic with IgA. IgA deposited in the mesangium is typically polymeric and
renal injury; presentation with oliguria is often associated with a par- of the IgA1 subclass, the pathogenic significance of which is not clear.
ticularly bad outcome. The performance of an urgent kidney biopsy is Abnormalities have been described in IgA production by plasma cells;
important in suspected cases of Goodpasture’s syndrome to confirm in IgA clearance, by the liver and in mesangial IgA clearance and recep-
the diagnosis and assess prognosis. Renal biopsies typically show focal tors for IgA. Currently, however, abnormalities in the O glycosylation
or segmental necrosis that later, with aggressive destruction of the capil- of the hinge region of primarily polymeric IgA1 seem to best account
laries by cellular proliferation, leads to crescent formation in Bowman’s for the pathogenesis of sporadic IgA nephropathy. Synthesis of poorly
space (see Fig. A3-14). As these lesions progress, there is concomitant galactosylated IgA1 results in exposure of N-acetyl-galactosomine in
interstitial nephritis with fibrosis and tubular atrophy. truncated IgA1 hinge regions which is recognized by IgG or IgA1 anti-
The presence of anti-GBM antibodies and complement is recognized bodies leading to formation of immune complexes in the circulation
on biopsy by linear immunofluorescent staining for IgG (rarely IgA). or in situ after glomerular deposition of galactose-deficient IgA1.
In testing serum for anti-GBM antibodies, it is particularly important The galactose-deficient IgA1 may evade liver catabolism and preferen-
that the α3 NC1 domain of collagen IV alone be used as the target. tially deposit in the mesangium. A second hit, such as a viral or other
This is because nonnephritic antibodies against the α1 NC1 domain antigen exposure, may be necessary for disease manifestation. Despite
are seen in paraneoplastic syndromes and cannot be discerned from the presence of elevated serum IgA levels in 20–50% of patients, and
assays that use whole basement membrane fragments as the binding IgA deposition in skin biopsies in 15–55% of patients, a renal biopsy is
target. Between 10 and 15% of sera from patients with Goodpasture’s necessary to confirm the diagnosis. Although the immunofluorescent
syndrome also contain ANCA antibodies against myeloperoxidase. pattern of IgA on renal biopsy defines IgA nephropathy in the proper

2140 Glomerular schematic 2 monocytes, which together damage the walls of small vessels. Endo-
thelial injury also attracts more leukocytes and extends the inflam-
mation. Granulomatosis with polyangiitis, microscopic polyangiitis,
Churg-Strauss syndrome, and renal-limited vasculitis belong to this
group because they are ANCA-positive and have a pauci-immune
glomerulonephritis with few immune complexes in small vessels and
glomerular capillaries. Patients with any of these diseases can have any
combination of the above serum antibodies, but anti-PR3 antibodies are
more common in granulomatosis with polyangiitis and anti-MPO anti-
bodies are more common in microscopic polyangiitis or Churg-Strauss.
Although each of these diseases has some unique clinical features, most
features do not predict relapse or progression, and as a group, they are
generally treated in the same way. Once diagnosed ANCA monitoring
has limited value, but targeted determination of ANCA levels may be
useful if a relapse is clinically suspected. Since mortality is high with-
out treatment, virtually all patients receive urgent treatment. Induction
therapy usually includes glucocorticoids and either cyclophosphamide
Mesangial deposits
plus more or rituximab. Plasmapheresis is recommended in rapidly progressive
mesangial cells IgA renal failure or pulmonary hemorrhage. Monthly “pulse” IV cyclo-
NEPHROPATHY phosphamide to induce remission of ANCA-associated vasculitis is as
effective as daily oral cyclophosphamide but may be associated with
increased relapses. Steroids are tapered soon after acute inflammation
subsides, and patients are maintained on cyclophosphamide or less
PART 9
toxic agents such as azathioprine, methotrexate, or rituximab for up to

a year to minimize the risk of relapse.
Granulomatosis with Polyangiitis Patients with this disease
classically present with fever, purulent rhinorrhea, nasal ulcers, sinus
clinical context, a variety of histologic lesions may be seen on light
pain, polyarthralgias/arthritis, cough, hemoptysis, shortness of breath,

microscopy (see Fig. A3-8), including DPGN; segmental sclerosis; and,
microscopic hematuria, and 0.5–1 g/24 h of proteinuria; occasionally
rarely, segmental necrosis with cellular crescent formation, which typically
there may be cutaneous purpura and mononeuritis multiplex. Presen-
presents as RPGN.
tation without renal involvement is termed limited granulomatosis
The two most common presentations of IgA nephropathy are recur-
with polyangiitis, although some of these patients will show signs of
rent episodes of macroscopic hematuria during or immediately follow-
renal injury later. Chest x-ray often reveals nodules and persistent
ing an upper respiratory infection often accompanied by proteinuria or
infiltrates, sometimes with cavities. Biopsy of involved tissue will
persistent asymptomatic microscopic hematuria. Nephrotic syndrome
show a small-vessel vasculitis and adjacent noncaseating granulomas.
is uncommon. Proteinuria can also first appear late in the course of the
Renal biopsies during active disease demonstrate segmental necrotizing
disease. Rarely patients present with acute renal failure and a rapidly
glomerulonephritis without immune deposits and have been classified
progressive clinical picture. IgA nephropathy is a benign disease for
as focal, mixed, crescentic or sclerotic (see Fig. A3-13). The disease
the majority of patients, and 5–30% of patients may go into a complete
is more common in patients exposed to silica dust and those with
remission, with others having hematuria but well preserved renal func- α1-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after
tion. In the minority of patients who have progressive disease, progres- achieving remission is common and is more common in patients with
sion is slow, with renal failure seen in only 25–30% of patients with IgA granulomatosis with polyangiitis than the other ANCA-associated vas-
nephropathy over 20–25 years. This risk varies considerably among culitis, necessitating diligent follow-up care. Although associated with
populations. Cumulatively, risk factors for the loss of renal function an unacceptable high mortality rate without treatment, the greatest
identified thus far account for <50% of the variation in observed threat to patients, especially elderly patients in the first year of therapy,
outcome but include the presence of hypertension or proteinuria, the is from adverse events, which are often secondary to treatment, rather
absence of episodes of macroscopic hematuria, male sex, older age of than active vasculitis. Patients should also be monitored long term for
onset, and extensive glomerulosclerosis or interstitial fibrosis on renal malignancy after immunosuppressive therapy.
biopsy. Several analyses in large populations of patients found persis-
tent proteinuria for 6 months or longer to have the greatest predictive Microscopic Polyangiitis Clinically, these patients look some-
power for adverse renal outcomes. what similar to those with granulomatosis with polyangiitis, except
There is no agreement on optimal treatment. Both large studies that they rarely have significant lung disease or destructive sinusitis. The
include patients with multiple glomerular diseases and small studies distinction is made on biopsy, where the vasculitis in microscopic
of patients with IgA nephropathy support the use of angiotensin- polyangiitis is without granulomas. Some patients will also have injury
converting enzyme (ACE) inhibitors in patients with proteinuria or limited to the capillaries and venules.
declining renal function. In patients with persistent proteinuria after
ACE inhibitor therapy, steroid treatment or other immunosuppressives Churg-Strauss Syndrome When small-vessel vasculitis is asso-
have demonstrated conflicting results. Tonsillectomy and fish oil have ciated with peripheral eosinophilia, cutaneous purpura, mononeuritis,
also been suggested in small studies to benefit select patients. When asthma, and allergic rhinitis, a diagnosis of Churg-Strauss syndrome
presenting as RPGN, patients typically receive steroids, cytotoxic is considered. Hypergammaglobulinemia, elevated levels of serum
agents, and plasmapheresis. IgE, or the presence of rheumatoid factor sometimes accompanies the
allergic state. Lung inflammation, including fleeting cough and pulmo-
■■ANCA SMALL-VESSEL VASCULITIS nary infiltrates, often precedes the systemic manifestations of disease
A group of patients with small-vessel vasculitis (arterioles, capillar- by years; lung manifestations are rarely absent. A third of patients
ies, and venules; rarely small arteries) and glomerulonephritis have may have exudative pleural effusions associated with eosinophils.
serum ANCA; the antibodies are of two types, anti-proteinase 3 (PR3) Small-vessel vasculitis and focal segmental necrotizing glomerulonephritis
or anti-myeloperoxidase (MPO) (Chap. 356); Lamp-2 antibodies have can be seen on renal biopsy, usually absent eosinophils or granulomas.
also been reported experimentally as potentially pathogenic. ANCA The cause of Churg-Strauss syndrome is autoimmune, but the inciting
are produced with the help of T cells and activate leukocytes and factors are unknown.

TABLE 308-4 Membranoproliferative Glomerulonephritis: Glomerular schematic 3 2141
Immunoglobulin-Mediated
Type I Disease—Most Common
Idiopathic
Subacute bacterial endocarditis Subendothelial
Widened deposits
Systemic lupus erythematosus mesangial
Hepatitis C and cryoglobulinemia
Mesangial
Mixed cryoglobulinemia interposition
Hepatitis C
Cancer: lung, breast and ovary (germinal)
Type II Disease
Idiopathic Macrophage and
mesangial cells
Dense Deposit Disease (immunoglobulin-mediated)
Type III Disease
Idiopathic
MEMBRANOPROLIFERATIVE
C3 Glomerulopathy: C3 Dominant, Non-Immunoglobulin-mediated GLOMERULONEPHRITIS TYPE I
Dense Deposit Disease (C3 dominant)
Idiopathic
Specific genetic mutations and/or autoantibodies to alternate complement
like lupus or cryoglobulinemia, or neoplastic diseases (Table 308-4).
pathway factors or regulatory factors of alternate complement pathway

A minority of cases of MPGN type I have C3 but not immunoglobu-
C3 Glomerulonephritis lin deposits on biopsy and are best considered as in the category of
Specific genetic mutations and/or autoantibodies to alternate complement a C3 glomerulopathy. Types II and III MPGN can be idiopathic, and
pathway factors or regulatory factors of alternate complement pathway immunoglobulin-mediated disease (driven by the classical comple-
ment pathway) but the majority of cases formerly defined as MPGN
type II and III are non-immunoglobulin-mediated and driven by the
C3 Glomerulopathies C3 glomerulopathy is a recent disease alternate complement pathway.
classification that is defined by the glomerular accumulation of C3 with Type I MPGN, the most proliferative of the three types, shows
little or no immunoglobulin and encompasses dense deposit disease mesangial proliferation with lobular segmentation on renal biopsy and
(DDD), formerly MPGN type II (see below), and C3 glomerulonephritis mesangial interposition between the capillary basement membrane
(C3GN), (Table 308-4). DDD is defined morphologically with dense and endothelial cells, producing a double contour sometimes called
deposits forming ribbons in the GBM. In the absence of this specific tram-tracking (see Fig. A3-9). (See Glomerular Schematic 3.) Subendo-
morphology the entity is categorized as C3GN. Both are associated thelial deposits with low serum levels of C3 are typical, although 50%
with the presence of a complement mutation believed to cause the renal of patients have normal levels of C3 and occasional intramesangial
pathology, including mutations in the complement factor H regulatory deposits. Low serum C3 and a dense thickening of the GBM containing
proteins (CFHR’s) genes. DDD is primarily a disease of children and ribbons of dense deposits and C3 characterize type II MPGN, dense
young adults while the other C3 glomerulopathies are reported to pres- deposit disease (see Fig. A3-10). Classically, the glomerular tuft has a
ent in an older age group (mean age 30). By definition kidneys with C3 lobular appearance; intramesangial deposits are rarely present and
glomerulopathy show sole or dominant staining for C3 but can have subendothelial deposits are generally absent. Proliferation in type III
variable light microscopy with mesangial proliferative or membrano- MPGN is less common than the other two types and is often focal;
proliferative patterns seen most commonly. Morphologically, many mesangial interposition is rare, and subepithelial deposits can occur
cases are not distinguishable from recovering post-infections GN. along widened segments of the GBM that appear laminated and
Patients with DDD present with proteinuria and/or hematuria with disrupted.
nephrotic range proteinuria in up to 2/3 of patients. Partial lipodystro- Classic type I MPGN is secondary to glomerular deposition of
phy and Drusen bodies in the retina may also be present. Prognosis is circulating immune complexes or their in situ formation. Patients
poor with 50% of patients progressing to ESRD. C3GN patients are clin- with MPGN present with proteinuria, hematuria, and pyuria (30%);
ically less well defined but ~2/3 have hematuria and 1/3 proteinuria. systemic symptoms of fatigue and malaise that are most common
In addition to renal biopsy serological and genetic evaluation may be in children with type I disease; or an acute nephritic picture with
indicated including measurement of C3 levels which are typically low RPGN and a speedy deterioration in renal function in up to 25% of
with normal C4 levels, C3 nephritic factor, Factor H, paraprotein detec- patients. Low serum C3 levels are common. Fifty percent of patients
tion and specific CFHR genetic mutations. The optimal therapies remain with MPGN develop ESRD 10 years after diagnosis, and 90% have
undefined but include inhibition of the renin-angiotensin system, renal insufficiency after 20 years. Nephrotic syndrome, hypertension,
anticoagulants, steroids and other immunosuppressants. Increasing and renal insufficiency all predict poor outcome. In the presence of
evidence suggests a benefit of therapy with eculizumab, a monoclonal proteinuria, treatment with inhibitors of the renin-angiotensin system
antibody directed at C5 which is activated by C3.. is prudent. Evidence for treatment with dipyridamole, Coumadin
(warfarin), or cyclophosphamide is not strongly established. There is
some evidence supporting the efficacy of treatment of primary MPGN
■■MEMBRANOPROLIFERATIVE with steroids, particularly in children, as well as reports of efficacy
GLOMERULONEPHRITIS with plasma exchange and other immunosuppressive drugs. If defects
MPGN is sometimes called mesangiocapillary glomerulonephritis or in the complement pathway are found, treatment with eculizumab is
lobar glomerulonephritis. It is an immune-mediated glomerulonephritis of hypothetical but unproven benefit. In secondary MPGN, treating the
characterized by thickening of the GBM with mesangioproliferative associated infection, autoimmune disease, or neoplasms is of demon-
changes; 70% of patients have hypocomplementemia. MPGN is rare strated benefit. In particular, pegylated interferon and ribavirin are
in African Americans, and idiopathic disease usually presents in child- useful in reducing viral load. Although all primary renal diseases can
hood or young adulthood. MPGN has been subdivided pathologically recur over time in transplanted renal allografts, patients with MPGN
into type I, type II, and type III disease. Type I MPGN is commonly are well known to be at risk for not only a histologic recurrence but also
associated with persistent hepatitis C infections, autoimmune diseases a clinically significant recurrence with loss of graft function.

2142 ■■MESANGIOPROLIFERATIVE Glomerular schematic 4
GLOMERULONEPHRITIS
Mesangioproliferative glomerulonephritis is characterized by expan-
sion of the mesangium, sometimes associated with mesangial hypercel-
lularity; thin, single contoured capillary walls; and mesangial immune
deposits. Clinically, it can present with varying degrees of proteinuria
and, commonly, hematuria. Mesangioproliferative disease may be seen
in IgA nephropathy, Plasmodium falciparum malaria, resolving postin-
fectious glomerulonephritis, and class II nephritis from lupus, all of
which can have a similar histologic appearance. With these secondary
entities excluded, the diagnosis of primary mesangioproliferative glomeru-
lonephritis is made in <15% of renal biopsies. As an immune-mediated
renal lesion with deposits of IgM, C1q, and C3, the clinical course is
variable. Patients with isolated hematuria may have a very benign
course, and those with heavy proteinuria occasionally progress to renal
failure. There is little agreement on treatment, but some clinical reports
suggest benefit from use of inhibitors of the renin-angiotensin system,
steroid therapy, and even cytotoxic agents.
MINIMAL
NEPHROTIC SYNDROME CHANGE DISEASE
Nephrotic syndrome classically presents with heavy proteinuria,
minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema,
and hypertension. If left undiagnosed or untreated, some of these (nephrosarca) that is responsive to intravenous albumin and diuretics.
PART 9
syndromes will progressively damage enough glomeruli to cause a fall This presentation must be distinguished from acute renal failure sec-
in GFR, producing renal failure. Multiple studies have noted that the ondary to hypovolemia. Acute tubular necrosis and interstitial inflam-
higher the 24-h urine protein excretion, the more rapid is the decline mation are also reported. In children, the abnormal urine principally
in GFR. contains albumin with minimal amounts of higher-molecular-weight
Therapies for various causes of nephrotic syndrome are noted under proteins, and is sometimes called selective proteinuria. Although up to
individual disease headings below. In general, all patients with hyper- 30% of children have a spontaneous remission, all children today are
cholesterolemia secondary to nephrotic syndrome should be treated treated with steroids; only children who are nonresponders are biop-
with lipid-lowering agents because they are at increased risk for car- sied in this setting. Primary responders are patients who have a com-
diovascular disease. Edema secondary to salt and water retention can plete remission (<0.2 mg/24 h of proteinuria) after a single course of
be controlled with the judicious use of diuretics, avoiding intravascular prednisone; steroid-dependent patients relapse as their steroid dose is
volume depletion. Venous complications secondary to the hypercoag- tapered. Frequent relapsers have two or more relapses in the 6 months
ulable state associated with nephrotic syndrome can be treated with following taper, and steroid-resistant patients fail to respond to steroid
anticoagulants. The losses of various serum binding proteins, such as therapy. Adults are not considered steroid-resistant until after 4 months
thyroid-binding globulin, lead to alterations in functional tests. Lastly, of therapy. Ninety to 95% of children will develop a complete remission
proteinuria itself is hypothesized to be nephrotoxic, and treatment of after 8 weeks of steroid therapy, and 80–85% of adults will achieve
proteinuria with inhibitors of the renin-angiotensin system can lower complete remission, but only after a longer course of 20–24 weeks.
urinary protein excretion. Patients with steroid resistance may have FSGS on repeat biopsy. Some
hypothesize that if the first renal biopsy does not have a sample of
■■MINIMAL CHANGE DISEASE deeper corticomedullary glomeruli, then the correct diagnosis of FSGS
MCD, sometimes known as nil lesion, causes 70–90% of nephrotic syn- may be missed.
drome in childhood but only 10–15% of nephrotic syndrome in adults. Relapses occur in 70–75% of children after the first remission, and
MCD usually presents as a primary renal disease but can be associated early relapse predicts multiple subsequent relapses, as do high levels
with several other conditions, including Hodgkin’s disease, allergies, of basal proteinuria. The frequency of relapses decreases after puberty.
or use of nonsteroidal anti-inflammatory agents; significant interstitial There is an increased risk of relapse following the rapid tapering of
nephritis often accompanies cases associated with nonsteroidal drug steroids in all groups. Relapses are less common in adults but are
use. MCD on renal biopsy shows no obvious glomerular lesion by light more resistant to subsequent therapy. Prednisone is first-line therapy,
microscopy and is negative for deposits by immunofluorescent micros- either given daily or on alternate days. Other immunosuppressive
copy, or occasionally shows small amounts of IgM in the mesangium drugs, such as cyclophosphamide, chlorambucil, and mycophenolate
(see Fig. A3-1). (See Glomerular Schematic 4.) Electron microscopy, mofetil, are saved for frequent relapsers, steroid-dependent patients,
however, consistently demonstrates an effacement of the foot processes or steroid-resistant patients. Cyclosporine can induce remission, but
supporting the epithelial podocytes with weakening of slit-pore mem- relapse is also common when cyclosporine is withdrawn. The long-
branes. The pathophysiology of this lesion is uncertain. Most agree there term prognosis in adults is less favorable when acute renal failure or
is a circulating cytokine, perhaps related to a T cell response that alters steroid resistance occurs.
capillary charge and podocyte integrity. The evidence for cytokine-
related immune injury is circumstantial and is suggested by the pres- ■■FOCAL SEGMENTAL GLOMERULOSCLEROSIS
ence of preceding allergies, altered cell-mediated immunity during FSGS refers to a pattern of renal injury characterized by segmental
viral infections, and the high frequency of remissions with steroids. glomerular scars that involve some but not all glomeruli; the clinical
MCD presents clinically with the abrupt onset of edema and neph- findings of FSGS largely manifest as proteinuria. When the secondary
rotic syndrome accompanied by acellular urinary sediment. Average causes of FSGS are eliminated (Table 308-5), the remaining patients
urine protein excretion reported in 24 h is 10 g with severe hypoalbu- are considered to have primary FSGS. The incidence of this disease is
minemia. Less common clinical features include hypertension (30% increasing, and it now represents up to one-third of cases of nephrotic
in children, 50% in adults), microscopic hematuria (20% in children, syndrome in adults and one-half of cases of nephrotic syndrome in
33% in adults), atopy or allergic symptoms (40% in children, 30% in African Americans, in whom it is seen more commonly. The pathogen-
adults), and decreased renal function (<5% in children, 30% in adults). esis of FSGS is probably multifactorial. Possible mechanisms include
The appearance of acute renal failure in adults is often seen more a T cell–mediated circulating permeability factor, increased soluble
commonly in patients with low serum albumin and intrarenal edema urokinase receptor levels, TGF-β–mediated cellular proliferation and

TABLE 308-5 Focal Segmental Glomerulosclerosis The pathologic changes of FSGS are most prominent in glomeruli 2143
Primary focal segmental glomerulosclerosis located at the corticomedullary junction (see Fig. A3-2), so if the renal
Secondary focal segmental glomerulosclerosis
biopsy specimen is from superficial tissue, the lesions can be missed,
which sometimes leads to a misdiagnosis of MCD. In addition to focal
Viruses: HIV/hepatitis B/parvovirus
and segmental scarring, other variants have been described, including
Hypertensive nephropathy
cellular lesions with endocapillary hypercellularity and heavy proteinuria;
Reflux nephropathy collapsing glomerulopathy (see Fig. A3-3) with segmental or global glom-
Cholesterol emboli erular collapse and a rapid decline in renal function; a hilar stalk lesion
Drugs: Heroin/analgesics/bisphosphonates/ecstasy (see Fig. A3-4); or the glomerular tip lesion (see Fig. A3-5), which may
Oligomeganephronia have a better prognosis. (See Glomerular Schematic 5.)
Renal dysgenesis FSGS can present with hematuria, hypertension, any level of
Alport’s syndrome proteinuria, or renal insufficiency. Nephrotic-range proteinuria,
Sickle cell disease African-American race, and renal insufficiency are associated with a
Lymphoma poor outcome, with 50% of patients reaching renal failure in 6–8 years.
Radiation nephritis FSGS rarely remits spontaneously, but treatment-induced remission
of proteinuria significantly improves prognosis. Treatment of patients
Familial podocytopathies
with primary FSGS should include inhibitors of the renin-angiotensin
NPHS1 mutation/nephrin
system. Based on retrospective studies, patients with nephrotic-range
NPHS2 mutation/podocin
proteinuria can be treated with steroids but respond far less often and
TRPC6 mutation/cation channel after a longer course of therapy than patients with MCD. Proteinuria
ACTN4 mutation/actinin remits in only 20–45% of patients receiving a course of steroids over
α-Galactosidase A deficiency/Fabry’s disease 6–9 months. Limited evidence suggests the use of cyclosporine in

N acetylneuraminic acid hydrolase deficiency/nephrosialidosis steroid-responsive patients helps ensure remissions. Relapse frequently
occurs after cessation of cyclosporine therapy, and cyclosporine itself
can lead to a deterioration of renal function due to its nephrotoxic
effects. A role for other agents that suppress the immune system such
matrix synthesis, and podocyte abnormalities associated with genetic as rituximab or mycophenolate mofetil has not been firmly established.
mutations. Risk polymorphisms at the APOL1 locus encoding apolipo- Primary FSGS recurs in 25–40% of patients given allografts at ESRD,
protein L1 expressed in podocytes substantially explain the increased leading to graft loss in half of those cases. In recurrent post-transplant
burden of FSGS among African Americans with or without HIV-associated FSGS many patients will achieve a full or partial remission with plas-
disease. mapheresis. The treatment of secondary FSGS typically involves treating
Glomerular schematic 5
Detachment
of cell from
GBM
Collapsed
capillary
and scar
Proliferation of
subepithelial cells
FOCAL
SCLEROSING
GLOMERULONEPHRITIS
Efferent
Afferent arteriole
arteriole

2144 TABLE 308-6 Membranous Glomerulonephritis of IMN patients alternatively have autoantibodies to thrombospondin
Primary/idiopathic membranous glomerulonephritis type-1 domain containing 7A. Both antigens co-localize within glomer-
Secondary membranous glomerulonephritis
ular subepithelial deposits with IgG4 (PLA2R). Other renal diseases do
not involve these autoantibodies. In most cases of secondary membra-
Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy,
filariasis nous nephropathy, these autoantibodies are absent with rare reports of
autoantibodies to PLA2R in membranous glomerulopathy associated
Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma
with hepatitis B and sarcoidosis. Circulating deposits and glomerular
Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents,
probenecid
deposits of these autoantibodies have correlated with the likelihood
of a spontaneous remission, severity of IMN, and the response to
Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis,
primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid, therapy. Eighty percent of patients with MGN present with nephrotic
myasthenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis syndrome and nonselective proteinuria. Microscopic hematuria is seen
Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes, but less commonly than in IgA nephropathy or FSGS. Spontaneous
Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian remissions occur in 20–33% of patients and often occur late in the
disease, angiofollicular lymph node hyperplasia course which make treatment decisions difficult. Low or absent levels
of autoantibodies to PLA2R assist in predicting both spontaneous and
treatment associated remissions. One-third of patients continue to have
relapsing nephrotic syndrome but maintain normal renal function, and
the underlying cause and controlling proteinuria. There is no role for approximately another third of patients develop renal failure or die
steroids or other immunosuppressive agents in secondary FSGS. from the complications of nephrotic syndrome. Male gender, older age,
hypertension, and the persistence of proteinuria are associated with
■■MEMBRANOUS GLOMERULONEPHRITIS worse prognosis. Although thrombotic complications are a feature of
MGN, or membranous nephropathy as it is sometimes called, accounts for all nephrotic syndromes, MGN has the highest reported incidences of
~20% of cases of nephrotic syndrome in adults, with a peak incidence renal vein thrombosis, pulmonary embolism, and deep-vein throm-
PART 9
between the ages of 30 and 50 years and a male to female ratio of 2:1. bosis. Prophylactic anticoagulation is controversial but has been rec-
IMN is rare in childhood and the most common cause of nephrotic ommended for patients with severe or prolonged proteinuria in the
syndrome in the elderly. In 20–30% of cases, MGN is secondary and is absence of risk factors for bleeding.
associated with a malignancy (solid tumors of the breast, lung, colon), In addition to the treatment of edema, dyslipidemia, and hyper-
infection (hepatitis B, syphilis, malaria, schistosomiasis), rheumato- tension, inhibition of the renin-angiotensin system is recommended.
logic disorders like lupus, rheumatoid arthritis, IgG4 diseases or drug Therapy with immunosuppressive drugs is also recommended for
exposure (Table 308-6). patients with primary MGN and persistent proteinuria (>3.0 g/24 h).
Uniform thickening of the basement membrane along the periph- The choice of immunosuppressive drugs for therapy is controversial,
eral capillary loops is seen by light microscopy on renal biopsy but current recommendations are to treat with steroids and cyclophos-
(see Fig. A3-7); this thickening needs to be distinguished from that seen phamide, chlorambucil, mycophenolate mofetil, or cyclosporine or
in diabetes and amyloidosis. (See Glomerular Schematic 6.) Immun- rituximab, an anti-CD20 antibody directed at B cells.
ofluorescence demonstrates diffuse granular deposits of IgG and C3,
and electron microscopy typically reveals electron-dense subepithelial ■■DIABETIC NEPHROPATHY
deposits. While different stages (I–V) of progressive membranous Diabetic nephropathy is the single most common cause of chronic renal
lesions have been described, some published analyses indicate the failure in the United States, accounting for 45% of patients receiving
degree of tubular atrophy or interstitial fibrosis is more predictive of renal replacement therapy, and is a rapidly growing problem world-
progression than is the stage of glomerular disease. The presence of wide. The dramatic increase in the number of patients with diabetic
subendothelial deposits or the presence of tubuloreticular inclusions nephropathy reflects the epidemic increase in obesity, metabolic syn-
strongly points to a diagnosis of membranous lupus nephritis, which drome, and type 2 diabetes mellitus. Approximately 40% of patients
may precede the extrarenal manifestations of lupus. In 70% of cases with types 1 or 2 diabetes develop nephropathy, but due to the higher
of IMN, autoantibodies against the M-type phospholipase A2 receptor prevalence of type 2 diabetes (90%) compared to type 1 (10%), the
circulate and bind to a conformational epitope present in the PLA2R majority of patients with diabetic nephropathy have type 2 disease.
on human podocytes, producing characteristic in situ deposits. 5–10% Renal lesions are more common in African-American, Native American,
Polynesian, and Maori populations. Risk factors for the development
of diabetic nephropathy include hyperglycemia, hypertension, dys-
lipidemia, smoking, a family history of diabetic nephropathy, and
Glomerular schematic 6
gene polymorphisms affecting the activity of the renin-angiotensin-
Foot process aldosterone axis.
fusion Within 1–2 years after the onset of clinical diabetes, morphologic
changes appear in the kidney. Thickening of the GBM is a sensitive
indicator for the presence of diabetes but correlates poorly with the
presence or absence of clinically significant nephropathy. The com-
Subepithelial
deposits
position of the GBM is altered notably with a loss of heparan sulfate
moieties that form the negatively charged filtration barrier. This change
results in increased filtration of serum proteins into the urine, predom-
inately negatively charged albumin. The expansion of the mesangium
due to the accumulation of extracellular matrix correlates with the clin-
ical manifestations of diabetic nephropathy (see stages in Fig. A3-20).
This expansion in mesangial matrix is associated with the development
of mesangial sclerosis. Some patients also develop eosinophilic, PAS+
nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules.
Immunofluorescence microscopy often reveals the nonspecific deposi-
tion of IgG (at times in a linear pattern) or complement staining without
immune deposits on electron microscopy. Prominent vascular changes
MEMBRANOUS are frequently seen with hyaline and hypertensive arteriosclerosis. This
GLOMERULONEPHRITIS
is associated with varying degrees of chronic glomerulosclerosis and

tubulointerstitial changes. Renal biopsies from patients with types 1 type 1 diabetes, intensive control of blood sugar clearly prevents the 2145
and 2 diabetes are largely indistinguishable. development or progression of diabetic nephropathy. The evidence for
These pathologic changes are the result of a number of postulated benefit of intensive blood glucose control in patients with type 2 dia-
factors. Multiple lines of evidence support an important role for betes is less certain, with current studies reporting conflicting results.
increases in glomerular capillary pressure (intraglomerular hyper- Controlling systemic blood pressure decreases renal and cardiovas-
tension) in alterations in renal structure and function. Direct effects cular adverse events in this high-risk population. The vast majority of
of hyperglycemia on the actin cytoskeleton of renal mesangial and patients with diabetic nephropathy require three or more antihyperten-
vascular smooth-muscle cells as well as diabetes-associated changes sive drugs including ACE inhibitors or angiotensin receptor blockers
in circulating factors such as atrial natriuretic factor, angiotensin II, (ARB) to achieve this goal. Drugs that inhibit the renin-angiotensin
and insulin-like growth factor (IGF) may account for this. Sustained system, independent of their effects on systemic blood pressure, have
glomerular hypertension increases matrix production, alterations in the been shown in numerous large clinical trials to slow the progression of
GBM with disruption in the filtration barrier (and hence proteinuria), diabetic nephropathy at early (microalbuminuria) and late (proteinuria with
and glomerulosclerosis. A number of factors have also been identified reduced glomerular filtration) stages. Since angiotensin II increases
that alter matrix production, including the accumulation of advanced efferent arteriolar resistance and, hence, glomerular capillary pressure,
glycosylation end products, circulating factors including growth hor- one key mechanism for the efficacy of inhibitors of the renin angioten-
mone, IGF-I, angiotensin II, connective tissue growth factor, TGF-β, sin system is reducing glomerular hypertension. Evidence suggests
and dyslipidemia. increased risk for cardiovascular adverse events with little evidence
The natural history of diabetic nephropathy in patients with types of efficacy in some patients with a combination of two drugs (ACE
1 and 2 diabetes is similar. However, since the onset of type 1 diabetes inhibitors, ARBs, or renin inhibitors) that suppress several compo-
is readily identifiable and the onset of type 2 diabetes is not, a patient nents of the renin-angiotensin system. Ongoing trials are examining
newly diagnosed with type 2 diabetes may present with advanced the hypotheses that other agents may be of benefit including sodium
diabetic nephropathy. At the onset of diabetes, renal hypertrophy and glucose transport 2 inhibitors, endothelin antagonists, and aldosterone

glomerular hyperfiltration are present. The degree of glomerular antagonists.
hyperfiltration correlates with the subsequent risk of clinically signifi-
cant nephropathy. In the ~40% of patients with diabetes who develop ■■GLOMERULAR DEPOSITION DISEASES
diabetic nephropathy, the earliest manifestation is an increase in Plasma cell dyscrasias producing excess light chain immunoglobulin
albuminuria detected by sensitive radioimmunoassay. Albuminuria in sometimes lead to the formation of glomerular and tubular deposits
the range of 30–300 mg/24 h is called microalbuminuria (Table 308-1). that cause heavy proteinuria and renal failure; the same is true for the
Microalbuminuria appears 5–10 years after the onset of diabetes. It is accumulation of serum amyloid A protein fragments seen in several
currently recommended to test patients with type 1 disease for microal- inflammatory diseases. This broad group of proteinuric patients has
buminuria 5 years after diagnosis of diabetes and yearly thereafter glomerular deposition disease.
and, because the time of onset of type 2 diabetes is often unknown, Light Chain Deposition Disease The biochemical characteris-
to test type 2 patients at the time of diagnosis of diabetes and yearly tics of nephrotoxic light chains produced in patients with light chain
thereafter. malignancies often confer a specific pattern of renal injury; that of
Patients with small increases in albuminuria increase their levels of either cast nephropathy (see Fig. A3-17), which causes renal failure but
urinary albumin excretion, typically reaching dipstick positive levels of not heavy proteinuria or amyloidosis, or light chain deposition disease
proteinuria (>300 mg albuminuria) 5–10 years after the onset of early (see Fig. A3-16), which produces nephrotic syndrome with renal fail-
albuminuria. Microalbuminuria is a potent risk factor for cardiovascu- ure. These latter patients produce kappa light chains that do not have
lar events and death in patients with type 2 diabetes. Many patients the biochemical features necessary to form amyloid fibrils. Instead,
with type 2 diabetes and microalbuminuria succumb to cardiovascular they self-aggregate and form granular deposits along the glomerular
events before they progress to proteinuria or renal failure. Proteinuria capillary and mesangium, tubular basement membrane, and Bowman’s
in frank diabetic nephropathy can be variable, ranging from 500 mg capsule. When predominant in glomeruli, nephrotic syndrome devel-
to 25 g/24 h, and is often associated with nephrotic syndrome. More ops, and about 70% of patients progress to dialysis. Light-chain depos-
than 90% of patients with type 1 diabetes and nephropathy have its are not fibrillar and do not stain with Congo red, but they are easily
diabetic retinopathy, so the absence of retinopathy in type 1 patients detected with anti–light chain antibody using immunofluorescence or
with proteinuria should prompt consideration of a diagnosis other as granular deposits on electron microscopy. A combination of the light
than diabetic nephropathy; only 60% of patients with type 2 diabetes chain rearrangement, self-aggregating properties at neutral pH, and
with nephropathy have diabetic retinopathy. There is a significant abnormal metabolism probably contribute to the deposition. Treatment
correlation between the presence of retinopathy and the presence of for light chain deposition disease is treatment of the primary disease
Kimmelstiel-Wilson nodules (see Fig. A3-20). Also, characteristically, and, if possible, autologous stem cell transplantation.
patients with advanced diabetic nephropathy have normal to enlarged
kidneys, in contrast to many other glomerular diseases where kidney Renal Amyloidosis Most renal amyloidosis is either the result of
size is usually decreased. Using the above epidemiologic and clinical primary fibrillar deposits of immunoglobulin light chains known as
data, and in the absence of other clinical or serologic data suggesting amyloid L (AL), or secondary to fibrillar deposits of serum amyloid
another disease, diabetic nephropathy is usually diagnosed without a A (AA) protein fragments (Chap. 108). Even though both occur for
renal biopsy. After the onset of proteinuria, renal function inexorably different reasons, their clinicopathophysiology is quite similar and will
declines, with 50% of patients reaching renal failure over another be discussed together. Amyloid infiltrates the liver, heart, peripheral
5–10 years; thus, from the earliest stages of microalbuminuria, it usually nerves, carpal tunnel, upper pharynx, and kidney, producing restrictive
takes 10–20 years to reach ESRD. However, up to 20–25% of patients cardiomyopathy, hepatomegaly, macroglossia, and heavy proteinuria
with type 2 diabetes and chronic kidney disease have never had sometimes associated with renal vein thrombosis. In systemic AL
albuminuria documented. It is not known if this represents an altered amyloidosis, also called primary amyloidosis, light chains produced in
natural history of diabetic nephropathy or another kidney disease that excess by clonal plasma cell dyscrasias are made into fragments by
happens to occur in a patient with diabetes. Once renal failure appears, macrophages so they can self-aggregate at acid pH. A disproportion-
survival on dialysis is shorter for patients with diabetes compared to ate number of these light chains (75%) are of the lambda class. About
other dialysis patients. Survival is best for patients who receive a trans- 10% of these patients have overt myeloma with lytic bone lesions and
plant from a living related donor. infiltration of the bone marrow with >30% plasma cells; nephrotic syn-
Good evidence supports the benefits of blood sugar and blood drome is common, and about 20% of patients progress to dialysis. AA
pressure control as well as inhibition of the renin-angiotensin system amyloidosis is sometimes called secondary amyloidosis and also presents
in retarding the progression of diabetic nephropathy. In patients with as nephrotic syndrome. It is due to deposition of β-pleated sheets of

2146 serum amyloid A protein, an acute phase reactant whose physiologic renal failure but do so later in life than males. Renal biopsy reveals
functions include cholesterol transport, immune cell attraction, and enlarged glomerular visceral epithelial cells packed with small clear
metalloproteases activation. Forty percent of patients with AA amyloid vacuoles containing globotriaosylceramide; vacuoles may also be
have rheumatoid arthritis, and another 10% have ankylosing spondyli- found in parietal and tubular epithelia (see Fig. A3-18). These vacuoles
tis or psoriatic arthritis; the rest derive from other lesser causes. Less of electron-dense materials in parallel arrays (zebra bodies) are easily
common in Western countries but more common in Mediterranean seen on electron microscopy. Ultimately, renal biopsies reveal FSGS.
regions, particularly in Sephardic and Iraqi Jews, is familial Mediterra- The nephropathy of Fabry’s disease typically presents in the third
nean fever (FMF). FMF is caused by a mutation in the gene encoding decade as mild to moderate proteinuria, sometimes with microscopic
pyrin, whereas Muckle-Wells syndrome, a related disorder, results from hematuria or nephrotic syndrome. Urinalysis may reveal oval fat bod-
a mutation in cryopyrin; both proteins are important in the apoptosis ies and birefringent glycolipid globules under polarized light (Maltese
of leukocytes early in inflammation; such proteins with pyrin domains cross). Renal biopsy is necessary for definitive diagnosis. Progression
are part of a pathway called the inflammasome. Receptor mutations to renal failure occurs by the fourth or fifth decade. Treatment with
in tumor necrosis factor receptor 1 (TNFR1)-associated periodic syn- inhibitors of the renin-angiotensin system is recommended. Treatment
drome also produce chronic inflammation and secondary amyloidosis. with recombinant α-galactosidase A clears microvascular endothelial
Fragments of serum amyloid A protein increase and self-aggregate deposits of globotriaosylceramide from the kidneys, heart, and skin. In
by attaching to receptors for advanced glycation end products in the patients with advanced organ involvement including chronic kidney
extracellular environment; nephrotic syndrome is common, and about disease, progression of disease occurs despite enzyme replacement
40–60% of patient’s progress to dialysis. AA and AL amyloid fibrils are therapy. Variable responses to enzyme therapy may be due to the
detectable with Congo red or in more detail with electron microscopy occurrence of neutralizing antibodies or differences in uptake of the
(see Fig. A3-15). Serum-free light chain nephelometry assays are useful enzyme. Graft and patient survival following renal transplantation in
in the early diagnosis and follow-up of disease progression. Biopsy of patients with Fabry’s are similar to other causes of ESRD.
involved liver or kidney is diagnostic 90% of the time when the pretest
probability is high; abdominal fat pad aspirates are positive about 70% PULMONARY-RENAL SYNDROMES
Several diseases can present with catastrophic hemoptysis and glom-
PART 9
of the time, but apparently less so when looking for AA amyloid. Amy-
loid deposits are distributed along blood vessels and in the mesangial erulonephritis associated with varying degrees of renal failure. The
regions of the kidney. The treatment for primary amyloidosis, melpha- usual causes include Goodpasture’s syndrome, granulomatosis with
lan, and autologous hematopoietic stem cell transplantation can delay polyangiitis, microscopic polyangiitis, Churg-Strauss vasculitis, and,
the course of disease in about 30% of patients. Secondary amyloidosis rarely, Henoch-Schönlein purpura or cryoglobulinemia. Each of these
is also relentless unless the primary disease can be controlled. Some diseases can also present without hemoptysis and are discussed in detail
new drugs in development that disrupt the formation of fibrils may be earlier in “Acute Nephritic Syndromes.” (See Glomerular Schematic 7.)
available in the future. Pulmonary bleeding in this setting is life-threatening and often results
in airway intubation, and acute renal failure requires dialysis. Diag-
Fibrillary-Immunotactoid Glomerulopathy Fibrillary- nosis is difficult initially because biopsies and serologic testing take
immunotactoid glomerulopathy is a rare (<1.0% of renal biopsies), time. Treatment with plasmapheresis and methylprednisolone is often
morphologically defined disease characterized by glomerular accu- empirical and temporizing until results of testing are available.
mulation of nonbranching randomly arranged fibrils. Some classify
amyloid and nonamyloid fibril-associated renal diseases all as fibrillary BASEMENT MEMBRANE SYNDROMES
glomerulopathies with immunotactoid glomerulopathy reserved for All kidney epithelia, including podocytes, rest on basement mem-
nonamyloid fibrillary disease not associated with a systemic illness. branes assembled into a planar surface through the interweaving of col-
Others define fibrillary glomerulonephritis as a nonamyloid fibrillary lagen IV with laminins, nidogen, and sulfated proteoglycans. Structural
disease with fibrils 12–24 nm and immunotactoid glomerulonephritis abnormalities in GBM associated with hematuria are characteristic of
with fibrils >30 nm. In either case, fibrillar/microtubular deposits of several familial disorders related to the expression of collagen IV genes.
oligoclonal or oligotypic immunoglobulins and complement appear The extended family of collagen IV contains six chains, which are
in the mesangium and along the glomerular capillary wall. Congo red expressed in different tissues at different stages of embryonic develop-
stains are negative. The cause of this “nonamyloid” glomerulopathy ment. All epithelial basement membranes early in human development
is mostly idiopathic; reports of immunotactoid glomerulonephritis are composed of interconnected triple-helical protomers rich in α1.α1.
describe an occasional association with chronic lymphocytic leukemia α2(IV) collagen. Some specialized tissues undergo a developmental
or B cell lymphoma. Both disorders appear in adults in the fourth switch replacing α1.α1.α2(IV) protomers with an α3.α4.α5(IV) collagen
decade with moderate to heavy proteinuria, hematuria, and a wide network; this switch occurs in the kidney (glomerular and tubular
variety of histologic lesions, including DPGN, MPGN, MGN, or mesan- basement membrane), lung, testis, cochlea, and eye, while an α5.α5.
gioproliferative glomerulonephritis. Nearly half of patients develop α6(IV) network appears in skin, smooth muscle, and esophagus and
renal failure over a few years. There is no consensus on treatment of along Bowman’s capsule in the kidney. This switch probably occurs
this uncommon disorder. The disease has been reported to recur fol- because the α3.α4.α5(IV) network is more resistant to proteases and
lowing renal transplantation in a minority of cases. ensures the structural longevity of critical tissues. When basement
membranes are the target of glomerular disease, they produce moder-
■■FABRY’S DISEASE
ate proteinuria, some hematuria, and progressive renal failure.
Fabry’s disease is an X-linked inborn error of globotriaosylceramide
metabolism secondary to deficient lysosomal α-galactosidase A activ- ■■ANTI-GBM DISEASE
ity, resulting in excessive intracellular storage of globotriaosylcera- Autoimmune disease where antibodies are directed against the α3 NC1
mide. Affected organs include the vascular endothelium, heart, brain, domain of collagen IV produces an anti-GBM disease often associated
and kidneys. Classically, Fabry’s disease presents in childhood in with RPGN and/or a pulmonary-renal syndrome called Goodpasture’s
males with acroparesthesias, angiokeratoma, and hypohidrosis. Over syndrome. Discussion of this disease is covered earlier in “Acute
time male patients develop cardiomyopathy, cerebrovascular disease, Nephritic Syndromes.”
and renal injury, with an average age of death around 50 years of
age. Hemizygotes with hypomorphic mutations sometimes present ■■ALPORT’S SYNDROME
in the fourth to sixth decade with single-organ involvement. Rarely, Classically, patients with Alport’s syndrome develop hematuria, thin-
dominant-negative α-galactosidase A mutations or female heterozy- ning and splitting of the GBMs, mild proteinuria (<1–2 g/24 h), which
gotes with unfavorable X inactivation present with mild single-organ appears late in the course, followed by chronic glomerulosclerosis
involvement. Rare females develop severe manifestations including leading to renal failure in association with sensorineural deafness.

Glomerular schematic 7 2147

RAPIDLY
PROGRESSIVE
GLOMERULONEPHRITIS
Some patients develop lenticonus of the anterior lens capsule, “dot multilamellations surrounding lucent areas that often contain granules
and fleck” retinopathy, and rarely, mental retardation or leiomyoma- of varying density—the so-called split basement membrane. In any
tosis. Approximately 85% of patients with Alport’s syndrome have Alport’s kidney, there are areas of thinning mixed with splitting of
an X-linked inheritance of mutations in the α5(IV) collagen chain the GBM. Tubules drop out, glomeruli scar, and the kidney eventually
on chromosome Xq22–24. Female carriers have variable penetrance succumbs to interstitial fibrosis. All affected members of a family with
depending on the type of mutation or the degree of mosaicism created X-linked Alport’s syndrome should be identified and followed, includ-
by X inactivation. Fifteen percent of patients have autosomal recessive ing mothers of affected males. Primary treatment is control of systemic
disease of the α3(IV) or α4(IV) chains on chromosome 2q35–37. Rarely, hypertension and use of ACE inhibitors to slow renal progression.
some kindred have an autosomal dominant inheritance of dominant- Although patients who receive renal allografts usually develop anti-
negative mutations in α3(IV) or α4(IV) chains. GBM antibodies directed toward the collagen epitopes absent in their
Pedigrees with the X-linked syndrome are quite variable in their native kidney, overt Goodpasture’s syndrome is rare and graft survival
rate and frequency of tissue damage leading to organ failure. Seventy is good.
percent of patients have the juvenile form with nonsense or missense
mutations, reading frame shifts, or large deletions and generally ■■THIN BASEMENT MEMBRANE DISEASE
develop renal failure and sensorineural deafness by age 30. Patients Thin basement membrane disease (TBMD) characterized by persistent
with splice variants, exon skipping, or missense mutations of α-helical or recurrent hematuria is not typically associated with proteinuria,
glycines generally deteriorate after the age of 30 (adult form) with hypertension, or loss of renal function or extrarenal disease. Although
mild or late deafness. Early severe deafness, lenticonus, or proteinuria not all cases are familial (perhaps a founder effect), it usually presents
suggests a poorer prognosis. Usually females from X-linked pedigrees in childhood in multiple family members and is also called benign famil-
have only microhematuria, but up to 25% of carrier females have been ial hematuria. Cases of TBMD have genetic defects in type IV collagen
reported to have more severe renal manifestations. Pedigrees with the but in contrast to Alport behave as an autosomal dominant disorder
autosomal recessive form of the disease have severe early disease in that in ~40% of families segregates with the COL(IV) α3/COL(IV) α4
both females and males with asymptomatic parents. loci. Mutations in these loci can result in a spectrum of disease ranging
Clinical evaluation should include a careful eye examination and from TBMD to autosomal dominant or recessive Alport’s. The GBM
hearing tests. However, the absence of extrarenal symptoms does not shows diffuse thinning compared to normal values for the patient’s
rule out the diagnosis. Since α5(IV) collagen is expressed in the skin, age in otherwise normal biopsies (see Fig. A3-19). The vast majority of
some X-linked Alport’s patients can be diagnosed with a skin biopsy patients have a benign course.
revealing the lack of the α5(IV) collagen chain on immunofluores-
cent analysis. Patients with mutations in α3(IV) or α4(IV) require a ■■NAIL-PATELLA SYNDROME
renal biopsy. Genetic testing can be used for the diagnosis of Alport’s Patients with nail-patella syndrome develop iliac horns on the pelvis
syndrome and the demonstration of the mode of inheritance. Early and dysplasia of the dorsal limbs involving the patella, elbows, and
in their disease, Alport’s patients typically have thin basement mem- nails, variably associated with neural-sensory hearing impairment,
branes on renal biopsy (see Fig. A3-19), which thicken over time into glaucoma, and abnormalities of the GBM and podocytes, leading to

2148 hematuria, proteinuria, and FSGS. The syndrome is autosomal domi- initiated with an ACE inhibitor can slow the rate of decline in renal
nant, with haploinsufficiency for the LIM homeodomain transcription function independent of effects on systemic blood pressure. Malignant
factor LMX1B; pedigrees are extremely variable in the penetrance for acceleration of hypertension complicates the course of chronic nephro-
all features of the disease. LMX1B regulates the expression of genes sclerosis, particularly in the setting of scleroderma or cocaine use (see
encoding α3 and α4 chains of collagen IV, interstitial type III collagen, Fig. A3-24). The hemodynamic stress of malignant hypertension leads
podocin, and CD2AP that help form the slit-pore membranes connect- to fibrinoid necrosis of small blood vessels, thrombotic microangiog-
ing podocytes. Mutations in the LIM domain region of LMX1B associ- raphy, a nephritic urinalysis, and acute renal failure. In the setting of
ate with glomerulopathy, and renal failure appears in as many as 30% renal failure, chest pain, or papilledema, the condition is treated as a
of patients. Proteinuria or isolated hematuria is discovered throughout hypertensive emergency.
life, but usually by the third decade, and is inexplicably more common
in females. On renal biopsy there is focal sclerosing glomerulonephri- ■■CHOLESTEROL EMBOLI
tis with specific lucent damage to the lamina densa of the GBM, an Aging patients with clinical complications from atherosclerosis some-
increase in collagen III fibrils along glomerular capillaries and in the times shower cholesterol crystals into the circulation—either spontane-
mesangium, and damage to the slit-pore membrane, producing heavy ously or, more commonly, following an endovascular procedure with
proteinuria not unlike that seen in congenital nephrotic syndrome. manipulation of the aorta—or with use of systemic anticoagulation.
Patients with renal failure do well with transplantation. Spontaneous emboli may shower acutely or shower subacutely and
somewhat more silently. Irregular emboli trapped in the microcircula-
■■GLOMERULAR-VASCULAR SYNDROMES tion produce ischemic damage that induces an inflammatory reaction.
A variety of diseases result in classic vascular injury to the glomerular Depending on the location of the atherosclerotic plaques releasing
capillaries. Most of these processes also damage blood vessels elsewhere these cholesterol fragments, one may see cerebral transient ischemic
in the body. The group of diseases discussed here lead to vasculitis, renal attacks; livedo reticularis in the lower extremities; Hollenhorst plaques
endothelial injury, thrombosis, ischemia, and/or lipid-based occlusions. in the retina with visual field cuts; necrosis of the toes; and acute glo-
merular capillary injury leading to FSGS sometimes associated with
ATHEROSCLEROTIC NEPHROPATHY
PART 9
hematuria, mild proteinuria, and loss of renal function, which typically

Aging in the developed world is commonly associated with the occlu- progresses over a few years. Occasional patients have fever, eosino-
sion of coronary and systemic blood vessels. The reasons for this include philia, or eosinophiluria. A skin biopsy of an involved area may be
obesity, insulin resistance, smoking, hypertension, and diets rich in diagnostic. Since tissue fixation dissolves the cholesterol, one typically
lipids that deposit in the arterial and arteriolar circulation, producing sees only residual, biconvex clefts in involved vessels (see Fig. A3-22).
local inflammation and fibrosis of small blood vessels. When the renal There is no therapy to reverse embolic occlusions, and steroids do not
arterial circulation is involved, the glomerular microcirculation is dam- help. Controlling blood pressure and lipids and cessation of smoking
aged, leading to chronic nephrosclerosis. Patients with GFRs <60 mL/min are usually recommended for prevention.
have more cardiovascular events and hospitalizations than those with
higher filtration rates. Several aggressive lipid disorders can accelerate ■■SICKLE CELL DISEASE
this process, but most of the time atherosclerotic progression to chronic Although individuals with SA-hemoglobin are usually asymptomatic,
nephrosclerosis is associated with poorly controlled hypertension. most will gradually develop hyposthenuria due to subclinical infarc-
Approximately 10% of glomeruli are normally sclerotic by age 40, tion of the renal medulla, thus predisposing them to volume depletion.
rising to 20% by age 60 and 30% by age 80. Serum lipid profiles in There is an unexpectedly high prevalence of sickle trait among dial-
humans are greatly affected by apolipoprotein E polymorphisms; the ysis patients who are African American. Patients with homozygous
E4 allele is accompanied by increases in serum cholesterol and is more SS-sickle cell disease and less commonly SC-sickle cell disease develop
closely associated with atherogenic profiles in patients with renal fail- chronic vasoocclusive disease in many organs. Polymers of deoxy-
ure. Mutations in E2 alleles, particularly in Japanese patients, produce genated SS-hemoglobin distort the shape of red blood cells. These
a specific renal abnormality called lipoprotein glomerulopathy associated cells attach to endothelia and obstruct small blood vessels, producing
with glomerular lipoprotein thrombi and capillary dilation. frequent and painful sickle cell crises over time. Vessel occlusions in
the kidney produce glomerular hypertension, FSGS, interstitial nephri-
■■HYPERTENSIVE NEPHROSCLEROSIS tis, and renal infarction associated with hyposthenuria, microscopic
Systemic hypertension causes permanent damage to the kidneys in hematuria, and even gross hematuria; some patients also present with
about 6% of patients with elevated blood pressure. As many as 27% MPGN. Renal function can be overestimated due to the increased
of patients with end-stage kidney disease have hypertension as a tubular secretion of creatinine seen in many patients with SS-sickle
primary cause. Although there is not a clear correlation between the cell. By the second or third decade of life, persistent vasoocclusive dis-
extent or duration of hypertension and the risk of end-organ damage, ease in the kidney leads to varying degrees of renal failure, and some
hypertensive nephrosclerosis is fivefold more frequent in African Ameri- patients end up on dialysis. Their prognosis on dialysis is poor and
cans than whites. Risk alleles associated with APOL1, a functional gene anemia management with erythropoiesis-stimulating agents compli-
for apolipoprotein L1 expressed in podocytes, substantially explains the cated. Treatment is directed to reducing the frequency of painful crises
increased burden of ESRD among African Americans. Associated risk and administering ACE inhibitors in the hope of delaying a progressive
factors for progression to end-stage kidney disease include increased decline in renal function. In sickle cell patients undergoing renal trans-
age, male gender, race, smoking, hypercholesterolemia, duration of plantation, renal graft survival is comparable to African Americans in
hypertension, low birth weight, and preexisting renal injury. Kidney the general transplant population.
biopsies in patients with hypertension, microhematuria, and moderate
proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and ■■THROMBOTIC MICROANGIOPATHIES
interstitial fibrosis in the absence of immune deposits (see Fig. A3-21). Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syn-
Today, based on a careful history, physical examination, urinalysis, and drome (HUS) represent a spectrum of thrombotic microangiopathies.
some serologic testing, the diagnosis of chronic nephrosclerosis is usu- TTP and HUS share the general features of idiopathic thrombocy-
ally inferred without a biopsy. Recent studies suggest, in the absence of topenic purpura, hemolytic anemia, fever, renal failure, and neurologic
diabetes, adults with hypertension and cardiovascular risk factors ben- disturbances. When patients, particularly children, have more evidence
efit from achieving a systolic BP <120 mmHg compared to <140 mmHg. of renal injury, their condition tends to be called HUS. In adults with
In the presence of kidney disease, most patients begin antihypertensive neurologic disease, it is considered to be TTP. In adults there is often
therapy with two drugs, classically a thiazide diuretic and an ACE a mixture of both, which is why they are often referred to as having
inhibitor; most will require three drugs. There is strong evidence in TTP/HUS. On examination of kidney tissue, there is evidence of glomerular
African Americans with hypertensive nephrosclerosis that therapy capillary endotheliosis associated with platelet thrombi, damage to the

capillary wall, and formation of fibrin material in and around glom- of cause, is treated presumptively as if the patient has endocarditis. The 2149
eruli (see Fig. A3-23). These tissue findings are similar to what is seen discussion of this disease can be found earlier, in the section “Acute
in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low Nephritic Syndromes.”
platelet count syndrome), malignant hypertension, and the antiphos-
pholipid syndrome. TTP/HUS is also seen in pregnancy; with the use Human Immunodeficiency Virus Renal disease is an impor-
of oral contraceptives or quinine; in renal transplant patients given tant complication of HIV disease. The risk of development of ESRD is
OKT3 for rejection; in patients taking the calcineurin inhibitors, cyclo- much higher in HIV-infected African Americans than in HIV-infected
sporine and tacrolimus, or in patients taking the antiplatelet agents, whites. About 50% of HIV-infected patients with kidney disease have
ticlopidine and clopidogrel; or following HIV infection. HIV-associated nephropathy (HIVAN) on biopsy. The lesion in HIVAN
Although there is no agreement on how much they share a final is FSGS, characteristically revealing a collapsing glomerulopathy
common pathophysiology, two general groups of patients are recog- (see Fig. A3-3) with visceral epithelial cell swelling, microcystic dila-
nized: childhood HUS associated with enterohemorrhagic diarrhea tation of renal tubules, and tubuloreticular inclusion. Renal epithelial
and TTP/HUS in adults. Childhood HUS is caused by a toxin released cells express replicating HIV virus, but host immune responses also
by Escherichia coli 0157:H7 and occasionally by Shigella dysenteriae. This play a role in the pathogenesis. HIVAN develops almost exclusively in
shiga toxin (verotoxin) directly injures endothelia, enterocytes, and patients of black race origin who have the APOL1 variant. HIVICK, HIV
renal cells, causing apoptosis, platelet clumping, and intravascular immune complex kidney disease is a group of immune complex-mediated
hemolysis by binding to the glycolipid receptors (Gb3). These receptors glomerular lesions seen in HIV patients, and on biopsy can look like a
are more abundant along endothelia in children compared to adults. constellation of other glomerular lesions, including postinfectious glom-
Shiga toxin also inhibits the endothelial production of ADAMTS13. erulonephritis, MGN, MPGN, DPGN, MCD, and IgA nephropathy. The
In familial cases of adult TTP/HUS, there is a genetic deficiency HIVICK effect is a complication of active HIV viremia.
of the ADAMTS13 metalloprotease that cleaves large multimers of HIV patients with FSGS typically present with nephrotic-range pro-
von Willebrand’s factor. Absent ADAMTS13, these large multimers teinuria and hypoalbuminemia, but unlike patients with other etiolo-
gies for nephrotic syndrome, they do not commonly have hypertension,

cause platelet clumping and intravascular hemolysis. An antibody to
ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but edema, or hyperlipidemia. Renal ultrasound also reveals large, echo-
not all; many patients also have antibodies to the thrombospondin genic kidneys despite the finding that renal function in some patients
receptor on selected endothelial cells in small vessels or increased declines rapidly. Treatment with inhibitors of the renin-angiotensin sys-
levels of plasminogen-activator inhibitor 1 (PAI-1). Patients can be tem decreases the proteinuria. Effective antiretroviral therapy benefits
tested for ADAMTS13 activity and, if low, the presence of antibodies to both the patient and the kidney and improves survival of HIV-infected
ADAMTS13 distinguishes the deficiency from the immune-mediated patients with HIVAN and in some cases HIVICK-associated chronic
disease. Some children with complement protein deficiencies express kidney disease or ESRD. In HIV-infected patients not yet on therapy,
atypical HUS (aHUS), which can be treated with liver transplant. The the presence of HIVAN is an indication to initiate therapy. Following
treatment of adult TTP/HUS with ADAMTS13 antibodies is daily plas- the introduction of antiretroviral therapy, survival on dialysis for the
mapheresis, which can be lifesaving. Plasmapheresis with fresh frozen HIV-infected patient has improved dramatically. Renal transplanta-
plasma is given until the platelet count rises, but in relapsing patients tions in HIV-infected patients without detectable viral loads or histories
it normally is continued well after the platelet count improves, and in of opportunistic infections provide a better survival benefit over dialy-
resistant patients twice-daily exchange may be helpful. Most patients sis. Following transplantation, patient and graft survival are similar to
respond within 2 weeks of daily plasmapheresis. Since TTP/HUS the general transplant population despite frequent rejections.
often has an autoimmune basis, there is an anecdotal role in relapsing Hepatitis B and C Typically, infected patients present with micro-
patients for using splenectomy, steroids, immunosuppressive drugs, scopic hematuria, nonnephrotic or nephrotic-range proteinuria, and
bortezomib, or rituximab, an anti-CD20 antibody. Patients without hypertension. There is a close association between hepatitis B infection
antibodies and a genetic deficiency of ADAMTS13 production can and polyarteritis nodosa with vasculitis appearing generally in the first
potentially be treated with fresh frozen plasma alone. Patients with 6 months following infection. Renal manifestations include renal artery
childhood HUS from infectious diarrhea are not given antibiotics, aneurysms, renal infarction, and ischemic scars. Alternatively, the hepati-
because antibiotics are thought to accelerate the release of the toxin and tis B carrier state can produce a MGN with predominant IgG1 deposition
the diarrhea is usually self-limited. No intervention appears superior to that is more common in children than adults, or MPGN that is more com-
supportive therapy in children with postdiarrheal HUS. mon in adults than in children. Renal histology is indistinguishable from
idiopathic MGN, type I or type 3 MPGN. Viral antigens most commonly,
■■ANTIPHOSPHOLIPID ANTIBODY SYNDROME
HBeAG, are found in the renal deposits. Cryoglobulinemic glomerulone-
(SEE CHAP. 350)
phritis has also been reported. There are no good treatment guidelines,
but interferon α-2b and antiviral agents which consist of either nucle-
GLOBAL CONSIDERATIONS otide or nucleoside reverse transcription inhibitors have been used to
some effect. Children have a good prognosis, with 60–65% achieving
■■INFECTIOUS DISEASE–ASSOCIATED SYNDROMES
spontaneous remission within 4 years. In contrast, 30% of adults have
A number of infectious diseases will injure the glomerular
renal insufficiency and 10% have renal failure 5 years after diagnosis.
capillaries as part of a systemic reaction producing an immune
Up to 30% of patients with chronic hepatitis C infection have some
response or from direct infection of renal tissue. Evidence of
renal manifestations. Patients often present with type II mixed cryo-
this immune response is collected by glomeruli in the form of immune
globulinemia, nephrotic syndrome, microscopic hematuria, abnormal
deposits that damage the kidney, producing moderate proteinuria and
liver function tests, depressed C3 levels, anti–hepatitis C virus (HCV)
hematuria. A high prevalence of many of these infectious diseases in
antibodies, and viral RNA in the blood. The renal lesions most com-
developing countries results in infection-associated renal disease being
monly seen, in order of decreasing frequency, are cryoglobulinemic
the most common cause of glomerulonephritis in many parts of the
glomerulonephritis, MGN, and type I MPGN but PAN, IgA and FSGS
world.
have been reported. With the availability of direct-acting antivirals,
Poststreptococcal Glomerulonephritis This form of glomer- including ledipasvir/sofosbuvir which can achieve a viral remission in
ulonephritis is one of the classic complications of streptococcal infec- >95% of patients, the prevalence of glomerular disease in HCV patients
tion. The discussion of this disease can be found earlier, in the section should decline. These drugs are currently the treatment of choice for
“Acute Nephritic Syndromes.” patients with HCV-related MPGN or PAN.
Subacute Bacterial Endocarditis Renal injury from persistent Other Viruses Other viral infections are occasionally associated
bacteremia absent the continued presence of a foreign body, regardless with glomerular lesions, but cause and effect are not well established.

2150 These viral infections and their respective glomerular lesions include: Other Parasites Renal involvement with toxoplasmosis infections
cytomegalovirus producing MPGN or FSGS; influenza and anti- is rare. When it occurs, patients present with nephrotic syndrome
GBM disease; measles-associated endocapillary proliferative glo- and have a histologic picture of MPGN. Fifty percent of patients with
merulonephritis, with measles antigen in the capillary loops and leishmaniasis will have mild to moderate proteinuria and microscopic
mesangium; parvovirus causing mild proliferative or mesangioprolif- hematuria, but renal insufficiency is rare. Acute DPGN, MGN, and
erative glomerulonephritis or FSGS; mumps and mesangioproliferative mesangioproliferative glomerulonephritis have all been observed on
glomerulonephritis; Epstein-Barr virus producing MPGN, diffuse biopsy. Filariasis and trichinosis are caused by nematodes and are
proliferative nephritis, or IgA nephropathy; dengue hemorrhagic fever sometimes associated with glomerular injury presenting with pro-
causing endocapillary proliferative glomerulonephritis; Hanta virus teinuria, hematuria, and a variety of histologic lesions that typically
and mesangial proliferative glomerulonephritis and coxsackievirus resolve with eradication of the infection.
producing focal glomerulonephritis or DPGN.
Syphilis Secondary syphilis, with rash and constitutional symp- The GISEN Group (Gruppo Italiano di Studi Epidemiologici in
toms, develops weeks to months after the chancre first appears and Nefrologia): Randomised placebo-controlled trial of effect of rami-
occasionally presents with the nephrotic syndrome from MGN caused pril on decline in glomerular filtration rate and risk of terminal renal
by subepithelial immune deposits containing treponemal antigens. failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857,
Other lesions have also rarely been described including interstitial 1997.
syphilitic nephritis. The diagnosis is confirmed with nontreponemal Kopp JB et al: APOL1 genetic variants in focal segmental glomerulo-
and treponemal tests for Treponema pallidum. The renal lesion responds sclerosis and HIV-associated nephropathy. J Am Soc Nephrol 22:2129,
to treatment with penicillin or an alternative drug, if allergic. Addi- 2011.
tional testing for other sexually transmitted diseases is an important Kupin WL: Viral-associated GN: Hepatitis C and HIV. Clin J Am Soc
part of disease management. Nephrol 12:1337, 2017.
Lewis EJ et al: Renoprotective effect of the angiotensin-receptor antag-
Leprosy Despite aggressive eradication programs, ~400,000 new onist irbesartan in patients with nephropathy due to type 2 diabetes.
PART 9
cases of leprosy appear annually worldwide. The diagnosis is best

N Engl J Med 345:851, 2001.
made in patients with multiple skin lesions accompanied by sensory
Pickering MC et al: C3 glomerulopathy: Consensus report. Kidney Int
loss in affected areas, using skin smears showing paucibacillary or mul-
84:1079, 2013.
tibacillary infection (WHO criteria). Leprosy is caused by infection with
Ronco P, Debiec H: Membranous nephropathy: A fairy tale for immu-
Mycobacterium leprae and can be classified by Ridley-Jopling criteria
nopathologists, nephrologists and patients. Mol Immunol 68:57, 2015.

into various types: tuberculoid, borderline tuberculoid, mid-borderline
and borderline lepromatous, and lepromatous. Renal involvement in
leprosy is related to the quantity of bacilli in the body, and the kidney
is one of the target organs during splanchnic localization. In some
309 Polycystic
series, all cases with borderline lepromatous and lepromatous types
of leprosy have various forms of renal involvement including FSGS, Kidney Disease
mesangioproliferative glomerulonephritis, or renal amyloidosis; much
less common are the renal lesions of DPGN and MPGN. Treatment of and Other Inherited
the infection with multi-drug therapy can reduce the incidence of renal
disease or produce remission of the renal disease.
Disorders of Tubule
Growth and Development
Malaria There are 300–500 million incident cases of malaria each
year worldwide, and the kidney is commonly involved. Glomerulo- Jing Zhou, Martin R. Pollak
nephritis is due to immune complexes containing malarial antigens
that are implanted in the glomerulus. In malaria from P. falciparum,
mild proteinuria is associated with subendothelial deposits, mesangial
deposits, and mesangioproliferative glomerulonephritis that usu- The polycystic kidney diseases are a group of genetically heteroge-
ally resolve with treatment. In quartan malaria from infection with neous disorders and a leading cause of kidney failure. The autosomal
Plasmodium malariae, children are more commonly affected and renal dominant form of polycystic kidney disease (ADPKD) is the most com-
involvement is more severe. Transient proteinuria and microscopic mon life-threatening monogenic disease, affecting 12 million people
hematuria can resolve with treatment of the infection. However, resis- worldwide. The autosomal recessive form of polycystic kidney disease
tant nephrotic syndrome with progression to renal failure over 3–5 (ARPKD) is rarer but affects the pediatric population. Kidney cysts
years does happen, as <50% of patients respond to steroid therapy. are often seen in a wide range of syndromic diseases. Recent studies
Affected patients with nephrotic syndrome have thickening of the have shown that defects in the structure or function of the primary
glomerular capillary walls, with subendothelial deposits of IgG, IgM, cilia may underline this group of genetic diseases collectively termed
and C3 associated with a sparse membranoproliferative lesion. The rare ciliopathies (Table 309-1).
mesangioproliferative glomerulonephritis reported with Plasmodium ■■AUTOSOMAL DOMINANT POLYCYSTIC
vivax or Plasmodium ovale typically has a benign course. Acute kidney KIDNEY DISEASE
injury can often complicate these glomerulopathies.
Etiology and Pathogenesis (Fig. 309-1) ADPDK is character-
Schistosomiasis Schistosomiasis affects >300 million people ized by progressive formation of epithelial lined cysts in the kidney.
worldwide and primarily involves the urinary and gastrointestinal tracts. Although cysts only occur in 5% of the tubules in the kidney, the
Glomerular involvement varies with the specific strain of schistosomia- enormous growth of these cysts ultimately leads to the loss of normal
sis; Schistosoma mansoni is most commonly associated with clinical renal surrounding tissues and loss of renal function. The cellular defects
disease, and the glomerular lesions can be classified: Class I is a mesan- in ADPKD that have been known for a long time are increased cell
gioproliferative glomerulonephritis; class II is an extracapillary proliferative proliferation and fluid secretion, decreased cell differentiation, and
glomerulonephritis; class III is a membranoproliferative glomerulonephritis; abnormal extracellular matrix. ADPKD is caused by mutations in
class IV is a focal segmental glomerulonephritis; and class V is amyloidosis. PKD1 and PKD2 which, respectively, code for polycystin-1 (PC1) and
Classes I–II often remit with treatment of the infection, but classes III polycystin-2 (PC2). PC1 is a large 11- transmembrane protein that func-
and IV lesions are associated with IgA immune deposits and progress tions like a G-protein coupled receptor. PC2 is a calcium-permeable
despite antiparasitic and/or immunosuppressive therapy. six transmembrane protein that structurally belongs to the transient

TABLE 309-1 Inherited Diseases Commonly Associated with a Cystic Phenotype 2151
MODE OF
DISEASE INHERITANCE RENAL ABNORMALITIES OTHER CLINICAL FEATURES GENES
Autosomal dominant AD Cortical and medullary cysts Liver, pancreatic cysts, hypertension, PKD1, PKD2
polycystic kidney disease subarachnoid hemorrhage
Autosomal recessive AR Distal and collecting duct Oligohydramnios if severe, hypertension, PKHD1
polycystic kidney disease cysts ascending cholangitis, liver fibrosis
Medullary cystic kidney AD Small fibrotic kidneys; In adults, gout UMOD
(Autosomal dominant medullary cysts MUC1
tubulointerstital kidney
REN
disease)
Nephronophthisis AR Small fibrotic kidneys; Growth retardation, anemia, (visual NPHP1-20, IQCB1, CEP290, GLIS2,
medullary cysts loss, liver fibrosis, cerebellar ataxia if RPGRIP1L, NEK8, SDCCAG8,
associated with another syndrome) TMEM67, TTC21B
Senior-Loken syndrome AR Renal cysts Juvenile nephronophthisis, Leber NPHP1-6, SDCCAG8
amaurosis
Leber congenital amaurosis AR Renal cysts Visual impairment in first year of life; GUCY2D, RPE65, LCA3-14 (including
pigmentary retinopathy LCA10, CEP290)
Meckel-Gruber syndrome AR Cortical and medullary cysts CNS anomalies, polydactyly, congenital MKS1, TMEM216, TMEM67, CEP290,
heart defects RPGRIP1L, CC2D2A, TCTN2, B9D1,
B9D2, NPHP3
Bardet-Biedl syndrome AR Renal cysts Obesity, polydactyly, retinitis pigmentosa, BBS1, 2, ARL6, BBS4,5, MKKS, BBS7,
anosmia, congenital heart defects, mental TTC8, BBS9, 10, TRIM32, BBS12,
CHAPTER 309 Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development
retardation MKS1, CEP290, C2ORF86; modifiers
MKS1, MKS3, CCDC28B
Oral-facial-digital syndrome AR Renal cysts Oral cavity, face, and digit anomalies; OFD1
type I CNS abnormalities; cystic kidney disease;
X-linked with male lethality, primary ciliary
dyskinesia
Cranioectodermal dysplasia AR Renal cysts Skeletal dysplasia; thoracic deformities; IFT80
(Sensenbrenner syndrome) polydactyly; renal cysts; retinitis
pigmentosa
Tuberous sclerosis AD Renal cysts Angiomyolipomas; renal cell carcinoma TSC1, TSC2
Facial angiofibromas; CNS hamartomas
Von Hippel-Lindau disease AD Renal cysts Renal cell carcinoma, retinal VHL
angiomas; CNS hemangioblastomas;
pheochromocytomas
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system.
receptor potential (TRP) cation channel family. PC1 and PC2 are widely the patients with ADPKD are clinically diagnosed during their lifetime.
expressed in almost all tissues and organs. PC1 expression is high in ADPKD is genetically heterogeneous. The first disease gene (PKD1) was
development and low in the adult, whereas PC2 expression is relatively localized to the region of the alpha-globin gene on chromosome 16p13 in
constant. PC1/2 are found on the primary cilium, a hair-like struc- 1985, and a second disease gene (PKD2) locus was mapped to chromo-
ture present on the apical membrane of a cell, in addition to the cell some 4q21-q23 in 1993. Mutations of PKD1 and PKD2 are responsible for
membranes and cell-cell junctions of tubular epithelial cells. Defects ~85% and ~15% of ADPKD cases, respectively. However, patients with
in the primary cilia are linked to a wide spectrum of human diseases, PKD2 mutations may be >15% because they tend to have milder clinical
collectively termed ciliopathies. The most common phenotype shared disease and, as a result, under-diagnosed. Embryonic lethality of Pkd1
by many ciliopathies is kidney cysts. PC1 and PC2 bind to each other and Pkd2 knockout mice suggest human homozygotes may be lethal, thus
via their respective C-terminal tails to form a receptor-channel com- not clinically recognized.
plex and regulate each other’s function. The PC1/2 protein complex PKD1 is comprised of 46 exons occupying ~52 kb of genomic DNA.
serves as a mechanosensor or chemical sensor and regulates calcium It produces a ~14 kb transcript that encodes polycystin-1, a protein
and G-protein signaling. The PC1/2 protein complex may also directly of ~4300 amino acids. A feature of the PKD1 gene is that the 5’ three-
regulate a number of cellular functions including the cell cycle, the quarters of PKD1 have been duplicated at six other sites on chromo-
actin cytoskeleton, planar cell polarity (PCP), and cell migration. This some 16p, and many of them produce mRNA transcripts, which pro-
protein complex has also been implicated in regulating a number of vides a major challenge for genetic analysis of the duplicated region.
signaling pathways, including Wnt, mammalian target of rapamycin PKD2 is a single-copy gene with 15 exons producing a ~5.3 kb mRNA
(mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K/Akt), G transcript that encodes polycystin-2, a protein of 968 amino acids. A
protein–coupled receptor (GPCR), and epidermal growth factor recep- third gene GANAB, encoding the glucosidase IIa subunit, was recently
tor (EGFR), as well as in the localization and activity of cystic fibrosis reported to cause ADPKD, but patients with mutations in this gene
transmembrane conductance regulator (CFTR). One hypothesis is all appear to have polycystic liver disease, and their kidney disease is
that loss of ciliary function of PC1 and PC2 leads to aberrant calcium milder than that in classic ADPKD.
signaling and a subsequent increase of adenylyl cyclase activity and In ADPKD patients, every cell carries a germline mutant allele of
decrease of phosphodiesterase activity, which, in turn, causes increased either PKD1 or PKD2. However, cysts develop in only a small fraction
cellular cAMP. Increased cAMP promotes protein kinase A activity, of the nephrons. Cysts are thought to originate from clonal growth of
among other effectors, and, in turn, leads to cyst growth by promoting single cells that have received a somatic “second hit” mutation in the
proliferation and fluid secretion of cyst-lining cells through chloride “normal” allele of the PKD1 or PKD2 gene. Accumulating evidence in
and aquarporin channels in ADPKD kidneys. mouse models now shows that partial loss of function of the second
ADPKD is inherited as an autosomal dominant trait with complete allele of Pkd1 in a proliferative environment is sufficient for cysto-
penetrance, but variable expressivity. The disease affects all ethnic groups genesis, suggesting that a critical amount of PKD1 is needed in a cell.
worldwide with an estimated prevalence of 1:1000 to 1:400. Only half of Somatic inactivation of the second allele of Pkd1 in adult mice results

2152
Primary clia
“9 + 0”
Ca2+
Extracellular signals
Kif3A/B Receptors
BBSome
NPHP1 FPC
Ciliary Membrane Polycystin-1 Polycystin-2
ADPKD (PKD1/PKD2) Ca2+, Wnt, SHH, cAMP

and other signaling events
Kinesin-2 ARPKD (PKHD1)
Dynein
Defective
Motor Planar cell polarity
Joubert
Cell proliferation
Ca2+
Wnt
Hh
Transition
Nephronophthisis (NPHP) During development
Zone
morphogenesis
Basal Body
Meckel Post development
PART 9
maintenance
Bardet Biedl (BBS)
Severe disease Mild disease
Early quick onset Late slow onset
Nucleus
FIGURE 309-1 Scheme of the primary cilium and cystic kidney disease proteins. Left: a scheme of the primary cilium. Primary cilia share a “9+0” organization of
microtubule doublets. Proteins are transported into the cilium by motor protein kinesin 2 and transported out of the cilium by dynein. The cilium is connected to the
basal body through the transition zone. Middle: topology of ADPKD and ARPKD proteins polycystin 1, polycystin 2, and FPC are shown. Localization of disease proteins
in the cilium, the transition zone and the basal body are color coded. Right: potential disease mechanisms due to cilium mediated signaling events.
in very slow onset of cyst development in the kidney, but a “third hit” hypocitraturia may be important in the pathogenesis of renal stones in
such as an additional genetic or epigenetic event, the inactivation of a ADPKD. Renal cell carcinoma is a rare complication of ADPKD with
growth suppressor gene, the activation of a growth promoting gene(s), no apparent increased frequency compared to the general population.
or an event like renal injury that activates the developmental program, However, in ADPKD these tumors are more often bilateral at presen-
may promote rapid cyst formation. tation, multicentric, and sarcomatoid in type. Radiological imaging is
often not helpful in distinguishing cyst infection and cyst hemorrhage
Clinical Manifestations ADPKD is characterized by the pro- because of their complexity. CT scan and magnetic resonance imaging
gressive bilateral formation of renal cysts. Focal renal cysts are typically (MRI) are often useful in distinguishing a malignancy from a complex
detected in affected subjects aged <30 years. Hundreds to thousands cyst. Cardiovascular complications are the major cause of mortality in
of cysts are usually present in the kidneys of most patients in the patients with ADPKD. Hypertension is common, and typically occurs
fifth decade (Fig. 309-2). Enlarged kidneys can each reach a fourfold before any reduction in glomerular filtration rate (GFR). Hypertension
increase in length, and weigh up to 20 times the normal weight. The is a risk factor for both cardiovascular and kidney disease progres-
clinical presentations of ADPKD are highly variable. While many sion in ADPKD. Notably, some normotensive patients with ADPKD
patients are asymptomatic until the fourth to fifth decade of life and may also have left ventricular hypertrophy. Hypertension in ADPKD
are diagnosed by incidental discoveries of hypertension or abdominal may result from the increased activation of the renin-angiotensin-
masses, back or flank pain is a frequent symptom in ~60% of patients aldosterone system, increased sympathetic nerve activity, and impaired
with ADPKD. The pain may result from renal cyst infection, hemor- endothelial cilium function-dependent relaxation of small resistant
rhage, or nephrolithiasis. Gross hematuria resulting from cyst rupture blood vessels.
occurs in ~ 40% of patients during the course of their disease, and many The progression of ADPKD has striking inter- and intrafamilial vari-
of them will have recurrent episodes. Flank pain and hematuria may ability. The disease can present as early as in utero, but end-stage renal
coexist if the cyst that ruptures is connected with the collecting system. disease (ESRD) typically occurs in late middle age. Risk factors include
Proteinuria is usually a minor feature of ADPKD. Infection is the sec- early diagnosis of ADPKD, hypertension, gross hematuria, multiple
ond most common cause of death for patients with ADPKD. Up to half pregnancies, and large kidney size. Liver cysts derived from the biliary
of patients with ADPKD will have one or more episodes of renal infec- epithelia are the most common extrarenal complication. Polycystic liver
tion during their lifetime. An infected cyst and acute pyelonephritis are disease associated with ADPKD is different from autosomal dominant
the most common renal infections often due to gram-negative bacteria, polycystic liver disease (ADPLD), which is caused by mutations in at
which are associated with fever and flank pain, with or without bacte- least two distinct genes (PRKCSH and SEC63) and does not progress to
remia. These complications and renal insufficiency often correlate with renal failure. Massive polycystic liver disease occurs almost exclusively
structural abnormality of the renal parenchyma. Kidney stones occur in in women with ADPKD, particularly those with multiple pregnancies.
~20% of patients with ADPKD. Different from the general population, Heterozygous loss-of-function variants in PKHD1, ALG8, GANAB, and
more than half of the stones in patients with ADPKD are composed SEC61B are now found in ADPLD. ALG8, GANAB, and SEC61B, all
of uric acid, with the remainder due to calcium oxalate. Distal acidi- encode ER proteins that are involved in the same pathway as GIIβ and
fication defects, abnormal ammonium transport, low urine pH, and SEC63, and each appears to affect PC1 biogenesis.

value of 96% and specificity value of 100%. The presence of at least two 2153
cysts in each kidney and at least four cysts in each kidney, respectively, are
required for the diagnosis among at-risk subjects aged 30–59 years and
aged ≥60 years with a sensitivity value of 100% and specificity value
of 100%. This is because there is an increased frequency of developing
simple renal cysts with age. Conversely, in subjects aged between 30
and 59 years the absence of at least two cysts in each kidney, which is
associated with a false negative rate of 0%, can be used for disease
exclusion. These criteria have a lower sensitivity for patients with a
PKD2 mutation because a late onset of ADPKD2. CT scan and T2-MRI,
with and without contrast enhancement, are more sensitive than
ultrasonography and can detect cysts of smaller size. However, a CT
scan exposes the patient to radiation and radiocontrast, which may
cause serious allergic reactions and nephrotoxicity in patients with
renal insufficiency. T2-MRI, with gadolinium as a contrast agent, has
minimal renal toxicity and can detect cysts of only 2–3 mm in diameter.
However, a large majority of cysts may still be below the detection
level. Genetic testing by linkage analyses and mutational analyses
are available for ambiguous cases. Because of the large size of PKD1
gene and the presence of multiple highly homologous pseudogenes,
mutational analysis of PKD1 gene is difficult and costly. Application of
new technologies such as paired-end next generation sequencing with
multiplexing individually bar-coded long range PCR libraries may
reduce the costs and improve the sensitivity for clinical genetic testing.
TREATMENT
Autosomal Dominant Polycystic Kidney Disease
No specific treatment to prevent cyst growth or the decline of renal
function has been approved by U.S. Food and Drug Administration.
Blood pressure control to a target of 140/90 mmHg is recommended
according to the guidelines from the eighth report of the Joint National
FIGURE 309-2 Photograph showing a kidney from a patient with autosomal
Committee on Prevention, Detection, Evaluation, and Treatment of
dominant polycystic kidney disease. The kidney has been cut open to expose High Blood Pressure (JNC VIII report) for reducing cardiovascular
the parenchyma and internal aspects of cysts. complications in ADPKD and renal disease progression. More rig-
orous blood pressure control does not equal greater clinical benefits.
Maintaining a target systolic blood pressure to 110 mmHg in patients
Intracranial aneurysm (ICA) occurs four to five times more frequent
with moderate or advanced disease may increase the risk of renal
in APDKD patients than that seen in the general population and cause
disease progression by reducing renal blood flow. Lipid-soluble anti-
high mortality. The disease gene products PC1 and PC2 may be directly
biotics against common gram-negative enteric organisms include
responsible for defects in arterial smooth muscle cells and myofibrob-
trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol,
lasts. The focal nature and the natural history of ICA in ADPKD remain
and are preferred for cyst infection because most renal cysts are not
unclear. A family history of ICA is a risk factor of aneurysm rupture in
connected to glomerular filtration and antibiotics that are capable
ADPKD, whether hypertension and cigarette smoking are indepen-
to penetrate the cyst walls are likely to be more effective. Treat-
dent risk factors is not clear. About 20–50% of patients may experience
ment often requires 4–6 weeks. The treatment of kidney stones in
“warning headaches” preceding the index episode of subarachnoid
ADPKD includes standard measures such as analgesics for pain
hemorrhage due to ruptured ICA. A CT scan is generally used as the
relief, and hydration to ensure adequate urine flow. Management
first diagnostic test. A lumbar puncture may be used to confirm the
of chronic flank, back, or abdominal pain due to renal enlargement
diagnosis. The role of radiological screening for ICA in asymptomatic
may include both pharmacologic (non-narcotic and narcotic anal-
patients with ADPKD remains unclear. ADPKD patients with a posi-
gesics) and non-pharmacological (transcutaneous electrical nerve
tive family history of ICAs may undergo pre-symptomatic screening
stimulation, acupuncture, and biofeedback). Occasionally surgical
of ICAs by MR angiography. Other vascular abnormalities in ADPKD
decompression of cysts may be necessary. More than half of ADPKD
patients include diffuse arterial dolichoectasias of the anterior and pos-
patients eventually require peritoneal dialysis, hemodialysis, or
terior cerebral circulation, which can predispose to arterial dissection
kidney transplantation. Peritoneal dialysis may not be suitable for
and stroke. Mitral valve prolapse occurs in up to 30% of patients with
some patients with massively enlarged polycystic kidneys due to
ADPKD, and tricuspid valve prolapse is less common. Other valvular
the small intraabdominal space for efficient peritoneal exchange
abnormalities occurring with increased frequency in ADPKD patients
of fluid and solutes and increased chance of abdominal hernia and
include insufficiency of the mitral, aortic, and tricuspid valves. Most
back pain. Patients with very large polycystic kidneys and recurrent
patients are asymptomatic but some may progress and require valve
renal cyst infection may require pretransplant nephrectomy or bilat-
replacement. The prevalence of colonic diverticulae and abdominal
eral nephrectomy to accommodate the allograft and reduce the pain.
wall hernias are also increased in ADPKD patients.
Specific treatment strategies to ADPKD have focused on slowing
Diagnosis Diagnosis is typically made from a positive family renal disease progression and lowering cardiovascular risk. For the
history consistent with autosomal dominant inheritance and multiple latter, the main approach is to control blood pressure by inhibiting
kidney cysts bilaterally. Renal ultrasonography is often used for pre- the renin-angiotensin-aldosterone system. The HALT PKD trial
symptomatic screening of at-risk subjects and for evaluation of poten- was set to evaluate the impact of intensive blockade of the renin-
tial living-related kidney donors from ADPKD families. The presence angiotensin-aldosterone system, and levels of blood pressure control
of at least two renal cysts (unilateral or bilateral) is sufficient for diagnosis on progressive renal disease. This trial found that rigorous blood-
among at-risk subjects between 15 and 29 years of age with a sensitivity pressure control could slow cyst growth. Most approaches target the

2154 slowing of renal disease progression by inhibiting cell proliferation life. In the classic group, most patients are born with renal insufficiency
and fluid secretion. Several clinical trials have been conducted and ESRD. However, infants often have a transient improvement in
targeting cell proliferation: sirolimus and everolimus, inhibitors of their GFR; death from renal insufficiency at this stage is rare. Some
the mammalian target of rapamycin (mTOR) pathway; OPC31260 patients are diagnosed after the neonatal stage, which form the older
and tolvaptan, which inhibits cyclic adenosine monophosphate group. Morbidity and mortality in this group often involve systemic
(cAMP) pathways by antagonizing the activation of vasopressin V2 hypertension, progressive renal insufficiency, and liver manifestations.
receptor (V2R) in collecting ducts and reduces cell proliferation by The hallmarks of ARPKD liver disease are biliary dysgenesis due to a
decreasing renal cAMP levels; and somatostatin analogues, which primary ductal plate malformation with associated periportal fibrosis,
reduces cAMP levels by binding to several G-protein coupled recep- namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic
tors. The TAMPO and ALADIN trials showed that V2R antagonists bile ducts (Caroli disease). CHF and Caroli disease can then lead to
and somatostatin analogues (octreotide-LAR groups) respectively portal hypertension exhibiting hepatosplenomegaly, variceal bleeding,
slowed the decline of renal function. Some side effects, such as liver and cholangitis. Some patients with the diagnosis of ARPKD at 1 year
function impairment, polydipsia, and diarrhea, have been observed of age with nephromegaly exhibit slowly declining renal function over
for tolvaptan and cholecystitis for octreotide-LAR. A recent report 20 years with only minimally enlarged kidneys at ESRD, and markedly
also showed that tolvaptan reduces renal pain. DIPAK, a small atrophic kidneys following renal transplantation. The slow progres-
multi-center European study, showed that nerve block may be used sion of renal disease is likely due to increasing fibrosis rather than the
to relieve pain in ADPKD patients suffering with refractory chronic development of cysts. Systemic hypertension is common in all ARPKD
pain. A combination of different growth inhibitors may enhance patients, even those with normal renal function.
efficacy and reduce side effects.
Additional preclinical studies in animal models include the use
Diagnosis Ultrasonography, CT, and MRI all can be used for diag-
nosis. Ultrasonography reveals large, echogenic kidneys with poor
of inhibitors to nonreceptor tyrosine kinase Src, B-raf, cycline-
corticomedullary differentiation. The diagnosis can be made in utero
dependent kinase (CDK), transcription factors STAT3 and STAT6
after 24 weeks of gestation in severe cases. Macrocysts generally are
(pyrimethamine and leflunomide), purinergic receptors, hepatoc-
not common at birth in ARPKD patients. The absence of renal cysts in
PART 9
yte growth factor receptor, glucosylceramide, and agonists to per-

either parent, particularly if they are >40 years of age on ultrasonogra-
oxisome proliferator-activated receptor-gamma (PPARγ) receptors
phy helps distinguish ARPKD from ADPKD in older patients. Clinical,
(thiazolidodinediones). Recently, several microRNAs have been
laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathol-
identified that mediate disease progression, which may prove to be
ogy demonstrating characteristic ductal plate abnormalities, family
a new therapeutic target. Food restriction in mouse models of the
history of affected siblings, or parental consanguinity suggestive of

disease was reported to reduce cyst area, kidney fibrosis, inflamma-
autosomal recessive inheritance is helpful. The lack of mutational hot
tion, and injury. Branched chain amino acids appear to enhance cyst
spots and the large and complex genomic structure of PKHD1 make
development in a mouse model.
molecular diagnosis difficult, however, presymptomatic screen of other
at-risk members in a family with already identified ARPKD mutations
■■AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY is straightforward and inexpensive.
DISEASE
Genetic Considerations ARPKD is a significant hereditary TREATMENT
renal disease in childhood, with an estimated prevalence of 1 in Autosomal Recessive Polycystic Kidney Disease
20,000 live births. A carrier frequency of up to 1:70 has been
reported. Mutations in a single gene, PKHD1, are responsible for all the There is no specific therapy for ARPKD. Appropriate neonatal inten-
clinical presentations of ARPKD. PKHD1, localized on human chromo- sive care, blood pressure control, dialysis, and kidney transplan-
some region 6p21.1-6p12.2, is one of the largest genes in the genome, tation increase survival into adulthood. Complications of hepatic
occupies ~450 kb of DNA, and contains at least 86 exons. It produces fibrosis may necessitate liver transplantation. Patients with severe
multiple alternatively spliced transcripts. The largest transcript encodes Caroli disease may need porto-systemic shunting. Upcoming ther-
fibrocystin/polyductin (FPC), which is a large receptor-like integral apies may target abnormal cell signaling mechanisms, as described
membrane protein of 4074 amino acids. FPC has a single transmem- above for ADPKD.
brane, a large N-terminal extracellular region, and a short intracellular
cytoplasmic domain. FPC is localized on the primary cilia of epithelia
cells of cortical and medullary collecting ducts and cholangiocytes of OTHER DISEASES CHARACTERIZED BY
bile ducts, similar to polycystins and several other ciliopathy proteins. LARGE KIDNEY CYSTS
FPC is also expressed on the basal body and plasma membrane. The
large extracellular domain of FPC is presumed to bind to an as yet
■■TUBEROUS SCLEROSIS
Tuberous sclerosis (TS) is a rare autosomal dominant syndrome caused
unknown ligand(s), and is involved in cell-cell and cell-matrix interac-
by mutations in one of two genes, TSC1, encoding hamartin, or, TSC2,
tions. FPC interacts with ADPKD protein PC2, and may also participate
encoding tuberin. Published estimates of prevalence vary widely, but it
in regulation of the mechanosensory function of the primary cilia,
certainly occurs in <1:5,000 births. Kidney cysts are a frequent feature
calcium signaling, and PCP, suggesting a common mechanism under-
of this condition, as are two other abnormalities of kidney growth,
lying cystogenesis between ADPKD and ARPKD. FPC is also found on
renal cell carcinoma and renal angiomyolipomas. TS is a syndrome
the centrosomes and mitotic spindle, and may regulate centrosome
affecting multiple organ systems. Other features of TS include benign
duplication and mitotic spindle assembly during cell division. A large
growths in the nervous system, eyes, heart, lung, liver, and the skin.
number of various mutations have been found throughout PKHD1,
Essentially all TS patients have such skin lesions, and a large propor-
and are unique to individual families. Most patients are compound
tion of patients have neurologic and cognitive manifestations. The
heterozygotes for PKHD1 mutations. Patients with two truncation
TSC2 gene is adjacent to PKD1 in the human genome. Some patients
mutations appear to have an earlier onset of the disease.
have deletions in their genomic DNA that inactivate these two genes.
Clinical Features Classic ARPKD is generally diagnosed in utero Such individuals may have manifestations of both ADPKD and TS.
or within the neonatal period, and characterized by greatly enlarged The most common kidney finding in TS is the presence of angiomy-
echogenic kidneys in diseased fetuses. Reduced fetal urine production olipomas. These growths tend to be multiple and bilateral. While they
may contribute to oligohydroaminos and pulmonary hypoplasia. are usually benign, they may bleed. Surgical removal is often recom-
About 30% of affected neonates die shortly after birth due to respiratory mended as a prophylactic measure in people with angiomyolipomas
insufficiency. Close to 60% of mortality occurs within the first month of >4 cm in diameter. The cysts in TS are radiographically similar to those

seen in ADPKD. In contrast to ADPKD, there is a clearly increased uric acid levels. The disease-causing MUC1 mutations that have been 2155
risk of renal cell carcinoma in TS patients. Regular periodic imaging is reported all alter a highly repetitive region within the MUC1 gene,
recommended in TS patients with kidney involvement to screen for the leading to a large “neoprotein” fragment that may lead to toxic effects
development of renal cell carcinoma. These cysts may rarely become on the kidney tubule.
large and hemorrhagic, occasionally requiring nephrectomy when Clinically, patients with MCKD I exhibit slowly progressive CKD
nephron-sparing surgery is not possible. in adulthood, with only minimal amounts of increased urine protein
Although not common, TS may lead to significant chronic kidney and occasional renal cysts seen on ultrasound examination. Kidney
disease (CKD) and progress to end-stage kidney failure. Patients with histology shows tubulointerstitial fibrosis and tubular atrophy. The
TS and CKD typically have an unremarkable urine sediment and only mechanisms by which MUC1 mutations cause human kidney disease
minimal to mild amounts of proteinuria. are not known. Disease does not recur in transplanted kidneys.
Mechanistically, the TSC1 and TSC2 gene products tuberin and
hamartin interact physically. This protein complex is localized to the ADTKD-UMOD ADTKD-IUMOD (also called MCKD II) is caused
base of the cilia and inhibits intracellular signaling processes mediated by mutations in the UMOD gene, which encodes the protein uromod-
by mTOR (mammalian target of rapamycin), leading to abnormal ulin, also known as Tamm-Horsfall protein. Uromodulin is also found
growth in a number of tissues. Investigation of mTOR inhibitors as on the centrosome, the mitotic spindle, and the primary cilia; it colocal-
therapy for TS is ongoing. There is increasing optimism that this class izes with nephrocystin-1 and KIF3A on the cilia. UMOD mutations also
of drugs will become commonplace for prevention of the renal and cause the conditions that have been referred to as familial juvenile hype-
non-renal manifestations of TS. ruricemic nephropathy (HNFJ1) and glomerulocystic kidney disease
(GCKD), although it is not clear that these different names represent
■■VON HIPPEL-LINDAU DISEASE clearly distinct disorders. The term uromodulin-associated kidney disease
Von Hippel-Lindau disease (VHL) is an inherited cancer syndrome with (or UAKD) has been suggested as a better name for MCKD II and the
renal manifestations. VHL is an autosomal dominant condition caused various other related UMOD-associated diseases. Despite the name,
kidney cysts are not a common feature of MCKD II. MCKD II should be
by mutations in the VHL tumor-suppressor gene. VHL is localized to
the primary cilia and is necessary for the formation of primary cilia. Like suspected clinically in patients with a family history of late onset kid-
many autosomal dominant cancer syndromes, VHL is recessive at the ney disease, benign urine sediments, absence of significant proteinuria,
cellular level: a somatic mutation in the second VHL allele leads to loss and hyperuricemia. Large genome-wide association studies have sug-
of VHL in the cell and abnormal growth. Kidney manifestations of VHL gested that certain common non-coding sequence variants in UMOD
include multiple bilateral kidney cysts, and renal cell carcinomas. Kid- are associated with a moderately increased risk of CKD in the general
ney cysts and carcinoma affects the majority of VHL patients. Non-renal population. UMOD-associated disease is often associated with gout.
features of VHL include pheochromocytomas, cerebellar hemangioblas-
Other Forms of Familial Tubulointerstitial Kidney
tomas, and retinal hemangiomas. While much rarer than ADPKD, it is
Disease A small number of families have been identified with
important for this entity to be considered in the differential diagnosis of
autosomal dominant tubulointerstitial kidney disease and hyperu-
an individual with newly recognized kidney cysts.
ricemia who lack UMOD mutations. Some of these families carry
In these patients, annual screening of the kidneys by imaging with
disease-segregating mutations in the renin gene REN (disease designa-
CT or MRI scanning is recommended for early detection of renal cell
tion ADTKD-REN). ADKTKD-REN patients demonstrate hyporenine-
carcinomas. Increasingly, nephron-sparing surgical approaches are
mia with mild hyperkalemia, and often have hyperuricemia and gout.
being used for removal of cancerous lesions in order to preserve kidney
There are other families who lack mutations in UMOD, MUC1, or REN
function.
mutation. Thus, mutations in other yet-to-be identified genes are able
to produce similar interstitial kidney disease, both with and without
OTHER INHERITED DISEASES OF TUBULE hyperuricemia.
GROWTH AND DEVELOPMENT Kidney biopsies in patients with any of various forms of MCKD
ADPKD is by far the most common adult onset single gene form of typically show interstitial fibrosis. These histologic features are not
adult onset kidney disease. The large cysts that are sometimes seen in diagnostic of any particular genetic entity, and the specific diagnosis
VHL and TS are similar in appearance to the cysts seen in ADPKD. A must be made by other means. Genetic tests for alterations in specific
variety of other inherited disorders affecting primarily tubule and renal genes are increasingly available in the clinical setting.
interstitial function can lead to CKD and eventual end-stage kidney Those patients with autosomal dominant interstitial kidney disease,
disease in the absence of large tubule-derived cysts. UMOD or REN mutations, with hyperuricemia and gout should be
Inherited diseases affecting the tubulointerstitial compartment of treated similarly to others with these findings, with uric-acid lowering
the kidney can lead to secondary glomerular stress and glomeruloscle- agents, such as allopurinol or febuxostat.
rosis with some degree of concomitant proteinuria. Similarly, disorders
of glomerular function will typically lead to secondary interstitial
fibrosis and tubule atrophy. From a clinical perspective, therefore, dis- NEPHRONOPHTHISIS
tinguishing between a genetic disease of the renal tubules and a disease A large and growing number of genetically distinct but related set of
of the glomerulus may not be easy, particularly in the absence of a gross autosomal recessive disorders are referred to as nephronophthisis, or
phenotype such as large kidney cysts. nephronophthisis-related ciliopathies. These entities should not be
confused with the adult onset autosomal dominant MCKD discussed
■■AUTOSOMAL DOMINANT INTERSTITIAL KIDNEY above, despite the often confusing nomenclature seen in older medical
DISEASE (MEDULLARY CYSTIC KIDNEY DISEASE) literature. Each of the individual forms of nephronophthisis is quite
The medullary cystic kidney diseases (MCKD) are autosomal dominant rare, but together this category constitutes the most common inher-
disorders. The term autosomal dominant tubulointerstitial kidney ited childhood form of kidney failure requiring kidney replacement
disease (ADTKD) is replacing MCKD as the preferred designation. therapy.
Despite the old nosology, kidney cysts are not invariably present. Older Like ADPKD and ARPKD, the various genetically heterogeneous
literature often grouped MCKD together with the childhood-onset dis- entities that fall under the category of nephronophthisis (NPHP) are
orders known as the nephronophthises, but these are distinct clinical disorders of ciliary function. Mutations in >90 genes have been identi-
and genetic entities. fied that lead to NPHP under an autosomal recessive pattern of inher-
itance. Some of these gene defects cause limited kidney disease, while
ADTKD-MUC1 Patients with medullary cystic kidney disease type many cause ciliopathies characterized by multiple organ involvement.
I (MCKD I) have mutations in the mucin 1 gene MUC1. In contrast The various forms of NPHP share common features, including tub-
to MCKD II patients, individuals with MCKD I do not have elevated ulointerstitial fibrosis, corticomedullary cysts, and progressive CKD,

2156 leading to renal failure. Proteinuria is absent or mild, and the urine as are kidney stones in the general population. MSK patients also
sediment is not active. often exhibit reduced kidney concentrating ability and an increased
NPHP is often divided into infantile, juvenile, and adolescent forms. frequency of urinary tract infections.
The juvenile form is the most frequent, and usually caused by mutations
in the NPHP2 gene. The infantile form, usually caused by NPHP2 muta- CAKUT
tions, is associated with end-stage kidney failure in early childhood. The structural abnormalities known as CAKUT (Congenital Abnor-
Patients with the adolescent form of NPHP typically develop end–stage malities of the Kidney and Urinary Tract) are a group of etiologically
kidney failure in early adulthood. Hypertension, if present, tends to be and phenotypically heterogeneous disorders. Some form of CAKUT is
a late finding in the course of the NPHPs. The products of the NPHP estimated to occur in up to 1 in 500 live births. Specific abnormalities
genes are referred to as nephrocystins. NPHP1 through NPHP20 have classified as part of the CAKUT spectrum include kidney hypoplasia,
been reported; some are referred to by other names, as well. kidney agenesis, ureteropelvic junction obstruction, and vesicoureteral
NPHP can present as an isolated finding, or be part of several reflux.
multi-organ syndromes. Neurologic abnormalities are present in a CAKUT can be the cause of clinically significant problems in both
significant number of patients. Bone and liver abnormities are seen in adults and children. However, it is a major contributor to kidney failure
some NPHP patients. Senior-Loken syndrome is defined by the pres- in children, accounting for more than one-third of end-stage kidney
ence of NPHP with retinitis pigmentosa. Joubert syndrome is defined disease in this group.
by multiple neurologic findings, including hypoplasia of the cerebel- CAKUT is typically a sporadic finding, but can also cluster in fam-
lar vermis. Some forms of this genetically heterogeneous syndrome ilies. Familial forms can be observed as parts of multisystem develop-
include NPHP as a component. mental syndromes. A growing list of specific genes have been identified
The multisystem disease Bardet-Biedl syndrome (BBS) is defined which when mutated lead to syndromic forms of CAKUT. For example,
clinically by a spectrum of features, including truncal obesity, cognitive the branchio-oto-renal syndrome, characterized by developmental
impairment, retinal dystrophy, polydactyly, developmental urogenital abnormalities in the neck, ears, and kidney, can be caused by mutations
abnormalities, and kidney cysts. The kidney phenotype is NPHP-like, in the EYA1 and SIX1 genes. Mutations in the PAX2 transcription factor
PART 9
with small cysts deriving from the tubules, tubulointerstitial and often gene can cause the autosomal dominant renal coloboma syndrome,
secondary glomerular disease, and urine concentrating defects. There characterized by optic nerve malformations and hypoplastic kidneys.
are 19 BBS genes cloned. BBS follows autosomal recessive inheritance. Recent work has demonstrated that a non-trivial fraction of children
Like ADPKD, ARPKD, and NPHP, BBS is a disease of abnormal ciliary with CKD have an unsuspected genomic imbalance, often disrupting
function. genes known to relevant to CAKUT and kidney development. It is not
The multiple genes and gene products (nephrocystins) that are uncommon for such genetic lesions that affect both kidney and neuro-
responsible for NPHP are expressed in cilia, basal bodies, and the cen- cognitive function.
trosomes of kidney tubules cells. It has been hypothesized that all of In many instances, CAKUT is caused by environmental influences
the NPHP gene defects lead to a clinical phenotype by interfering with rather than genetic alterations. For example, renal tubular dysgenesis,
the regulation of PCP. defined by altered tubule development, can be caused by prenatal
There are no specific clinical tests that define nephronophthisis. exposure of angiotensin converting enzyme inhibitors or angiotensin
Genetic diagnosis is possible, cumbersome because of the large num- receptor blockers.
ber of genes that can be responsible, but increasingly feasible due to
new DNA sequencing technologies. There are no specific therapies MITOCHONDRIAL DISEASE
for NPHP. Rather, therapy is aimed at treating signs of these dis- Inherited disorders of the mitochondrial genome (discussed elsewhere
eases as well as those systemic abnormalities seen with all CKDs. in this text [see also Chap. 472]) commonly affect kidney function. Thir-
Chronic dialysis or kidney transplantation are eventually required for teen of the genes involved in encoding components of the mitochondrial
NPHP-affected individuals. respiratory chain are located on the mitochondrial genome that is inher-
ited maternally. The remainder of these components is encoded by the
KARYOMEGALIC TUBULOINTERSTITIAL nuclear genome. These defects of oxidative phosphorylation may affect
NEPHRITIS multiple organs and tissues.
Karyomegalic tubulointerstitial nephritis is an exceptionally rare form Neuromuscular disease is the best recognized part of this complex
of kidney disease with adult-onset progressive kidney failure. Kidney phenotype. Kidney disease is now recognized as a common compo-
biopsy shows chronic tubulointerstitial nephritis, as well as intersti- nent, as well. Tubulointerstitial disease may be seen on kidney biopsy,
tial fibrosis. This is a recessive disorder caused by inheritance of two and progression to kidney failure may occur. Glomerular involvement,
mutant copies of the FAN1 gene. FAN1 encodes a component of a DNA manifest as proteinuria and glomerulosclerosis, can also develop.
repair machinery complex. Individuals with two mutant FAN1 gene are Changes in proximal tubule activity are the most common renal phe-
genetically sensitized to the effect of DNA damage. Kidney histology notype. Patients may have several defects in proximal tubule transport,
shows karyomegaly in addition to the non-specific findings of intersti- including the Fanconi syndrome. Some patients may also have acido-
tial fibrosis and tubular atrophy. sis, hypophosphatemic rickets, hypercalciuria, glycosuria, and tubular
proteinuria. Decreased urine concentrating ability is common.
MEDULLARY SPONGE KIDNEY
Medullary sponge kidney (MSK) is often grouped together with inher- ■■GLOBAL CONSIDERATIONS
ited disorders of the kidney affecting tubule growth and development, The disorders discussed above are all seen worldwide. In
although it is usually a sporadic finding rather than an inherited addition, a previously unrecognized epidemic of kidney dis-
phenotype. MSK is caused by developmental malformation and cystic ease is leading to very high rates of kidney failure in and near
dilatation of the renal collecting ducts. The medullary cysts seen in this the western coast of Central America. This mesoamerican nephropathy
entity can be quite variable in size. is particularly common in Nicaragua and El Salvador. Mesoamerican
MSK is usually a benign entity. The diagnosis of MSK is often made nephropathy patients do not have significant proteinuria, suggesting
incidentally. In the past, the diagnosis of MSK was often made by intra- that this is a disease of the kidney tubules and interstitium. The cause
venous pyelography (IVP). CT urography, which has replaced IVPs for is unknown, but some have suggested that a combination of toxic envi-
much routine kidney imaging, is not as sensitive in detecting MSK. ronmental factors and heat stress underlie the development of this
MSK is associated with an increased frequency of calcium phosphate kidney disease, which has a striking male predominance. However, the
and calcium oxalate kidney stones. Altered flow characteristics in the fact that in many families, a large fraction of the men are affected with
kidney tubules may lead to the development of formation of a nidus kidney disease has suggested that a strong genetic component is
for stone formation. Kidney stones in this group are treated the same involved, as well.

■■FURTHER READING TABLE 310-1 Classification of the Causes of Tubulointerstitial 2157
Arts HH, Knoers NV: Current insights into renal ciliopathies: What Diseases of the Kidney
can genetics teach us? Pediatr Nephrol 28:863, 2013. Acute Tubulointerstitial Disorders
Bleyer AJ et al: Autosomal dominant tubulointerstitial kidney disease.
Acute Interstitial Nephritis
Adv Chronic Kidney Dis 24:86, 2017.
Therapeutic agents
Grantham JJ et al: Detected renal cysts are tips of the iceberg in adults
with ADPKD. Clin J Am Soc Nephrol 7:1087, 2012. • Antibiotics (β-lactams, sulfonamides, quinolones, vancomycin, erythromycin,
linezolid, minocycline, rifampin, ethambutol, acyclovir)
Henske EP: Tuberous sclerosis and the kidney: From mesenchyme to
epithelium, and beyond. Pediatr Nephrol 20:854, 2005. • Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors
LaRiviere WB et al: Novel therapeutic approaches to autosomal domi- • Diuretics (rarely thiazides, loop diuretics, triamterene)
nant polycystic kidney disease. Transl Res 165:488, 2015. • Anticonvulsants (phenytoin, valproate, carbamazepine, phenobarbital)
Ong AC, Harris PC: A polycystin-centric view of cyst formation and • Miscellaneous (proton pump inhibitors, H2 blockers, captopril, mesalazine,
disease: The polycystins revisited. Kidney Int 88:699, 2015. indinavir, allopurinol, lenalidomide)
Porath B et al: Mutations in GANAB, encoding the glucosidase Infection
IIalpha subunit, cause autosomal-dominant polycystic kidney and • Bacteria (Streptococcus, Staphylococcus, Legionella, Salmonella, Brucella,
liver disease. Am J Hum Genet 98:1193, 2016. Yersinia, Corynebacterium diphtheriae)
Reddy BV, Chapman AB: The spectrum of autosomal dominant poly- • Viruses (EBV, CMV, hantavirus, polyomavirus, HIV)
cystic kidney disease in children and adolescents. Pediatr Nephrol • Miscellaneous (Leptospira, Rickettsia, Mycoplasma, Histoplasma)
32:31, 2017. Autoimmune
Vivante A, Hildebrandt F: Exploring the genetic basis of early-onset • Tubulointerstitial nephritis with uveitis (TINU)
chronic kidney disease. Nat Rev Nephrol 12:133, 2016. • Sjögren’s syndrome
Zhou J: Polycystins and primary cilia, primers for cell cycle progres- • Systemic lupus erythematosus
CHAPTER 310 Tubulointerstitial Diseases of the Kidney

sion. Ann Rev Physiol 71:83, 2009. • Granulomatous interstitial nephritis
• IgG4-related systemic disease
• Idiopathic autoimmune interstitial nephritis
Acute obstructive disorders
• Light chain cast nephropathy (“myeloma kidney”)
• Acute phosphate nephropathy
310 ofTubulointerstitial
• Acute urate nephropathy
Diseases Chronic Tubulointerstitial Disorders
the Kidney • Vesicoureteral reflux/reflux nephropathy
• Sickle cell disease
Laurence H. Beck, Jr., David J. Salant • Chronic exposure to toxins or therapeutic agents
• Analgesics, especially those containing phenacetin
• Lithium
Inflammation or fibrosis of the renal interstitium and atrophy of the • Heavy metals (lead, cadmium)
tubular compartment are common consequences of diseases that target • Aristolochic acid (Chinese herbal and Balkan endemic nephropathies)
the glomeruli or vasculature. Distinct from these secondary phenom- • Calcineurin inhibitors (cyclosporine, tacrolimus)
ena, however, are a group of disorders that primarily affect the tubules Metabolic Disturbances
and interstitium, with relative sparing of the glomeruli and renal ves- • Hypercalcemia and/or nephrocalcinosis
sels. Such disorders are conveniently divided into acute and chronic • Hyperuricemia
tubulointerstitial nephritis (TIN) (Table 310-1).
• Prolonged hypokalemia
Acute TIN most often presents with acute renal failure (Chap. 304).
• Hyperoxaluria
The acute nature of this group of disorders may be caused by aggres-
sive inflammatory infiltrates that lead to tissue edema, tubular cell • Cystinosis (see Chap. 309)
injury, and compromised tubular flow, or by frank obstruction of the Cystic and Hereditary Disorders (see Chap. 309)
tubules with casts, cellular debris, or crystals. There is sometimes flank • Polycystic kidney disease
pain due to distention of the renal capsule. Urinary sediment is often • Nephronophthisis
active with leukocytes and cellular casts, but depends on the exact • Adult medullary cystic disease
nature of the disorder in question. • Medullary sponge kidney
The clinical features of chronic TIN are more indolent and may
Miscellaneous
manifest with disorders of tubular function, including polyuria from
impaired concentrating ability (nephrogenic diabetes insipidus), defec- • Aging
tive proximal tubular reabsorption leading to features of Fanconi’s • Chronic glomerulonephritis
syndrome (glycosuria, phosphaturia, aminoaciduria, hypokalemia, • Chronic urinary tract obstruction
and type II renal tubular acidosis [RTA] from bicarbonaturia), or non- • Ischemia and vascular disease
anion-gap metabolic acidosis and hyperkalemia (type IV RTA) due • Radiation nephritis (rare)
to impaired ammoniagenesis, as well as progressive azotemia (rising Abbreviations: CMV, cytomegalovirus; COX, cyclooxygenase; EBV, Epstein-Barr virus.
creatinine and blood urea nitrogen [BUN]). There is often modest pro-
teinuria (rarely >2 g/d) attributable to decreased tubular reabsorption
of filtered proteins; however, nephrotic-range albuminuria may occur
in some conditions due to the development of secondary focal seg- fibrosis with patchy mononuclear cell infiltration and widespread
mental glomerulosclerosis (FSGS). Renal ultrasonography may reveal tubular atrophy, luminal dilation, and thickening of tubular basement
changes of “medical renal disease,” such as increased echogenicity of membranes. Because of the nonspecific nature of the histopathology,
the renal parenchyma with loss of corticomedullary differentiation, biopsy specimens rarely provide a specific diagnosis. Thus, diagnosis
prominence of the renal pyramids, and cortical scarring in some relies on careful analysis of history, drug or toxin exposure, associated
conditions. The predominant pathology in chronic TIN is interstitial symptoms, and imaging studies.

2158 ACUTE INTERSTITIAL NEPHRITIS Diagnosis Finding otherwise unexplained renal failure with or
In 1897, Councilman reported on eight cases of acute interstitial nephri- without oliguria and exposure to a potentially offending agent usually
tis (AIN) in the Medical and Surgical Reports of the Boston City Hospi- points to the diagnosis. Peripheral blood eosinophilia adds supporting
tal; three as a postinfectious complication of scarlet fever and two from evidence but is present in only a minority of patients. Urinalysis reveals
diphtheria. Later, he described the lesion as “an acute inflammation of pyuria with white blood cell casts and hematuria. Urinary eosinophils
the kidney characterized by cellular and fluid exudation in the intersti- are neither sensitive nor specific for AIN; therefore, testing is not
tial tissue, accompanied by, but not dependant on, degeneration of the recommended. Renal biopsy is generally not required for diagnosis
epithelium; the exudation is not purulent in character, and the lesions but reveals extensive interstitial and tubular infiltration of leukocytes,
may be both diffuse and focal.” Today AIN is far more often encoun- including eosinophils.
tered as an allergic reaction to a drug (Table 310-1). Immune-mediated
AIN may also occur as part of a known autoimmune syndrome, but in TREATMENT
some cases there is no identifiable cause despite features suggestive of
an immunologic etiology (Table 310-1). Allergic Interstitial Nephritis
■■ALLERGIC INTERSTITIAL NEPHRITIS Discontinuation of the offending agent often leads to reversal of the
Although biopsy-proven AIN accounts for no more than ~15% of cases renal injury. However, depending on the duration of exposure and
of unexplained acute renal failure, this is likely a substantial under- degree of tubular atrophy and interstitial fibrosis that has occurred,
estimate of the true incidence. This is because potentially offending the renal damage may not be completely reversible. Glucocorticoid
medications are more often identified and empirically discontinued in therapy may accelerate renal recovery, but does not appear to impact
a patient noted to have a rising serum creatinine, without the benefit of long-term renal survival. It is best reserved for those cases with
a renal biopsy to establish the diagnosis of AIN. severe renal failure in which dialysis is imminent or if renal func-
tion continues to deteriorate despite stopping the offending drug
Clinical Features The classic presentation of AIN, namely, fever, (Fig. 310-1 and Table 310-2).
rash, peripheral eosinophilia, and oliguric renal failure occurring after
PART 9
7–10 days of treatment with methicillin or another β-lactam antibiotic,

is the exception rather than the rule. More often, patients are found
■■SJÖGREN’S SYNDROME
Sjögren’s syndrome is a systemic autoimmune disorder that primarily
incidentally to have a rising serum creatinine or present with symp-
targets the exocrine glands, especially the lacrimal and salivary glands,
toms attributable to acute renal failure (Chap. 304). Atypical reactions
and thus results in symptoms, such as dry eyes and mouth, that consti-
can occur, most notably nonsteroidal anti-inflammatory drug (NSAID)-
tute the “sicca syndrome” (Chap. 354). TIN with a predominant lym-
induced AIN, in which fever, rash, and eosinophilia are rare, but acute
phocytic infiltrate is the most common renal manifestation of Sjögren’s
renal failure with heavy proteinuria is common. A particularly severe
syndrome and can be associated with distal RTA, nephrogenic diabetes
and rapid-onset AIN may occur upon reintroduction of rifampin after
insipidus, and moderate renal failure. Diagnosis is strongly supported
a drug-free period. More insidious reactions to the agents listed in
by positive serologic testing for anti-Ro (SS-A) and anti-La (SS-B)
Table 310-1 may lead to progressive tubulointerstitial damage. Exam-
antibodies. A large proportion of patients with Sjögren’s syndrome
ples include proton pump inhibitors and, rarely, sulfonamide and
also have polyclonal hypergammaglobulinemia. Treatment is initially
5-aminosalicylate (mesalazine and sulfasalazine) derivatives and
with glucocorticoids, although patients may require maintenance ther-
antiretrovirals. It is not clear if the recent association of proton pump
apy with azathioprine or mycophenolate mofetil to prevent relapse
inhibitors with incident chronic kidney disease involves an intermedi-
(Fig. 310-1 and Table 310-2).
ate step of prolonged, subclinical interstitial nephritis.
■■TUBULOINTERSTITIAL
NEPHRITIS WITH UVEITIS (TINU)
ARF with features of AIN TINU is a systemic autoimmune dis-
ease of unknown etiology. It accounts for
fewer than 5% of all cases of AIN, affects
Withdraw offending agent females three times more often than
males, and has a median age of onset of
Supportive care and close 15 years. Its hallmark feature, in addition to a
observation lymphocyte-predominant interstitial nephritis
(Fig. 310-2), is a painful anterior uveitis, often
bilateral and accompanied by blurred vision
and photophobia. Diagnosis is often con-
No improvement in 1 week founded by the fact that the ocular symptoms
Improvement
OR rapid progression precede or accompany the renal disease in
only one-third of cases. Additional extrarenal
features include fever, anorexia, weight loss,
abdominal pain, and arthralgia. The presence
Continue observation Classic allergic AIN Atypical features of such symptoms as well as elevated creatin-
ine, sterile pyuria, mild proteinuria, features
Corticosteroids Renal biopsy of Fanconi’s syndrome, and elevated erythro-
cyte sedimentation rate should raise suspicion
for this disorder. Serologies suggestive of the
more common autoimmune diseases are usu-
Classic AIN Granulomatous or other immune IN Fibrosis ally negative, and TINU is often a diagnosis
of exclusion after other causes of uveitis and
Corticosteroids Immunosuppressive drugs Conservative renal disease, such as Sjögren’s syndrome,
Behçet’s disease, sarcoidosis, and systemic
FIGURE 310-1 Algorithm for the treatment of allergic and other immune-mediated acute interstitial lupus erythematosus, have been considered.
nephritis (AIN). ARF, acute renal failure; IN, interstitial nephritis. See text for immunosuppressive drugs used Clinical symptoms are typically self-limited
for refractory or relapsing AIN. (Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998.) in children, but are more apt to follow a

TABLE 310-2 Indications for Corticosteroids and pulmonary, cutaneous, or other systemic manifestations of sarcoidosis 2159
Immunosuppressives in Interstitial Nephritis such as hypercalcemia. Most patients experience some improvement
Absolute Indications in renal function if treated early with glucocorticoids before the
development of significant interstitial fibrosis and tubular atrophy
• Sjögren’s syndrome
(Table 310-2). Other immunosuppressive agents may be required for
• Sarcoidosis
those who relapse frequently upon steroid withdrawal. Other immu-
• SLE interstitial nephritis nosuppressive agents may be required for those who relapse frequently
• Adults with TINU upon steroid withdrawal (Fig. 310-1). Tuberculosis should be ruled out
• Idiopathic and other granulomatous interstitial nephritis before starting treatment because this too is a rare cause of granuloma-
Relative Indications tous interstitial nephritis.
• Drug-induced or idiopathic AIN with:
■■IgG4-RELATED SYSTEMIC DISEASE
Rapid progression of renal failure A form of AIN characterized by a dense inflammatory infiltrate con-
Diffuse infiltrates on biopsy taining IgG4-expressing plasma cells can occur as a part of a syndrome
Impending need for dialysis known as IgG4-related systemic disease. Autoimmune pancreatitis,
Delayed recovery sclerosing cholangitis, retroperitoneal fibrosis, and a chronic sclerosing
• Children with TINU sialadenitis (mimicking Sjögren’s syndrome) may variably be present
• Postinfectious AIN with delayed recovery (?) as well. Fibrotic lesions that form pseudotumors in the affected organs
Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus;
soon replace the initial inflammatory infiltrates and often lead to
TINU, tubulointerstitial nephritis with uveitis. biopsy or excision for fear of true malignancy. Although the involve-
Source: Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998. ment of IgG4 in the pathogenesis is not understood, glucocorticoids
have been successfully used as first-line treatment in this group of
disorders, once they are correctly diagnosed.

relapsing course in adults. The renal and ocular manifestations gener-
ally respond well to oral glucocorticoids, although maintenance ther- ■■IDIOPATHIC AIN
apy with agents such as methotrexate, azathioprine, or mycophenolate Some patients present with typical clinical and histologic features of
may be necessary to prevent relapses (Fig. 310-1 and Table 310-2). AIN but have no evidence of drug exposure or clinical or serologic
■■SYSTEMIC LUPUS ERYTHEMATOSUS features of an autoimmune disease. The presence in some cases of auto-
An interstitial mononuclear cell inflammatory reaction often accom- antibodies to a tubular antigen, similar to that identified in rats with
panies the glomerular lesion in most cases of class III or IV lupus an induced form of interstitial nephritis, suggests that an autoimmune
nephritis (Chap. 308), and deposits of immune complexes can be response may be involved. Like TINU and granulomatous intersti-
identified in tubule basement membranes in ~50% of cases. Occasion- tial nephritis, idiopathic AIN is responsive to glucocorticoid therapy
ally, however, the tubulointerstitial inflammation predominates and but may follow a relapsing course requiring maintenance treatment
may manifest with azotemia and type IV RTA rather than features of with another immunosuppressive agent (Fig. 310-1 and Table 310-2).
glomerulonephritis. Recently, cases have been identified in which autoantibodies that may
be important in disease pathogenesis were seen to target antigens
■■GRANULOMATOUS INTERSTITIAL NEPHRITIS expressed by collecting duct or proximal tubular brush border.
Some patients may present with features of AIN but follow a pro-
tracted and relapsing course. Renal biopsy in such patients reveals a ■■INFECTION-ASSOCIATED AIN
more chronic inflammatory infiltrate with granulomas and multinu- AIN may also occur as a local inflammatory reaction to microbial
cleated giant cells. Most often, no associated disease or cause is found; infection (Table 310-1) and should be distinguished from acute bac-
however, some of these cases may have or subsequently develop the terial pyelonephritis (Chap. 130). Acute bacterial pyelonephritis does
not generally cause acute renal failure unless it affects both kidneys or
causes septic shock. Presently, infection-associated AIN is most often
seen in immunocompromised patients, particularly renal transplant
recipients with reactivation of polyomavirus BK (Chaps. 138 and 307).
* ■■CRYSTAL DEPOSITION DISORDERS AND

OBSTRUCTIVE TUBULOPATHIES
Acute renal failure may occur when crystals of various types are depos-
ited in tubular cells and interstitium or when they obstruct tubules.
* Oliguric acute renal failure, often accompanied by flank pain from
T tubular obstruction, may occur in patients treated with sulfadiazine
for toxoplasmosis, indinavir and atazanavir for HIV, and intravenous
acyclovir for severe herpesvirus infections. Urinalysis reveals “sheaf of
G * wheat” sulfonamide crystals, individual or parallel clusters of needle-
shaped indinavir crystals, or red-green birefringement needle-shaped
crystals of acyclovir. This adverse effect is generally precipitated by
hypovolemia and is reversible with saline volume repletion and drug
withdrawal. Distinct from the obstructive disease, a frank AIN from
indinavir crystal deposition has also been reported.
Acute tubular obstruction is also the cause of oliguric renal failure
FIGURE 310-2 Acute interstitial nephritis (AIN) in a patient who presented with in patients with acute urate nephropathy. It typically results from severe
acute iritis, low-grade fever, erythrocyte sedimentation rate of 103, pyuria and hyperuricemia from tumor lysis syndrome in patients with lympho- or
cellular casts on urinalysis, and a newly elevated serum creatinine of 2.4 mg/dL. myeloproliferative disorders treated with cytotoxic agents, but also may
Both the iritis and AIN improved after intravenous methylprednisolone. This PAS- occur spontaneously before the treatment has been initiated (Chap. 71).
stained renal biopsy shows a mononuclear cell interstitial infiltrate (asterisks) Uric acid crystallization in the tubules and collecting system leads to
and edema separating the tubules (T) and a normal glomerulus (G). Some of the
tubules contain cellular debris and infiltrating inflammatory cells. The findings in partial or complete obstruction of the collecting ducts, renal pelvis, or
this biopsy are indistinguishable from those that would be seen in a case of drug- ureter. A dense precipitate of birefringent uric acid crystals is found in
induced AIN. PAS, Periodic acid–Schiff. the urine, usually in association with microscopic or gross hematuria.

2160 Prophylactic allopurinol reduces the risk of uric acid nephropathy but laboratory detection of increased amounts of protein in a spot urine
is of no benefit once tumor lysis has occurred. Once oliguria has devel- specimen and a negative dipstick result are highly suggestive that the
oped, attempts to increase tubular flow and solubility of uric acid with urine contains Bence-Jones protein. Serum and urine should both be
alkaline diuresis may be of some benefit; however, emergent treatment sent for protein electrophoresis and for immunofixation for the detec-
with hemodialysis or rasburicase, a recombinant urate oxidase, is usu- tion and identification of a potential monoclonal band. A sensitive
ally required to rapidly lower uric acid levels and restore renal function. method is available to detect urine and serum free light chains.
Calcium oxalate crystal deposition in tubular cells and interstitium
may lead to permanent renal dysfunction in patients who survive
ethylene glycol intoxication, in patients with enteric hyperoxaluria
TREATMENT
from ileal resection or small-bowel bypass surgery, and in patients Light Chain Cast Nephropathy
with hereditary hyperoxaluria (Chap. 312). Acute phosphate nephrop-
athy is an uncommon but serious complication of oral Phosphosoda The goals of treatment are to correct precipitating factors such as
used as a laxative or for bowel preparation for colonoscopy. It results hypovolemia and hypercalcemia, discontinue potential nephrotoxic
from calcium phosphate crystal deposition in tubules and interstitium agents, and treat the underlying plasma cell dyscrasia (Chap. 107);
and occurs especially in subjects with underlying renal impairment plasmapheresis to remove light chains is of questionable value for
and hypovolemia. Consequently, Phosphosoda should be avoided in LCCN.
patients with chronic kidney disease.
■■LYMPHOMATOUS INFILTRATION OF THE KIDNEY
■■LIGHT CHAIN CAST NEPHROPATHY Interstitial infiltration by malignant B lymphocytes is a common
Patients with multiple myeloma may develop acute renal failure
autopsy finding in patients dying of chronic lymphocytic leukemia
in the setting of hypovolemia, infection, or hypercalcemia or after
and non-Hodgkin’s lymphoma; however, this is usually an incidental
exposure to NSAIDs or radiographic contrast media. The diagnosis of
finding. Rarely, such infiltrates may cause massive enlargement of the
light chain cast nephropathy (LCCN)—commonly known as myeloma
kidneys and oliguric acute renal failure. Although high-dose glucocor-
kidney—should be considered in patients who fail to recover when the
PART 9
ticoids and subsequent chemotherapy often result in recovery of renal

precipitating factor is corrected or in any elderly patient with otherwise
function, the prognosis in such cases is generally poor.
unexplained acute renal failure.
In this disorder, filtered monoclonal immunoglobulin light chains CHRONIC TUBULOINTERSTITIAL DISEASES
(Bence-Jones proteins) form intratubular aggregates with secreted Improved occupational and public health measures, together with the
Tamm-Horsfall protein in the distal tubule. Casts, in addition to banning of over-the-counter phenacetin-containing analgesics, has led
obstructing the tubular flow in affected nephrons, incite a giant cell to a dramatic decline in the incidence of chronic interstitial nephritis
or foreign body reaction and can lead to tubular rupture, resulting (CIN) from heavy metal—particularly lead and cadmium—exposure
in interstitial fibrosis (Fig. 310-3). Although LCCN generally occurs and analgesic nephropathy in North America. Today, CIN is most often
in patients with known multiple myeloma and a large plasma cell the result of renal ischemia or secondary to a primary glomerular dis-
burden, the disorder should also be considered as a possible diagnosis ease (Chap. 308). Other important forms of CIN are the result of devel-
in patients who have known monoclonal gammopathy even in the opmental anomalies or inherited diseases such as reflux nephropathy or
absence of frank myeloma. Filtered monoclonal light chains may also sickle cell nephropathy and may not be recognized until adolescence or
cause less pronounced renal manifestations in the absence of obstruc- adulthood. Although it is impossible to reverse damage that has already
tion, due to direct toxicity to proximal tubular cells and intracellular occurred, further deterioration may be prevented or at least slowed in
crystal formation. This may result in isolated tubular disorders such as such cases by treating glomerular hypertension, a common denominator
RTA or full Fanconi’s syndrome. in the development of secondary FSGS and progressive loss of function-
Diagnosis Clinical clues to the diagnosis include anemia, bone ing nephrons. Therefore, awareness and early detection of patients at
pain, hypercalcemia, and an abnormally narrow anion gap due risk may prevent them from developing end-stage renal disease (ESRD).
to hypoalbuminemia and hypergammaglobulinemia. Urinary dip-
sticks detect albumin but not immunoglobulin light chains; however,
■■VESICOURETERAL REFLUX AND REFLUX
NEPHROPATHY
Reflux nephropathy is the consequence of vesicoureteral reflux (VUR)
or other urologic anomalies in early childhood. It was previously called
chronic pyelonephritis because it was believed to result from recurrent
urinary tract infections (UTIs) in childhood. VUR stems from abnor-
mal retrograde urine flow from the bladder into one or both ureters
and kidneys because of mislocated and incompetent ureterovesical
valves (Fig. 310-4). Although high-pressure sterile reflux may impair
normal growth of the kidneys, when coupled with recurrent UTIs in
early childhood, the result is patchy interstitial scarring and tubular
atrophy. Loss of functioning nephrons leads to hypertrophy of the
remnant glomeruli and eventual secondary FSGS. Reflux nephropa-
thy often goes unnoticed until early adulthood when chronic kidney
disease is detected during routine evaluation or during pregnancy.
Affected adults are frequently asymptomatic, but may give a history
of prolonged bed-wetting or recurrent UTIs during childhood, and
exhibit variable renal insufficiency, hypertension, mild to moderate
proteinuria, and unremarkable urine sediment. When both kidneys
are affected, the disease often progresses inexorably over several years
to ESRD, despite the absence of ongoing urinary infections or reflux.
FIGURE 310-3 Histologic appearance of myeloma cast nephropathy. A A single affected kidney may go undetected, except for the presence
hematoxylin-eosin–stained kidney biopsy shows many atrophic tubules filled with of hypertension. Renal ultrasound in adults characteristically shows
eosinophilic casts (consisting of Bence-Jones protein), which are surrounded
by giant cell reactions. (Courtesy of Dr. Michael N. Koss, University of Southern asymmetric small kidneys with irregular outlines, thinned cortices, and
California Keck School of Medicine; with permission.) regions of compensatory hypertrophy (Fig. 310-4).

2161

A B
C
FIGURE 310-4 Radiographs of vesicoureteral reflux (VUR) and reflux nephropathy. A. Voiding cystourethrogram in a 7-month-old baby with bilateral high-grade
VUR evidenced by clubbed calyces (arrows) and dilated tortuous ureters (U) entering the bladder (B). B. Abdominal computed tomography scan (coronal plane
reconstruction) in a child showing severe scarring of the lower portion of the right kidney (arrow). C. Sonogram of the right kidney showing loss of parenchyma at the
lower pole due to scarring (arrow) and hypertrophy of the mid-region (arrowhead). (Courtesy of Dr. George Gross, University of Maryland Medical Center; with permission.)
TREATMENT ■■SICKLE CELL NEPHROPATHY

The pathogenesis and clinical manifestations of sickle cell nephrop-
Vesicoureteral Reflux and Reflux Nephropathy athy are described in Chap. 311. Evidence of tubular injury may be
evident in childhood and early adolescence in the form of polyuria
Maintenance of sterile urine in childhood has been shown to limit due to decreased concentrating ability or type IV RTA years before
scarring of the kidneys. Surgical reimplantation of the ureters into there is significant nephron loss and proteinuria from secondary FSGS.
the bladder to restore competency is indicated in young children Early recognition of these subtle renal abnormalities or development
with persistent high-grade reflux, but is ineffective and is not indi- of microalbuminuria in a child with sickle cell disease may warrant
cated in adolescents or adults after scarring has occurred. Aggressive consultation with a nephrologist and/or therapy with low-dose ACEIs.
control of blood pressure with an angiotensin-converting enzyme Papillary necrosis may result from ischemia due to sickling of red cells
inhibitor (ACEI) or angiotensin receptor blocker (ARB) and other in the relatively hypoxemic and hypertonic medullary vasculature and
agents is effective in reducing proteinuria and may significantly present with gross hematuria and ureteric obstruction by sloughed
forestall further deterioration of renal function. ischemic papillae (Table 310-3).

2162 TABLE 310-3 Major Causes of Papilary Necrosis ■■ARISTOLOCHIC ACID NEPHROPATHY
Analgesic nephropathy Two seemingly unrelated forms of CIN, Chinese herbal nephropathy
Sickle cell nephropathy
and Balkan endemic nephropathy, have recently been linked by the
underlying etiologic agent aristolochic acid and are now collectively
Diabetes with urinary tract infection
termed aristolochic acid nephropathy (AAN). In Chinese herbal
Prolonged NSAID use (rare)
nephropathy, first described in the early 1990s in young women tak-
Abbreviation: NSAID, nonsteroidal anti-inflammatory drug. ing traditional Chinese herbal preparations as part of a weight-loss
regimen, one of the offending agents has been identified as aristolo-
■■TUBULOINTERSTITIAL ABNORMALITIES chic acid, a known carcinogen from the plant Aristolochia. Multiple
ASSOCIATED WITH GLOMERULONEPHRITIS Aristolochia species have been used in traditional herbal remedies for
Primary glomerulopathies are often associated with damage to tubules centuries and continue to be available despite official bans on their use
and interstitium. This may occasionally be due to the same pathologic in many countries. Molecular evidence has also implicated aristolochic
process affecting the glomerulus and tubulointerstitium, as is the case acid in Balkan endemic nephropathy, a chronic TIN found primarily
with immune-complex deposition in lupus nephritis. More often, in towns along the tributaries of the Danube River and first described
however, chronic tubulointerstitial changes occur as a secondary conse- in the 1950s. Although the exact route of exposure is not known with
quence of prolonged glomerular dysfunction. Potential mechanisms by certainty, contamination of local grain preparations with the seeds of
which glomerular disease might cause tubulointerstitial injury include Aristolochia species seems most likely. Aristolochic acid, after prolonged
proteinuria-mediated damage to the epithelial cells, activation of tubu- exposure, produces renal interstitial fibrosis with a relative paucity of
lar cells by cytokines and complement, or reduced peritubular blood cellular infiltrates. The urine sediment is bland, with rare leukocytes
flow leading to downstream tubulointerstitial ischemia, especially in and only mild proteinuria. Anemia may be disproportionately severe
the case of glomeruli that are globally obsolescent due to severe glom- relative to the level of renal dysfunction. Definitive diagnosis of AAN
erulonephritis. It is often difficult to discern the initial cause of injury requires two of the following three features: characteristic histology
by renal biopsy in a patient who presents with advanced renal disease on kidney biopsy; confirmation of aristolochic acid ingestion; and
PART 9
in this setting. detection of aristolactam-DNA adducts in kidney or urinary tract tis-

sue. These latter lesions represent a molecular signature of aristolochic
■■ANALGESIC NEPHROPATHY acid–derived DNA damage and often consist of characteristic A:T-to-
Analgesic nephropathy results from the long-term use of com- T:A transversions. Due to this mutagenic activity, AAN is associated
pound analgesic preparations containing phenacetin (banned in the with a very high incidence of upper urinary tract urothelial cancers,
United States since 1983), aspirin, and caffeine. In its classic form, with risk related to cumulative dose. Surveillance with computed
analgesic nephropathy is characterized by renal insufficiency, papillary tomography, ureteroscopy, and urine cytology is warranted, and
necrosis (Table 310-3) attributable to the presumed concentration of consideration should be given to bilateral nephroureterectomy once a
the drug to toxic levels in the inner medulla, and a radiographic con- patient has reached ESRD.
stellation of small, scarred kidneys with papillary calcifications best
appreciated by computed tomography (Fig. 310-5). Patients may also ■■KARYOMEGALIC INTERSTITIAL NEPHRITIS
have polyuria due to impaired concentrating ability and non-anion-gap Karyomegalic interstitial nephritis is an unusual form of slowly pro-
metabolic acidosis from tubular damage. Shedding of a sloughed gressive chronic kidney disease with mild proteinuria, interstitial
necrotic papilla can cause gross hematuria and ureteric colic due to fibrosis, tubular atrophy, and oddly enlarged nuclei of proximal tubu-
ureteral obstruction. Individuals with ESRD as a result of analgesic lar epithelial cells. It has been linked to mutations in FAN1, a nuclease
nephropathy are at increased risk of a urothelial malignancy compared involved in DNA repair, which may render carriers of the mutation
to patients with other causes of renal failure. Recent cohort studies susceptible to environmental DNA-damaging agents.
in individuals with normal baseline renal function suggest that the
moderate chronic use of current analgesic preparations available in the ■■LITHIUM-ASSOCIATED NEPHROPATHY
United States, including acetaminophen and NSAIDs, does not seem The use of lithium salts for the treatment of manic-depressive illness
to cause the constellation of findings known as analgesic nephropathy, may have several renal sequelae, the most common of which is neph-
although volume-depleted individuals and those with chronic kidney rogenic diabetes insipidus manifesting as polyuria and polydipsia.
disease are at higher risk of NSAID-related renal toxicity. Nonetheless, Lithium accumulates in principal cells of the collecting duct by enter-
it is recommended that heavy users of acetaminophen and NSAIDs be ing through the epithelial sodium channel (ENaC), where it inhibits
screened for evidence of renal disease. glycogen synthase kinase 3β and downregulates vasopressin-regulated
aquaporin water channels. Less frequently, chronic TIN develops after
prolonged (>10–20 years) lithium use and is most likely to occur in
patients who have experienced repeated episodes of toxic lithium
levels. Findings on renal biopsy include interstitial fibrosis and tubular
atrophy that are out of proportion to the degree of glomerulosclerosis
or vascular disease, a sparse lymphocytic infiltrate, and small cysts or
dilation of the distal tubule and collecting duct that are highly char-
acteristic of this disorder. The degree of interstitial fibrosis correlates
with both duration and cumulative dose of lithium. Individuals with
lithium-associated nephropathy are typically asymptomatic, with min-
imal proteinuria, few urinary leukocytes, and normal blood pressure.
Some patients develop more severe proteinuria due to secondary FSGS,
which may contribute to further loss of renal function.
TREATMENT
Lithium-Associated Nephropathy
FIGURE 310-5 Radiologic appearance of analgesic nephropathy. A noncontrast
computed tomography scan shows an atrophic left kidney with papillary
Renal function should be followed regularly in patients taking lith-
calcifications in a garland pattern. (Reprinted by permission from Macmillan ium, and caution should be exercised in patients with underlying
Publishers, Ltd., MM Elseviers et al: Kidney International 48:1316, 1995.) renal disease. The use of amiloride to inhibit lithium entry via ENaC

has been effective to prevent and treat lithium-induced nephrogenic allopurinol and other agents. However, there is emerging evidence 2163
diabetes insipidus, but it is not clear if it will prevent lithium- that hyperuricemia is an independent risk factor for the development
induced CIN. Once lithium-associated nephropathy is detected, the of chronic kidney disease, perhaps through endothelial damage. The
discontinuation of lithium in attempt to forestall further renal deteri- complex interactions of hyperuricemia, hypertension, and renal failure
oration can be problematic, as lithium is an effective mood stabilizer are still incompletely understood.
that is often incompletely substituted by other agents. Furthermore, Presently, gouty nephropathy is most likely to be encountered in
despite discontinuation of lithium, chronic renal disease in such patients with severe tophaceous gout and prolonged hyperuricemia
patients is often irreversible and can slowly progress to ESRD. The from a hereditary disorder of purine metabolism (Chap. 410). This
most prudent approach is to monitor lithium levels frequently and should be distinguished from juvenile hyperuricemic nephropathy,
adjust dosing to avoid toxic levels (preferably <1 meq/L). This a form of medullary cystic kidney disease caused by mutations in
is especially important because lithium is cleared less effectively uromodulin (UMOD) (Chap. 309) and now grouped into the larger
as renal function declines. In patients who develop significant category of autosomal dominant tubulointerstitial kidney disease. His-
proteinuria, ACEI or ARB treatment should be initiated. tologically, the distinctive feature of gouty nephropathy is the presence
of crystalline deposits of uric acid and monosodium urate salts in the
■■CALCINEURIN-INHIBITOR NEPHROTOXICITY kidney parenchyma. These deposits not only cause intrarenal obstruc-
The calcineurin inhibitor (CNI) immunosuppressive agents cyclospo- tion but also incite an inflammatory response, leading to lymphocytic
rine and tacrolimus can cause both acute and chronic renal injury. infiltration, foreign-body giant cell reaction, and eventual fibrosis,
Acute forms can result from vascular causes such as vasoconstriction especially in the medullary and papillary regions of the kidney. Since
or the development of thrombotic microangiopathy, or can be due to a patients with gout frequently suffer from hypertension and hyperlip-
toxic tubulopathy. Chronic CNI-induced renal injury is typically seen idemia, degenerative changes of the renal arterioles may constitute a
in solid organ (including heart-lung and liver) transplant recipients striking feature of the histologic abnormality, out of proportion to the
and manifests with a slow but irreversible reduction of glomerular other morphologic defects. Clinically, gouty nephropathy is an insid-

filtration rate, with mild proteinuria and arterial hypertension. Hyper- ious cause of chronic kidney disease. Early in its course, glomerular
kalemia is a relatively common complication and is caused, in part, filtration rate may be near normal, often despite morphologic changes
by tubular resistance to aldosterone. The histologic changes in renal in medullary and cortical interstitium, proteinuria, and diminished
tissue include patchy interstitial fibrosis and tubular atrophy, often in a urinary concentrating ability. Treatment with allopurinol and urine
“striped” pattern. In addition, the intrarenal vasculature often demon- alkalinization is generally effective in preventing uric acid nephrolith-
strates hyalinosis, and focal glomerulosclerosis can be present as well. iasis and the consequences of recurrent kidney stones; however, gouty
Similar changes may occur in patients receiving CNIs for autoimmune nephropathy may be intractable to such measures. Furthermore, the use
diseases, although the doses are generally lower than those used for of allopurinol in asymptomatic hyperuricemia has not been consistently
organ transplantation. Dose reduction or CNI avoidance appears to shown to improve renal function.
mitigate the chronic tubulointerstitial changes, but may increase the
■■HYPERCALCEMIC NEPHROPATHY
risk of rejection and graft loss.
(See also Chap. 403) Chronic hypercalcemia, as occurs in primary
■■HEAVY METAL (LEAD) NEPHROPATHY hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intox-
Heavy metals, such as lead or cadmium, can lead to a chronic tubu- ication, or metastatic bone disease, can cause tubulointerstitial disease
lointerstitial process after prolonged exposure. The disease entity is no and progressive renal failure. The earliest lesion is a focal degenerative
longer commonly diagnosed, because such heavy metal exposure has change in renal epithelia, primarily in collecting ducts, distal tubules,
been greatly reduced due to the known health risks from lead and the and loops of Henle. Tubular cell necrosis leads to nephron obstruction
consequent removal of lead from most commercial products and fuels. and stasis of intrarenal urine, favoring local precipitation of calcium
Nonetheless, occupational exposure is possible in workers involved in salts and infection. Dilation and atrophy of tubules eventually occur,
the manufacture or destruction of batteries, removal of lead paint, or as do interstitial fibrosis, mononuclear leukocyte infiltration, and inter-
manufacture of alloys and electrical equipment (cadmium) in countries stitial calcium deposition (nephrocalcinosis). Calcium deposition may
where industrial regulation is less stringent. In addition, ingestion of also occur in glomeruli and the walls of renal arterioles.
moonshine whiskey distilled in lead-tainted containers has been one of Clinically, the most striking defect is an inability to maximally con-
the more frequent sources of lead exposure. centrate the urine, due to reduced collecting duct responsiveness to
Early signs of chronic lead intoxication are attributable to proximal arginine vasopressin and defective transport of sodium and chloride
tubule dysfunction, particularly hyperuricemia as a result of dimin- in the loop of Henle. Reductions in both glomerular filtration rate and
ished urate secretion. The triad of “saturnine gout,” hypertension, and renal blood flow can occur, both in acute and in prolonged hypercal-
renal insufficiency should prompt a practitioner to ask specifically cemia. Eventually, uncontrolled hypercalcemia leads to severe tubu-
about lead exposure. Unfortunately, evaluating lead burden is not lointerstitial damage and overt renal failure. Abdominal x-rays may
as straightforward as ordering a blood test; the preferred methods demonstrate nephrocalcinosis as well as nephrolithiasis, the latter due
involve measuring urinary lead after infusion of a chelating agent or by to the hypercalciuria that often accompanies hypercalcemia.
radiographic fluoroscopy of bone. Several recent studies have shown Treatment consists of reducing the serum calcium concentration
an association between chronic low-level lead exposure and decreased toward normal and correcting the primary abnormality of calcium
renal function, although either of these two factors may have been the metabolism (Chap. 403). Renal dysfunction of acute hypercalcemia
primary event. In those patients who have CIN of unclear origin and an may be completely reversible. Gradual progressive renal insufficiency
elevated total body lead burden, repeated treatments of lead chelation related to chronic hypercalcemia, however, may not improve even with
therapy have been shown to slow the decline in renal function. correction of the calcium disorder.
METABOLIC DISORDERS ■■HYPOKALEMIC NEPHROPATHY

Disorders leading to excessively high or low levels of certain elec- Patients with prolonged and severe hypokalemia from chronic laxative
trolytes and products of metabolism can also lead to chronic kidney or diuretic abuse, surreptitious vomiting, or primary aldosteronism
disease if untreated. may develop a reversible tubular lesion characterized by vacuolar
degeneration of proximal and distal tubular cells. Eventually, tubular
■■CHRONIC URIC ACID NEPHROPATHY atrophy and cystic dilation accompanied by interstitial fibrosis may
The constellation of pathologic findings that represent gouty nephrop- ensue, leading to irreversible chronic kidney disease. Timely correction
athy are very uncommon nowadays and are more of historical inter- of the hypokalemia will prevent further progression, but persistent
est than clinical importance, as gout is typically well managed with hypokalemia can cause ESRD.

2164 GLOBAL PERSPECTIVE accompanied by microangiopathic hemolytic anemia (MAHA) with its
The causes of acute and CIN vary widely across the globe. typical features of thrombocytopenia and schistocytes, but not always.
Analgesic nephropathy continues to be seen in countries In the kidney, TMA is characterized by swollen endocapillary cells
where phenacetin-containing compound analgesic prepara- (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis,
tions are readily available. Adulterants in unregulated herbal and tra- and a membranoproliferative pattern in the glomerulus. Fibrin thrombi
ditional medicaments pose a threat of toxic interstitial nephritis, as may extend into the arteriolar vascular pole, producing glomerular col-
exemplified by aristolochic acid contamination of herbal slimming lapse and at times cortical necrosis. In kidneys that recover from acute
preparations. Contamination of food sources with toxins, such as the TMA, secondary focal segmental glomerulosclerosis may develop.
recent outbreak of nephrolithiasis and acute renal failure from mela- Diseases associated with this lesion include thrombotic thrombocy-
mine contamination of infant milk formula, poses a continuing risk. topenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant
Large-scale exposure to aristolochic acid remains prevalent in many hypertension, scleroderma renal crisis, antiphospholipid syndrome,
Asian countries where traditional herbal medicine use is common. preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet
Although industrial exposure to lead and cadmium has largely disap- count) syndrome, HIV infection, and radiation nephropathy. TMA can
peared as a cause of CIN in developed nations, it remains a risk for also be seen in myeloproliferative neoplasm (MPN)-related glomerul-
nephrotoxicity in countries where such exposure is less well controlled. opathy and POEMS (polyneuropathy, endocrinopathy, organomegaly,
New endemic forms of chronic kidney disease continue to be described. monoclonal gammopathy and skin changes) syndrome which are not
Most notable is the nephropathy found among Pacific coastal planta- associated with MAHA.
tion workers in Central America that is estimated to have claimed
20,000 lives thus far due to the development of end-stage kidney dis- ■■HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC
ease. This entity has been named Mesoamerican nephropathy, although THROMBOCYTOPENIC PURPURA
similar pathophysiologic mechanisms may also be at play in other HUS and TTP are the prototypes for MAHA. Historically, HUS and
regional forms of chronic kidney disease in Sri Lanka and southern TTP were distinguished mainly by their clinical and epidemiologic
India. Although a variety of etiologic factors have been proposed, the differences. TTP develops more commonly in adults and was thought
to have more neurologic complications while HUS occurs more fre-
PART 9
most likely cause appears to be related to repetitive episodes of heat

exposure, dehydration or volume depletion, and consequent metabolic quently in children, particularly when associated with hemorrhagic
changes leading to uricosuria and elevated levels of vasopressin. diarrhea. However, atypical HUS (aHUS) can have its first appearance
Global warming and regional temperature variability have been pro- in adulthood, and better testing has revealed that neurologic involve-
posed as contributors to these newly described forms of kidney ment is as common in HUS as in TTP. Currently, HUS and TTP can
disease. be differentiated etiologically and treated according to their specific

pathophysiologic features.
■■FURTHER READING Hemolytic-Uremic Syndrome HUS is loosely defined by the
Bleyer AJ, Kmoch S: Autosomal dominant tubulointerstitial kidney presence of MAHA and renal impairment. At least four variants are
disease: Of names and genes. Kidney Int 86:459, 2014. recognized. The most common is Shiga toxin–producing Escherichia coli
Correa-Rotter R et al: CKD of unknown origin in Central America: (STEC) HUS, which is also known as D+ (diarrhea-associated) HUS or
The case for a Mesoamerican nephropathy. Am J Kidney Dis 63:506, enterohemorrhagic E. coli (EHEC) HUS. Most cases involve children
2014. <5 years of age, but adults also are susceptible, as evidenced by a 2011
Muriithi AK et al: Clinical characteristics, causes and outcomes of outbreak in northern Europe. Diarrhea, often bloody, precedes MAHA
acute interstitial nephritis in the elderly. Kidney Int 87:458, 2015. within 1 week in >80% of cases. Abdominal pain, cramping, and
Praga M et al: Changes in the aetiology, clinical presentation and man- vomiting are frequent, whereas fever is typically absent. Neurologic
agement of acute interstitial nephritis, an increasingly common cause symptoms, including dysphasia, hyperreflexia, blurred vision, memory
of acute kidney injury. Nephrol Dial Transplant 30:1472, 2015. deficits, encephalopathy, perseveration, and agraphia, often develop,
Raissian Y et al: Diagnosis of IgG4-related tubulointerstitial nephritis. especially in adults. Seizures and cerebral infarction can occur in
J Am Soc Nephrol 22:1343, 2011. severe cases. STEC HUS is caused by the Shiga toxins (Stx1 and Stx2),
which are also referred to as verotoxins. These toxins are produced by
certain strains of E. coli and Shigella dysenteriae. In the United States
and Europe, the most common STEC strain is O157:H7, but HUS has
been reported with other strains (O157/H–, O111:H–, O26:H11/H–,
311 Vascular
O145:H28, and O104:H4). After entry into the circulation, Shiga toxin
Injury to the binds to the glycolipid surface receptor globotriaosylceramide (Gb3),
Kidney which is richly expressed on cells of the renal microvasculature. Upon
binding, the toxin enters the cells, inducing inflammatory cytok-
ines (interleukin 8 [IL-8], monocyte chemotactic protein 1 [MCP-1],
Ronald S. Go, Nelson Leung and stromal cell–derived factor 1 [SDF-1]) and chemokine receptors
(CXCR4 and CXCR7); this action results in platelet aggregation
and the microangiopathic process. Streptococcus pneumoniae can also
The renal circulation is complex and is characterized by a highly cause HUS. Certain strains produce a neuraminidase that cleaves the
perfused arteriolar network, reaching cortical glomerular structures N-acetylneuraminic acid moieties normally covering the Thomsen-
adjacent to lower-flow vasa recta that descend into medullary seg- Friedenreich antigen on platelets and endothelial cells. Exposure of this
ments. Disorders of the larger vessels, including renal artery stenosis cryptic antigen to preformed IgM results in severe MAHA.
and atheroembolic disease, are discussed elsewhere (Chap. 322). This Atypical HUS or complement medicated HUS is the result of com-
chapter examines primary disorders of the renal microvessels, many of plement dysregulation. The complement dysregulation can be congen-
which are associated with thrombosis and hemolysis. ital or acquired. The affected patients often have a low C3 and a normal
C4 levels characteristic of alternative pathway activation. Factor H
THROMBOTIC MICROANGIOPATHY deficiency, the most common defect, has been linked to families with
Thrombotic microangiopathy (TMA) is a pathologic lesion char- aHUS. Factor H competes with factor B to prevent the formation of
acterized by endothelial cell injury in the terminal arterioles and C3bBb and acts as a cofactor for factor I, which proteolytically degrades
capillaries. Platelet and hyaline thrombi causing partial or complete C3b. More than 70 mutations of the factor H gene have been identi-
occlusion are integral to the histopathology of TMA. TMA is usually fied. Most are missense mutations that produce abnormalities in the

C-terminus region, affecting its binding to C3b but not its concentra- 2165
TREATMENT
tion. Other mutations result in low levels or the complete absence of the
protein. Deficiencies in other complement-regulatory proteins, such as HUS/TTP
factor I, factor B, membrane cofactor protein (CD46), C3, complement
factor H–related protein 1 (CFHR1), CFHR3, CFHR5, and thrombo- Treatment should be based on pathophysiology. Autoantibody-
modulin, have also been reported. Finally, an autoimmune variant of mediated TTP and DEAP HUS respond to the combination of
aHUS has been discovered. DEAP (deficiency of CFHR plasma proteins plasma exchange and prednisone. In addition to removing the
and CFH autoantibody positive) HUS occurs when an autoantibody autoantibodies, plasma exchange with fresh-frozen plasma replaces
to factor H is formed. DEAP HUS is often associated with a deletion ADAMTS13. Twice-daily plasma exchanges with administration of
of an 84-kb fragment of the chromosome that encodes for CFHR1 and rituximab may be effective in refractory cases. Plasma infusion is
CFHR3. The autoantibody blocks the binding of factor H to C3b and usually sufficient to replace the ADAMTS13 in Upshaw-Schülman
surface-bound C3 convertase. Renal injury is often severe resulting in syndrome. Plasma exchange should be considered if larger volumes
end stage renal disease. The severity of the renal injury and recurrence are necessary. Drug-induced TMA secondary to endothelial damage
after kidney transplant depend on the complement regulatory protein. typically does not respond to plasma exchange and is treated primar-
ily by discontinuing use of the agent and providing supportive care.
Similarly, STEC HUS should be treated with supportive measures
Thrombotic Thrombocytopenic Purpura Traditionally, TTP
as plasma exchange has not been found to be effective. Antimotility
is characterized by the pentad: MAHA, thrombocytopenia, neuro-
agents and antibiotics increase the incidence of HUS among children,
logic symptoms, fever, and renal failure. The pathophysiology of TTP
but azithromycin was recently found to decrease the duration of
involves the accumulation of ultra-large multimers of von Willebrand
bacterial shedding by adults. Plasma infusion/exchange is effective
factor as a result of the absence or markedly decreased activity of the
in certain types of aHUS as it replaces complement-regulatory pro-
plasma protease ADAMTS13, a disintegrin and metalloproteinase with
teins. Eculizumab is a monoclonal antibody to C5 that is approved
a thrombospondin type 1 motif, member 13. TTP is now defined as
for use in aHUS which has been shown to abort MAHA and
CHAPTER 311 Vascular Injury to the Kidney

MAHA associated with ADAMTS13 activity of (<5–10%). These ultra-
improve renal function. Antibiotics and washed red cells should be
large multimers form clots and shear erythrocytes, resulting in MAHA;
given in neuraminidase-associated HUS, and plasmapheresis may
however, the absence of ADAMTS13 alone may not by itself produce
be helpful. However, plasma and whole-blood transfusion should
TTP. Often, an additional inflammatory trigger (such as infection, sur-
be avoided since these products contain IgM, which may exacerbate
gery, pancreatitis, or pregnancy) is required to initiate clinical TTP. This
MAHA. Finally, combined factor H and ADAMTS13 deficiency have
may be mediated by human neutrophil peptides that inhibit cleavage
been reported. The affected patients are generally less responsive to
of von Willebrand factor by ADAMTS13.
plasma infusion, a result illustrating the complexity of the manage-
Data from the Oklahoma TTP/HUS Registry suggest an incidence
ment of these cases.
rate of 2.9 cases/106 patients in the United States. The median age of
onset is 40 years. The incidence is more than nine times higher among
blacks than among non-blacks. Like that of systemic lupus erythema-
tosus, the incidence of TTP is nearly three times higher among women ■■HEMATOPOIETIC STEM CELL TRANSPLANTATION–
than among men. If untreated, TTP has a mortality rate exceeding 90%. ASSOCIATED THROMBOTIC MICROANGIOPATHY
Even with modern therapy, 20% of patients die within the first month (HSCT-TMA)
from complications of microvascular thrombosis. HSCT-TMA develops after HSCT, with an incidence of ~8%. Etio-
The classic form of TTP is idiopathic TTP, which is the result of a logic factors include conditioning regimens, immunosuppression,
severe deficiency in ADAMTS13. In the past, TTP had traditionally infections, and graft-versus-host disease. Other risk factors include
been associated with infection, malignancy, and intense inflammation female sex and human leukocyte antigen (HLA)–mismatched donor
(e.g., pancreatitis), but ADAMTS13 activity is typically not decreased grafts. HSCT-TMA usually occurs within the first 100 days of HSCT.
in these conditions and therefore should be not considered TTP. In Table 311-1 lists definitions of HSCT-TMA currently used for clinical
idiopathic TTP, the formation of an autoantibody to ADAMTS13 trials. Diagnosis may be difficult since thrombocytopenia, anemia,
(IgG or IgM) either increases its clearance or inhibits its activity. and renal insufficiency are common after HSCT. HSCT-TMA carries
Upshaw-Schülman syndrome is a hereditary condition characterized a high mortality rate (75% within 3 months). The majority of patients
by congenital deficiency of ADAMTS13. TTP in these patients can start have >10% ADAMTS13 activity, and plasma exchange is beneficial
within the first weeks of life but in some instances may not present in <25% of patients. Discontinuation of calcineurin inhibitors and
until adulthood, especially during pregnancy. Both environmental and treatment of infections or sinusoidal obstruction syndrome (if present)
genetic factors are thought to influence the development of TTP. Plasma
transfusion is an effective strategy for prevention and treatment.
TABLE 311-1 Criteria for Establishing Microangiopathic Kidney
Drug-induced TMA is a recognized complication of treatment Injury Associated with Hematopoietic Stem Cell Transplantation
with some chemotherapeutic agents, immunosuppressive agents,
BLOOD AND MARROW TRANSPLANT
and quinine. Two different mechanisms are now recognized. Toxic or CLINICAL TRIALS NETWORK
endothelial damage (pathologically similar to that of HUS) is the main INTERNATIONAL WORKING GROUP TOXICITY COMMITTEE
cause of the TMA that develops in association with chemotherapeu- 4% schistocytes in the blood RBC fragmentation and at least 2
tic agents (e.g., mitomycin C, gemcitabine) and immunosuppressive schistocytes per high-power field
agents (cyclosporine, interferon, sirolimus, and tacrolimus). This De novo, prolonged, or progressive Concurrent increase in LDH
process is usually dose-dependent. Alternatively, TMA may develop thrombocytopenia concentration above baseline
as a result of drug-induced autoantibodies. This form is less likely A sudden and persistent increase in Negative direct and indirect Coombs
to be dose-dependent and can, in fact, occur after a single dose in LDH concentration test
patients with previous exposure. ADAMTS13 deficiency is found in Decrease in hemoglobin level Concurrent renal and/or neurologic
fewer than half of patients with clopidogrel-associated TTP. Quinine or increased RBC transfusion dysfunction without other
appears to induce autoantibodies to granulocytes, lymphocytes, endo- requirement explanations
thelial cells, and platelet glycoprotein Ib/IX or IIb/IIIa complexes, but Decrease in haptoglobin
not to ADAMTS13. Quinine-associated TTP is more common among concentration
women. TMA has also been reported with drugs that inhibit vascular Note: These features underscore the need to identify pathways of hemolysis and
endothelial growth factor, such as bevacizumab; the mechanism is not thrombocytopenia that accompany deterioration of kidney function.
completely understood. Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.

2166 are recommended. Treatment with rituximab and defibrotide may also Treatment with ACE inhibition is the first-line therapy unless con-
be helpful, but clinical trial data are lacking. traindicated. The goal of therapy is to reduce systolic and diastolic
blood pressure by 20 mmHg and 10 mmHg, respectively, every 24 h
■■HIV-RELATED TMA until blood pressure is normal. Additional antihypertensive therapy
HIV-related TMA is a complication encountered mainly before wide- may be given once the dose of drug for ACE inhibition is maximized.
spread use of highly active antiretroviral therapy. It is seen in patients Both ACE inhibitors and angiotensin II receptor antagonists are effec-
with advanced AIDS and low CD4+ T cell counts although it can be the tive, although data suggest that treatment with ACE inhibitors is supe-
first manifestation of HIV infection. The presence of MAHA, thrombo- rior. ACE inhibition alone does not prevent scleroderma renal crisis,
cytopenia, and renal failure are suggestive, but renal biopsy is required but it does reduce the impact of hypertension. Intravenous iloprost has
for diagnosis since other renal diseases are also associated with HIV been used in Europe for blood pressure management and improvement
infection. Thrombocytopenia may prohibit renal biopsy in some of renal perfusion. Kidney transplantation is not recommended for
patients. The mechanism of injury is unclear, although HIV can induce 2 years after the start of dialysis since delayed recovery may occur.
apoptosis in endothelial cells. ADAMTS13 activity is not reduced in
these patients. Cytomegalovirus co-infection may also be a risk factor. ■■ANTIPHOSPHOLIPID SYNDROME
Effective antiviral therapy is key, while plasma exchange should be Antiphospholipid syndrome (Chap. 350) can be either primary or
limited to patients who have evidence of TTP. secondary to systemic lupus erythematosus. It is characterized by a
■■RADIATION NEPHROPATHY predisposition to systemic thrombosis (arterial and venous) and fetal
Either local or total body irradiation can produce microangiopathic morbidity mediated by antiphospholipid antibodies—mainly anticar-
injury. The kidney is one of the most radiosensitive organs, and injury diolipin antibodies (IgG, IgM, or IgA), lupus anticoagulant, or anti-β-2
can result with as little as 4–5 Gy. Such injury is characterized by glycoprotein I antibodies (antiβ2GPI). Patients with both anticardiolipin
renal insufficiency, proteinuria, and hypertension usually developing antibodies and antiβ2GPI appear to have the highest risk of thrombo-
≥6 months after radiation exposure. Renal biopsy reveals classic TMA sis. The vascular compartment within the kidney is the main site of
with damage to glomerular, tubular, and vascular cells, but systemic renal involvement. Arteriosclerosis is commonly present in the arcuate
PART 9
evidence of MAHA is uncommon. Because of its high incidence and intralobular arteries. In the intralobular arteries, fibrous intimal
after allogeneic HSCT, radiation nephropathy is often referred to as hyperplasia characterized by intimal thickening secondary to intense
bone marrow transplant nephropathy. No specific therapy is available, myofibroblastic intimal cellular proliferation with extracellular matrix
although observational evidence supports renin-angiotensin system deposition is frequently seen along with onion-skinning. Arterial and
blockade. arteriolar fibrous and fibrocellular occlusions are present in more than
two-thirds of biopsy samples. Cortical necrosis and focal cortical atro-

■■SCLERODERMA (PROGRESSIVE SYSTEMIC phy may result from vascular occlusion. TMA is commonly present in
SCLEROSIS) renal biopsies, although signs of MAHA and platelet consumption are
Kidney involvement is common (up to 52%) in patients with wide- usually absent. TMA is especially common in the catastrophic variant
spread scleroderma, with 20% of cases resulting directly from sclero- of antiphospholipid syndrome. In patients with secondary antiphos-
derma renal crisis. Other renal manifestations in scleroderma include pholipid syndrome, other glomerulopathies may be present, including
transient (prerenal) or medication-related forms of acute kidney injury membranous nephropathy, minimal change disease, focal segmental
(e.g., associated with D-penicillamine, nonsteroidal anti-inflammatory glomerulosclerosis, and pauci-immune crescentic glomerulonephritis.
drugs, or cyclosporine). Scleroderma renal crisis occurs in 12% of Large vessels can be involved in antiphospholipid syndrome and
patients with diffuse systemic sclerosis but in only 2% of those with may form the proximal nidus near the ostium for thrombosis of the
limited systemic sclerosis. Scleroderma renal crisis is the most severe renal artery. Renal vein thrombosis can occur and should be suspected
manifestation of renal involvement, and is characterized by accelerated in patients with lupus anticoagulant who develop nephrotic-range
hypertension, a rapid decline in renal function, nephrotic range pro- proteinuria. Progression to end-stage renal disease can occur, and a
teinuria, and hematuria. Retinopathy and encephalopathy may accom- thrombosis may form in the vascular access and the renal allografts.
pany the hypertension. Salt and water retention with microvascular Hypertension is common. Treatment entails lifelong anticoagulation.
injury can lead to pulmonary edema. Cardiac manifestations, including Glucocorticoids may be beneficial in accelerated hypertension. Immu-
myocarditis, pericarditis, and arrhythmias, denote an especially poor nosuppression and plasma exchange may be helpful for catastrophic
prognosis. Although MAHA is present in more than half of patients, episodes of antiphospholipid syndrome but by themselves do not
coagulopathy is rare. reduce recurrent thrombosis.
The renal lesion in scleroderma renal crisis is characterized by arcu-
ate artery intimal and medial proliferation with luminal narrowing. ■■HELLP SYNDROME
This lesion is described as “onion-skinning” and can be accompanied HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome
by glomerular collapse due to reduced blood flow. Histologically, scle- is a dangerous complication of pregnancy associated with microvas-
roderma renal crisis is indistinguishable from malignant hypertension, cular injury. Occurring in 0.2–0.9% of all pregnancies and in 10–20%
with which it can coexist. Fibrinoid necrosis and thrombosis are com- of women with severe preeclampsia, this syndrome carries a mortality
mon. Before the availability of angiotensin-converting enzyme (ACE) rate of 7.4–34%. Most commonly developing in the third trimester, 10%
inhibitors, the mortality rate for scleroderma renal crisis was >90% at of cases occur before week 27 and 30% post-partum. Although a strong
1 month. Introduction of renin-angiotensin system blockade has low- association exists between HELLP syndrome and preeclampsia, nearly
ered the mortality rate to 30% at 3 years. Nearly two-thirds of patients 20% of cases are not preceded by recognized preeclampsia. Risk factors
with scleroderma renal crisis may require dialysis support, with recov- include abnormal placentation, family history, and elevated levels of
ery of renal function in 50% (median time, 1 year). Glomerulonephritis fetal mRNA for FLT1 (vascular endothelial growth factor receptor 1)
and vasculitis associated with antineutrophil cytoplasmic antibodies and endoglin. Patients with HELLP syndrome have higher levels of
and systemic lupus erythematosus have been described in patients inflammatory markers (C-reactive protein, IL-1Ra, and IL-6) and soluble
with scleroderma. An association has been found with a speckled HLA-DR than do those with preeclampsia alone.
pattern of antinuclear antibodies and with antibodies to RNA poly- Renal failure occurs in half of patients with HELLP syndrome,
merases I and III. Anti-U3-RNP may identify young patients at risk although the etiology is not well understood. Limited data suggest
for scleroderma renal crisis. Anticentromere antibody, in contrast, is a that renal failure is the result of both preeclampsia and acute tubular
negative predictor of this disorder. Because of the overlap between scle- necrosis. Renal histologic findings are those of TMA with endothe-
roderma renal crisis and other autoimmune disorders, a renal biopsy is lial cell swelling and occlusion of the capillary lumens, but luminal
recommended for patients with atypical renal involvement, especially thrombi are typically absent. However, thrombi become more common
if hypertension is absent. in severe eclampsia and HELLP syndrome. Although renal failure is

common, the organ that defines this syndrome is the liver. Subcapsular ■■SICKLE CELL NEPHROPATHY 2167
hepatic hematomas sometimes produce spontaneous rupture of the Renal complications in sickle cell disease result from occlusion of the
liver and can be life-threatening. Neurologic complications such as vasa recta in the renal medulla. The low partial pressure of oxygen
cerebral infarction, cerebral and brainstem hemorrhage, and cerebral and high osmolarity predispose to hemoglobin S polymerization and
edema are other potentially life-threatening complications. Nonfatal erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and
complications include placental abruption, permanent vision loss papillary necrosis (which can also occur in sickle trait). The kidney
due to Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy) responds by increases in blood flow and glomerular filtration rate
retinopathy, pulmonary edema, bleeding, and fetal demise. mediated by prostaglandins. This dependence on prostaglandins may
Many features are shared by HELLP syndrome and MAHA. Diag- explain the greater reduction of glomerular filtration rate by nonste-
nosis of HELLP syndrome is complicated by the fact that aHUS and roidal anti-inflammatory drugs in these patients than in others. The
TTP also can be triggered by pregnancy and complement mutations glomeruli are typically enlarged. Intracapillary fragmentation and
are common (30–40%) among patients with HELLP syndrome. Patients phagocytosis of sickled erythrocytes are thought to be responsible
with antiphospholipid syndrome also have an elevated risk of HELLP for the membranoproliferative glomerulonephritis–like lesion, and
syndrome. A history of MAHA before pregnancy is of diagnostic value. focal segmental glomerulosclerosis is seen in more advanced cases.
Serum levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP Proteinuria is present in 20–30%, and nephrotic-range proteinuria is
syndrome but not to the levels seen in TTP (<5%). Determination of associated with progression to renal failure. ACE inhibitors reduce
the ratio of lactate dehydrogenase to aspartate aminotransferase may proteinuria, although data are lacking on prevention of renal failure.
be helpful. This ratio is 13:1 in patients with HELLP syndrome and Patients with sickle cell disease are also more prone to acute renal fail-
preeclampsia as opposed to 29:1 in patients without preeclampsia. ure. The cause is thought to reflect microvascular occlusion associated
Other markers, such as antithrombin III (decreased in HELLP syndrome with nontraumatic rhabdomyolysis, high fever, infection, and general-
but not in TTP) and d-dimer (elevated in HELLP syndrome but not in ized sickling. Chronic kidney disease is present in 12–20% of patients.
TTP), may also be useful. HELLP syndrome usually resolves spontane- Despite the frequency of renal disease, hypertension is uncommon in
CHAPTER 311 Vascular Injury to the Kidney

ously after delivery, although a small percentage of HELLP cases occur patients with sickle cell disease.
post-partum. Glucocorticoids may decrease inflammatory markers,
although two randomized controlled trials failed to show much benefit.
Plasma exchange should be considered if hemolysis is refractory to RENAL VEIN THROMBOSIS
glucocorticoids and/or delivery, especially if TTP has not been ruled Renal vein thrombosis either can present with flank pain, tenderness,
out. hematuria, rapid decline in renal function, and proteinuria or can
be silent. Occasionally, renal vein thrombosis is identified during a
Myeloproliferative Neoplasm-Related Glomerulopathy workup for pulmonary embolism. The left renal vein is more com-
While MAHA is often present in TMA, this is not true for all lesions. monly involved, and two-thirds of cases are bilateral. Etiologies can be
Two conditions are now recognized to present with renal TMA but no divided into three broad categories: endothelial damage, venous stasis,
evidence of systemic MAHA. The first is MPN-related glomerulopa- and hypercoagulability. Homocystinuria, endovascular intervention,
thy. MPN represents a group of clonal disorders that includes chronic and surgery can produce vascular endothelial damage. Dehydration,
myelogenous leukemia (CML), polycythemia vera (PV), essential which is more common among male patients, is a common cause of
thrombocythemia (ET), primary myelofibrosis (PMF), systemic masto- stasis in the pediatric population. Stasis also can result from compres-
cytosis, chronic eosinophilic leukemia not otherwise specified, chronic sion and kinking of the renal veins from retroperitoneal processes such
neutrophilic leukemia, and unclassifiable MPN. These patients present as retroperitoneal fibrosis and abdominal neoplasms. Thrombosis can
with renal impairment and nephrotic range proteinuria. MPN-related occur throughout the renal circulation, including the renal veins, with
glomerulopathy usually occurs late in the course of the hematologic antiphospholipid syndrome. Renal vein thrombosis can also be sec-
condition as median time from diagnosis of MPN to glomerulopathy ondary to nephrotic syndrome, particularly membranous nephropathy.
was 7.2 years. Renal biopsy shows mesangial expansion, hypercellu- Other hypercoagulable states less commonly associated with renal vein
larity, mesangial and segmental sclerosis, luminal hyalinosis, loss of thrombosis include proteins C and S, antithrombin deficiency, factor V
overlying podocytes, and adhesions to Bowman’s capsule and dupli- Leiden, disseminated malignancy, and oral contraceptives. Severe neph-
cation of glomerular basement membranes. Foot process effacement rotic syndrome may also predispose patients to renal vein thrombosis.
ranges from 30 to 95%. Arteriosclerosis is common and ranges from Diagnostic screening can be performed with Doppler ultrasonogra-
mild to severe. Arteriolar hyalinosis can also be seen. Extremedullary phy, which is more sensitive than ultrasonography alone. Computed
hematopoiesis can sometimes be seen especially in patients with mye- tomography angiography is ~100% sensitive. Magnetic resonance
lofibrosis. MPGN-related glomerulopathy may develop while patients angiography is another option but is more expensive. Treatment for
are on treatment with hydroxyurea and JAK2 inhibitors. No standard renal vein thrombosis consists of anticoagulation and therapy for
treatment is available. RAS blockade and corticosteroids have been the underlying cause. Endovascular thrombolysis may be considered
tried with mixed results. in severe cases. Occasionally, nephrectomy may be undertaken for
POEMS Syndrome POEMS syndrome is a systemic disease char- life-threatening complications. Vena caval filters are often used to pre-
acterized by polyneuropathy, organomegaly, endocrinopathy, mono- vent migration of thrombi.
clonal gammopathy, and skin changes. Peripheral neuropathy with
severe motorsensory deficit is the hallmark of the disease. Another ■■FURTHER READING
characteristic is that >95% of monoclonal light chain is of the lambda Al-Nouri ZL et al: Drug-induced thrombotic microangiopathy:
isotype. IgA also makes up about 50% of the monoclonal protein. A systematic review of published reports. Blood 125:616, 2015.
Organomegaly can involve any organ and often presents as lymph- Bose N et al: Scleroderma renal crisis. Sem Arthritis and Rheumatism
adenopathy. In the kidney, the hypertrophy frequently is unilateral. 44:687, 2015.
One study suggests the difference in kidney size is due to unilateral Bresin E et al: Combined complement gene mutations in atypical
contraction; however, a volumemetric study showed that enlargement hemolytic uremic syndrome influence clinical phenotype. J Am Soc
is responsible for the difference in kidney size in some patients. Glo- Nephrol 24:475, 2013.
merulomegaly is not uncommon. Lobular appearance, endothelial George JN, Nester CM: Syndromes of thrombotic microangiopathy.
cell swelling, hypercellularity, mesangiolysis, microaneurysm, and N Engl J Med 371:1847, 2014.
glomerular enlargement are reminiscent of membranoproliferative Go RS et al: Thrombotic Microangiopathy Care Pathway: A Consen-
glomerulonephritis. Most patients present with mild to moderate renal sus Statement for the Mayo Clinic Complement Alternative Pathway-
impairment and low grade proteinuria. Progression to end stage renal Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group.
disease is rare. Mayo Clin Proc 91:1189, 2016.

2168 urologic emergency (“pus under pressure”) and requires urgent inter-
312 Nephrolithiasis
Gary C. Curhan
vention to reestablish drainage.
■■PATHOGENESIS
In the consideration of the processes involved in crystal formation, it is
helpful to view urine as a complex solution. A clinically useful concept
is supersaturation (the point at which the concentration product exceeds
Nephrolithiasis, or kidney stone disease, is a common, painful, and costly the solubility product). However, even though the urine in most indi-
condition. Each year, billions of dollars are spent on nephrolithiasis- viduals is supersaturated with respect to one or more types of crystals,
related activity, with the majority of expenditures on surgical treat- the presence of inhibitors of crystallization prevents the majority of
ment of existing stones. While a stone may form due to crystallization the population from continuously forming stones. The most clinically
of lithogenic factors in the upper urinary tract, it can subsequently important inhibitor of calcium-containing stones is urine citrate. While
move into the ureter and cause renal colic. Although nephrolithiasis the calculated supersaturation value does not perfectly predict stone
is rarely fatal, patients who have had renal colic report that it is the formation, it is a useful guide as it integrates the multiple factors that
worst pain they have ever experienced. The evidence on which to base are measured in a 24-h urine collection.
clinical recommendations is not as strong as desired; nonetheless, most Recent studies have changed the paradigm for the site of initiation
experts agree that the recurrence of most, if not all, types of stones of stone formation. Renal biopsies of stone formers have revealed cal-
can be prevented with careful evaluation and targeted recommen- cium phosphate in the renal interstitium. It is hypothesized that this
dations. Preventive treatment may be lifelong; therefore, an in-depth calcium phosphate deposits at the thin limb of the loop of Henle, and
understanding of this condition must inform the implementation of then extends down to the papilla and erodes through the papillary
tailored interventions that are most appropriate for and acceptable to epithelium, where it provides a site for deposition of calcium oxalate
the patient. and calcium phosphate crystals. The majority of calcium oxalate stones
There are several types of kidney stones. It is clinically important to grow on calcium phosphate at the tip of the renal papilla (Randall’s
identify the stone type, which informs prognosis and selection of the plaque). Tubular plugs of calcium phosphate may be the initiating
PART 9
optimal preventive regimen. Calcium oxalate stones are most common event in calcium phosphate stone development. Thus, the process of
(~75%); next, in order, are calcium phosphate (~15%), uric acid (~8%), stone formation may begin years before a clinically detectable stone is
struvite (~1%), and cystine (<1%) stones. Many stones are a mixture of identified. The processes involved in interstitial deposition are under
crystal types (e.g., calcium oxalate and calcium phosphate) and also active investigation.
contain protein in the stone matrix. Rarely, stones are composed of

medications, such as acyclovir, atazanavir, and triamterene. Stones that ■■RISK FACTORS
form as a result of an upper tract infection, if not appropriately treated, Risk factors for nephrolithiasis can be categorized as dietary, nondi-
can have devastating consequences and lead to end-stage renal disease. etary, or urinary. These risk factors vary by stone type and by clinical
Consideration should be given to teaching practitioners strategies to characteristics.
prevent recurrence of all stone types and the related morbidity. Dietary Risk Factors Patients who develop stones often change
their diet; therefore, studies that retrospectively assess diet may be
■■EPIDEMIOLOGY hampered by recall bias. Some studies have examined the relation
Nephrolithiasis is a global disease. Data suggest an increasing between diet and changes in the lithogenic composition of the urine,
prevalence, likely due to Westernization of lifestyle habits often using calculated supersaturation. However, the composition of
(e.g., dietary changes, increasing body mass index). National the urine does not perfectly predict risk, and not all components that
Health and Nutrition Examination Survey data for 2007–2010 indicate modify risk are included in the calculation of supersaturation. Thus,
that up to 19% of men and 9% of women will develop at least one stone dietary associations are best investigated by prospective studies that
during their lifetime. The prevalence is ~50% lower among black indi- examine actual stone formation as the outcome. Dietary factors that are
viduals than among whites. The incidence of nephrolithiasis (i.e., the associated with an increased risk of nephrolithiasis include animal pro-
rate at which previously unaffected individuals develop their first tein, oxalate, sodium, sucrose, and fructose. Dietary factors associated
stone) also varies by age, sex, and race. Among white men, the peak with a lower risk include calcium, potassium, and phytate.
annual incidence is ~3.5 cases/1000 at age 40 and declines to
~2 cases/1000 by age 70. Among white women in their thirties, the CALCIUM The role of dietary calcium deserves special attention.
annual incidence is ~2.5 cases/1000; the figure decreases to ~1.5/1000 Although in the distant past dietary calcium had been suspected of
at age 50 and beyond. In addition to the medical costs associated with increasing the risk of stone disease, several prospective observational
nephrolithiasis, this condition also has a substantial economic impact, studies and a randomized controlled trial have demonstrated that
as those affected are often of working age. Once an individual has had higher dietary calcium intake is related to a lower risk of stone forma-
a stone, the prevention of a recurrence is essential. Published recur- tion. The reduction in risk associated with higher calcium intake may
rence rates vary by the definitions and diagnostic methods used. Some be due to a reduction in intestinal absorption of dietary oxalate that
reports have relied on symptomatic events, while others have been results in lower urine oxalate. Low calcium intake is contraindicated
based on imaging. Most experts agree that radiographic evidence of a as it increases the risk of stone formation and may contribute to lower
second stone should be considered to represent a recurrence, even if the bone density in stone formers.
stone has not yet caused symptoms. Despite similar bioavailability, supplemental calcium may increase
the risk of stone formation. The discrepancy between the risks from
■■ASSOCIATED MEDICAL CONDITIONS dietary calcium and calcium supplements may be due to the timing of
Nephrolithiasis is a systemic disorder. Several conditions predispose supplemental calcium intake or to higher total calcium consumption
to stone formation, including gastrointestinal malabsorption (e.g., leading to higher urinary calcium excretion.
Crohn’s disease, gastric bypass surgery), primary hyperparathyroid- OXALATE Urinary oxalate is derived from both endogenous produc-
ism, obesity, type 2 diabetes mellitus, and distal renal tubular acidosis. tion and absorption of dietary oxalate. Owing to its low and often
A number of other medical conditions are more likely to be present in variable bioavailability, much of the oxalate in food may not be read-
individuals with a history of nephrolithiasis, including hypertension, ily absorbed. However, absorption may be higher in stone formers.
gout, cardiovascular disease, cholelithiasis, reduced bone mineral Although observational studies demonstrate that dietary oxalate is
density, and chronic kidney disease. only a weak risk factor for stone formation, urinary oxalate is a strong
Although nephrolithiasis does not directly cause upper urinary risk factor for calcium oxalate stone formation, and efforts to avoid
tract infections (UTIs), a UTI in the setting of an obstructing stone is a high oxalate intake should thus be beneficial.

OTHER NUTRIENTS Several other nutrients have been studied and URINE CITRATE Urine citrate is a natural inhibitor of calcium-contain- 2169
implicated in stone formation. Higher intake of animal protein may ing stones; thus, lower urine citrate excretion increases the risk of stone
lead to increased excretion of calcium and uric acid as well as to formation. Citrate reabsorption is influenced by the intracellular pH of
decreased urinary excretion of citrate, all of which increase the risk of proximal tubular cells. Metabolic acidosis, including that due to higher
stone formation. Higher sodium and sucrose intake increases calcium animal flesh intake, will lead to a reduction in citrate excretion by
excretion independent of calcium intake. Higher potassium intake increasing reabsorption of filtered citrate. However, a notable propor-
decreases calcium excretion, and many potassium-rich foods increase tion of patients have lower urine citrate for reasons that remain unclear.
urinary citrate excretion due to their alkali content. Other dietary URINE URIC ACID Higher urine levels of uric acid—a risk factor for
factors that have been inconsistently associated with lower stone risk uric acid stone formation—are found in individuals with excess purine
include magnesium and phytate. consumption and rare genetic conditions that lead to overproduction of
Vitamin C supplements are associated with an increased risk of uric acid. This characteristic does not appear to be associated with the
calcium oxalate stone formation in men, possibly because of raised risk of calcium oxalate stone formation.
levels of oxalate in urine. Thus, male calcium oxalate stone formers
should be advised to avoid vitamin C supplements. Although high URINE pH Urine pH influences the solubility of some crystal types. Uric
doses of supplemental vitamin B6 may be beneficial in selected acid stones form only when the urine pH is consistently ≤5.5 or lower,
patients with type 1 primary hyperoxaluria, the risk is not reduced whereas calcium phosphate stones are more likely to form when the
in other patients. urine pH is ≥6.5 or higher. Cystine is more soluble at higher urine pH.
Calcium oxalate stones are not influenced by urine pH.
FLUIDS AND BEVERAGES The risk of stone formation increases as urine
volume decreases. When the urine output is <1 L/d, the risk of stone Genetic Risk Factors The risk of nephrolithiasis is more
formation more than doubles. Fluid intake is the main determinant of than twofold greater in individuals with a family history of stone
urine volume, and the importance of fluid intake in preventing stone disease. This association is likely due to a combination of genetic
formation has been demonstrated in observational studies and in a predisposition and similar environmental exposures. While a number
CHAPTER 312 Nephrolithiasis

randomized controlled trial. Observational studies have found that of rare monogenic disorders cause nephrolithiasis, the genetic contrib-
coffee, tea, beer, wine, and orange juice are associated with a reduced utors to common forms of stone disease remain to be determined.
risk of stone formation. Sugar-sweetened beverage consumption may The two most common and well-characterized rare monogenic
increase risk. disorders that lead to stone formation are primary hyperoxaluria and
cystinuria. Primary hyperoxaluria is an autosomal recessive disorder
Nondietary Risk Factors Age, race, body size, and environment that causes excessive endogenous oxalate generation by the liver, with
are important risk factors for nephrolithiasis. The incidence of stone consequent calcium oxalate stone formation and crystal deposition in
disease is highest in middle-aged white men, but stones can form in organs. Intraparenchymal calcium oxalate deposition in the kidney can
infants as well as in the elderly. There is geographic variability, with eventually lead to renal failure. Cystinuria is an autosomal recessive
the highest prevalence in the southeastern United States. Weight gain disorder that causes abnormal reabsorption of filtered basic amino
increases the risk of stone formation, and the increasing prevalence of acids. The excessive urinary excretion of cystine, which is poorly solu-
nephrolithiasis in the United States may be due in part to the increas- ble, leads to cystine stone formation. Cystine stones are visible on plain
ing prevalence of obesity. Environmental and occupational influences radiographs and often manifest as staghorn calculi or multiple bilateral
that may lead to lower urine volume, such as working in a hot envi- stones. Repeat episodes of obstruction and instrumentation can cause a
ronment or lack of ready access to water or a bathroom, are important reduction in the glomerular filtration rate (GFR).
considerations.
Urinary Risk Factors • URINE VOLUME As mentioned above, APPROACH TO THE PATIENT
lower urine volume results in higher concentrations of lithogenic Nephrolithiasis
factors and is a common and readily modifiable risk factor. A random-
ized trial has demonstrated the effectiveness of higher fluid intake in Evidence-based guidelines for the evaluation and treatment of
increasing urine volume and reducing the risk of stone recurrence. nephrolithiasis have been recently published. Although there is
limited evidence for several aspects, there are standard approaches
URINE CALCIUM Higher urine calcium excretion increases the likeli- to patients with acute and chronic presentations that can reasonably
hood of formation of calcium oxalate and calcium phosphate stones. guide the clinical evaluation.
While the term hypercalciuria is often used, there is no widely accepted It typically requires weeks to months (and often much longer) for
cutoff that distinguishes between normal and abnormal urine calcium a kidney stone to grow to a clinically detectable size. Although the
excretion. In fact, the relation between urine calcium and stone risk passage of a stone is a dramatic event, stone formation and growth
appears to be continuous; thus, the use of an arbitrary threshold should are characteristically clinically silent. A stone can remain asymp-
be avoided. Levels of urine calcium excretion are higher in individuals tomatic in the kidney for years or even decades before signs (e.g.,
with a history of nephrolithiasis; however, the mechanisms remain hematuria) or symptoms (e.g., pain) become apparent. Thus, it is
poorly understood. Greater gastrointestinal calcium absorption is one important to remember that the onset of symptoms, typically attrib-
important contributor, and greater bone turnover (with a resultant utable to a stone moving into the ureter, does not provide insight
reduction in bone mineral density) may be another. Primary renal into when the stone actually formed. The factors that induce stone
calcium loss, with lower serum calcium concentrations and elevated movement are unknown.
serum levels of parathyroid hormone (PTH) (and a normal 25-hydroxy
vitamin D level), is rare. CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS
There are two common presentations for individuals with an acute
URINE OXALATE Higher urine oxalate excretion increases the likelihood
stone event: renal colic and painless gross hematuria. Renal colic is
of calcium oxalate stone formation. As for urine calcium, no definition
a misnomer because pain typically does not subside completely;
for “abnormal” urine oxalate excretion is widely accepted. Given that
rather, it varies in intensity. When a stone moves into the ureter, the
the relation between urine oxalate and stone risk is continuous, simple
discomfort often begins with a sudden onset of unilateral flank pain.
dichotomization of urine oxalate excretion is not helpful in assessing
The intensity of the pain can increase rapidly, and there are no
risk. The two sources of urine oxalate are endogenous generation and
alleviating factors. This pain, which is accompanied often by nausea
dietary intake. Dietary oxalate is the major contributor and also the
and occasionally by vomiting, may radiate, depending on the loca-
source that can be modified. Notably, higher dietary calcium intake
tion of the stone. If the stone lodges in the upper part of the ureter,
reduces gastrointestinal oxalate absorption and thereby reduces urine
pain may radiate anteriorly; if the stone is in the lower part of the
oxalate.

2170
ureter, pain can radiate to the ipsilateral testicle in men or the ipsi-
lateral labium in women. Occasionally, a patient has gross hematuria
without pain.
Other diagnoses may be confused with acute renal colic. If the
stone is lodged at the right ureteral pelvic junction, symptoms may
mimic those of acute cholecystitis. If the stone blocks the ureter as
it crosses over the right pelvic brim, symptoms may mimic acute
appendicitis, whereas blockage at the left pelvic brim may be con-
fused with acute diverticulitis. If the stone lodges in the ureter at the
ureterovesical junction, the patient may experience urinary urgency
and frequency. In female patients, the latter symptoms may lead
to an incorrect diagnosis of bacterial cystitis; the urine will contain
red and white blood cells, but the urine culture will be negative. An
obstructing stone with proximal infection may present as acute pye-
lonephritis. A UTI in the setting of ureteral obstruction is a medical
emergency that requires immediate restoration of drainage by place-
ment of either a ureteral stent or a percutaneous nephrostomy tube.
Other conditions to consider in the differential diagnosis include
muscular or skeletal pain, herpes zoster, duodenal ulcer, abdominal
aortic aneurysm, gynecologic conditions, ureteral stricture, and
ureteral obstruction by materials other than a stone, such as a blood FIGURE 312-2 Coronal noncontrast CT image from a patient who presented with
clot or sloughed papilla. Extraluminal processes can lead to ureteral left-sided renal colic. An obstructing calculus, present in the distal left ureter at
compression and obstruction; however, because of the gradual the level of S1, measures 10 mm in maximal dimension. There is severe left
PART 9
onset, these conditions do not typically present with renal colic. hydroureteronephrosis and associated left perinephric fat stranding. In addition,
there is a nonobstructing 6-mm left renal calculus in the interpolar region. (Image
DIAGNOSIS AND INTERVENTION courtesy of Dr. Stuart Silverman, Brigham and Women’s Hospital.)
Serum chemistry findings are typically normal, but the white blood
cell count may be elevated. Examination of the urine sediment will offers the advantage of avoiding radiation and provides information
usually reveal red and white blood cells and occasionally crystals on hydronephrosis, but it is not as sensitive as CT and images only
(Fig. 312-1). The absence of hematuria does not exclude a stone, the kidney and possibly the proximal segment of the ureter; thus
particularly when urine flow is completely obstructed by a stone. most ureteral stones are not detectable by ultrasound.
The diagnosis is often made on the basis of the history, physi- Many patients who experience their first episode of colic seek
cal examination, and urinalysis. Thus, it may not be necessary to emergent medical care. Randomized trials have demonstrated that
wait for radiographic confirmation before treating the symptoms. parenterally administered nonsteroidal anti-inflammatory drugs (such
The diagnosis is confirmed by an appropriate imaging study— as ketorolac) are just as effective as opioids in relieving symptoms
preferably helical computed tomography (CT), which is highly sen- and have fewer side effects. Excessive fluid administration has not
sitive, allows visualization of uric acid stones (traditionally consid- been shown to be beneficial; therefore, the goal should be to maintain
ered “radiolucent”), and does not require radiocontrast (Fig. 312-2). euvolemia. If the pain can be adequately controlled and the patient
Helical CT detects stones as small as 1 mm that may be missed by is able to take fluids orally, hospitalization can be avoided. Use of an
other imaging modalities. alpha blocker may increase the rate of spontaneous stone passage.
Typically, helical CT reveals a ureteral stone or evidence of recent Urologic intervention should be postponed unless there is evi-
passage (e.g., perinephric stranding or hydronephrosis), whereas a dence of UTI, a low probability of spontaneous stone passage (e.g., a
plain abdominal radiograph (kidney/ureter/bladder, or KUB) can stone measuring ≥6 mm or an anatomic abnormality), or intractable
miss a stone in the ureter or kidney, even if it is radiopaque, and pain. A ureteral stent may be placed cystoscopically, but this proce-
does not provide information on obstruction. Abdominal ultrasound dure typically requires general anesthesia, and the stent can be quite
FIGURE 312-1 Urine sediment from a patient with calcium oxalate stones (left) and a patient with cystine stones (right). Calcium oxalate dihydrate crystals are
bipyramidally shaped, and cystine crystals are hexagonal. (Left panel image courtesy of Dr. John Lieske, Mayo Clinic.)

2171
uncomfortable, may cause gross hematuria, and may increase the The results from 24-h urine collections serve as the cornerstone on
risk of UTI. which therapeutic recommendations are based. Recommendations
If an intervention is indicated, the selection of the most appro- on lifestyle modification should be deferred until urine collection
priate intervention is determined by the size, location, and compo- is complete. As a baseline assessment, patients should collect at
sition of the stone; the urinary tract anatomy; and the experience least two 24-h urine samples while consuming their usual diet and
of the urologist. Extracorporeal shockwave lithotripsy (ESWL), the usual volume of fluid. The following factors should be measured:
least invasive option, uses shock waves generated outside the total volume, calcium, oxalate, citrate, uric acid, sodium, potassium,
body to fragment the stone, but is being used less frequently. An phosphorus, pH, and creatinine. When available, the calculated
endourologic approach, now more frequently used than ESWL, supersaturation is also informative. There is substantial day-to-day
can remove a stone by basket extraction or laser fragmentation. For variability in the 24-h excretion of many relevant factors; therefore,
large upper-tract stones, percutaneous nephrostolithotomy has the obtaining values from two collections is important before commit-
highest likelihood of rendering the patient stone-free. Advances ting a patient to long-term lifestyle changes or medication. The
in urologic approaches and instruments have nearly eliminated interpretation of the 24-h urine results should take into account
the need for open surgical procedures such as ureterolithotomy or that the collections are usually performed on a weekend day when
pyelolithotomy. the patient is staying at home; an individual’s habits may differ
dramatically (beneficially or detrimentally) at work or outside the
EVALUATION FOR STONE PREVENTION home. Specialized testing, such as calcium loading or restriction, is
More than half of first-time stone formers will have a recurrence not recommended as it does not influence clinical recommendations.
within 10 years. A careful evaluation is indicated to identify predis- Stone composition analysis is essential if a stone or fragment is
posing factors, which can then be modified to reduce the risk of new available; patients should be encouraged to retrieve passed stones.
stone formation. It is appropriate to proceed with an evaluation even The stone type cannot be determined with certainty from 24-h urine
after the first stone if the patient is interested because recurrences results, but pure uric acid stones can be identified by low Hounsfield
CHAPTER 312 Nephrolithiasis

are common and are usually preventable with inexpensive lifestyle units on CT.
modifications or other treatments.
IMAGING
HISTORY The “gold standard” diagnostic test is helical CT without contrast.
A detailed history, obtained from the patient and from a thorough If not already performed during an acute episode, a low-dose CT
review of medical records, should include the number and fre- should be considered to definitively establish the baseline stone
quency of episodes (distinguishing stone passage from stone for- burden. A suboptimal imaging study may not detect a residual stone
mation) and previous imaging studies, interventions, evaluations, that, if subsequently passed, would be mistaken for a new stone. In
and treatments. Inquiries about the patient’s medical history should this instance, the preventive medical regimen might be unnecessar-
cover UTIs, bariatric surgery, gout, hypertension, and diabetes melli- ily changed as the result of a preexisting stone.
tus. A family history of stone disease may reveal a genetic predispo- Recommendations for follow-up imaging should be tailored to
sition. A complete list of current prescription and over-the-counter the individual patient. While CT provides the best information, the
medications as well as vitamin and mineral supplements is essential. radiation dose is higher than from other modalities; therefore, CT
The review of systems should focus on identifying possible etiologic should be performed only if the results will lead to a change in clin-
factors related to low urine volume (e.g., high insensible losses) ical recommendations. Although they are less sensitive, renal ultra-
and gastrointestinal malabsorption as well as on ascertaining how sound or a KUB examinaion is typically used to minimize radiation
frequently the patient voids during the day and overnight. exposure, with recognition of the limitations.
A large body of compelling evidence has demonstrated the PREVENTION OF NEW STONE FORMATION
important role of diet in stone disease. Thus, the dietary history
should encompass information on usual dietary habits (meals and Recommendations for preventing stone formation depend on the
snacks), calcium intake, consumption of high-oxalate foods (spin- stone type and the results of metabolic evaluation. After remediable
ach, rhubarb, potatoes), and fluid intake (including amount of spe- secondary causes of stone formation (e.g., primary hyperparathy-
cific beverages typically consumed). Amount and frequency of use roidism) are excluded, the focus should turn to modification of the
of vitamin and mineral supplements should be carefully assessed. urine composition to reduce the risk of new stone formation. The
urinary constituents are continuous variables, and the associated
PHYSICAL EXAMINATION risk is continuous; thus, there are no definitive thresholds. Dichot-
The physical examination should assess weight, blood pressure, omization into “normal” and “abnormal” can be misleading and
costovertebral angle tenderness, and lower-extremity edema as well should be avoided.
as signs of other systemic conditions such as primary hyperparathy- For all stone types, consistently diluted urine reduces the like-
roidism and gout. lihood of crystal formation. The urine volume should be at least
2 L/d. Because of differences in insensible fluid losses and fluid
LABORATORY EVALUATION intake from food sources, the required total fluid intake will vary
If not recently measured, the following serum levels should be from person to person. Rather than specify how much to drink, it is
determined: electrolytes (to uncover hypokalemia or renal tubular more helpful to educate patients about how much more they need to
acidosis), creatinine, calcium, and uric acid. The PTH level should be drink in light of their 24-h urine volume. For example, if the daily
measured if indicated by high-normal or elevated serum and urine urine volume is 1.5 L, then the patient should be advised to drink
calcium concentrations. Often, 25-hydroxy vitamin D is measured at least 0.5 L more per day in order to increase the urine volume to
in concert with PTH to investigate the possible role of secondarily the goal of 2 L/day.
elevated PTH levels in the setting of vitamin D insufficiency.
The urinalysis, including examination of the sediment, can pro-
vide useful information. In individuals with asymptomatic residual ■■RECOMMENDATIONS FOR SPECIFIC STONE TYPES
renal stones, red and white blood cells are frequently present in
Calcium Oxalate Risk factors for calcium oxalate stones include
urine. If there is concern about the possibility of an infection, a urine
higher urine calcium, higher urine oxalate, and lower urine citrate. This
culture should be performed. The sediment may also reveal crystals
stone type is insensitive to pH in the physiologic range.
(Fig. 312-1), which may help identify the stone type and also provide
Individuals with higher urine calcium excretion tend to absorb a
prognostic information, as crystalluria is a strong risk factor for new
higher percentage of ingested calcium. Nevertheless, dietary calcium
stone formation.
restriction is not beneficial and, in fact, is likely to be harmful (see

2172 “Dietary Risk Factors,” above). In a randomized trial in men with high consistent inverse association between the DASH diet and risk of stone
urine calcium and recurrent calcium oxalate stones, a diet containing formation.
1200 mg of calcium and a low intake of sodium and animal protein
significantly reduced subsequent stone formation from that with a Calcium Phosphate Calcium phosphate stones share risk factors
low-calcium diet (400 mg/d). Excessive calcium intake (>1200 mg/d) with calcium oxalate stones, including higher concentrations of urine
should be avoided. calcium and lower concentrations of urine citrate, but additional fac-
A thiazide diuretic, in doses higher than those used to treat hyper- tors deserve attention. Higher urine phosphate levels and higher urine
tension, can substantially lower urine calcium excretion. Several ran- pH (typically ≥6.5) are associated with an increased likelihood of cal-
domized controlled trials have demonstrated that thiazide diuretics, cium phosphate stone formation. Calcium phosphate stones are more
most commonly chlorthalidone, can reduce calcium oxalate stone common in patients with distal renal tubular acidosis and primary
recurrence by ~50%. When a thiazide is prescribed, dietary sodium hyperparathyroidism.
restriction is essential to obtain the desired reduction in urinary cal- There are no randomized trials on which to base preventive recom-
cium excretion and minimize urinary potassium losses. While bisphos- mendations for calcium phosphate stone formers, so the interventions
phonates may reduce urine calcium excretion in some individuals, are focused on modification of the recognized risk factors. Thiazide
there are no data on whether this class of medication can reduce stone diuretics (with sodium restriction) may be used to reduce urine cal-
formation; therefore, bisphosphonates cannot be recommended solely cium, as described above for calcium oxalate stones. In patients with
for stone prevention at present but they can be used to treat those indi- low urine citrate levels, alkali supplements (e.g., potassium citrate or
viduals with low bone density. bicarbonate) may be used to increase these concentrations. However,
A reduction in urine oxalate will in turn reduce the supersaturation the urine pH of these patients should be monitored initially because
of calcium oxalate. In patients with the common form of nephrolith- supplemental alkali can raise urine pH, thereby potentially increas-
iasis, avoiding high-dose vitamin C supplements is the only known ing the risk of stone formation. Because these patients tend to have a
strategy that reduces endogenous oxalate production. urinary acidification defect, reducing the urine pH is not an option.
Oxalate is a metabolic end product; therefore, any dietary oxalate Reduction of dietary phosphate may be beneficial by reducing urine
phosphate excretion.
PART 9
that is absorbed will be excreted in the urine. Reducing absorption

of exogenous oxalate involves two approaches. First, the avoidance
Uric Acid The two main risk factors for uric acid stones are per-
of foods that contain high amounts of oxalate, such as spinach, rhu-
sistently low urine pH and higher uric acid excretion. Urine pH is the
barb, almonds, and potatoes, is prudent. However, extreme oxalate
predominant influence on uric acid solubility; therefore, the mainstay
restriction has not been demonstrated to reduce stone recurrence and
of prevention of uric acid stone formation entails increasing urine
could be harmful to overall health, given other health benefits of many

pH. Alkalinizing the urine can be readily achieved by increasing the
foods that are erroneously considered to be high in oxalate. Contro-
intake of foods rich in alkali (e.g., fruits and vegetables) and reducing
versy exists regarding the most clinically relevant measure of the
the intake of foods that produce acid (e.g., animal flesh). If necessary,
oxalate content of foods (e.g., bioavailability). Notably, the absorption
supplementation with bicarbonate or citrate salts (preferably potas-
of oxalate is reduced by higher calcium intake; therefore, individuals
sium-based) can be used to reach the recommended pH goal of 6.5
with higher-than-desired urinary oxalate should be counseled to con-
throughout the day and night.
sume adequate calcium. Oxalate absorption can be influenced by the
Urine uric acid excretion is determined by uric acid generation. Uric
intestinal microbiota, depending on the presence of oxalate-degrading
acid is the end product of purine metabolism; thus, reduced consump-
bacteria. Currently, however, there are no available therapies to alter
tion of purine-containing foods can lower urine uric acid excretion. It is
the microbiota that beneficially affect urinary oxalate excretion over
noteworthy that the serum uric acid level is dependent on the fractional
the long term.
excretion of uric acid and therefore does not provide information on
Citrate is a natural inhibitor of calcium oxalate and calcium phos-
urine uric acid excretion. For example, an individual with high uric
phate stones. Higher-level consumption of foods rich in alkali (i.e.,
acid generation and concurrent high fractional excretion of uric acid
fruits and vegetables) can increase urine citrate. For patients with
will have high urine uric acid excretion with a normal (or even low)
lower urine citrate in whom dietary modification does not adequately
serum uric acid level. If alkalinization of the urine alone is not suc-
increase urine citrate, the addition of supplemental alkali (typically
cessful and if dietary modifications do not reduce urine uric acid suffi-
potassium citrate or bicarbonate) will lead to an increase in urinary
ciently, then the use of a xanthine oxidase inhibitor, such as allopurinol
citrate excretion. Sodium salts, such as sodium bicarbonate, while
or febuxostat, can reduce urine uric acid excretion by 40–50%.
successful in raising urine citrate, are typically avoided due to the
adverse effects of sodium on urine calcium excretion. Urine pH in the Cystine Cystine excretion is not easily modified. Long-term dietary
physiologic range does not influence calcium oxalate stone formation. cystine restriction is not feasible and is unlikely to be successful; thus
Past reports suggested that higher levels of urine uric acid may the focus for cystine stone prevention is on increasing cystine solubility.
increase the risk of calcium oxalate stones, but more recent studies This goal may be achieved by treatment with medication that cova-
do not support this association. However, allopurinol reduced stone lently binds to cystine (tiopronin or penicillamine) and a medication
recurrence in one randomized controlled trial in patients with calcium that raises urine pH. Tiopronin is the preferred choice due to its better
oxalate stones and high urine uric acid levels. The lack of association adverse event profile. The preferred alkalinizing agent to achieve a
between urine uric acid level and calcium oxalate stones suggests urine pH of 7.5 is potassium citrate or bicarbonate as sodium salts may
that a different mechanism underlies the observed beneficial effect of increase cystine excretion. As with all stone types, and especially in
allopurinol. patients with cystinuria, maintaining a high urine volume is an essen-
Additional dietary modifications may be beneficial in reducing stone tial component of the preventive regimen.
recurrence. Restriction of nondairy animal protein (e.g., meat, chicken,
seafood) is a reasonable approach and may result in higher excretion Struvite Struvite stones, also known as infection stones or
of citrate and lower excretion of calcium. In addition, reducing sodium triple-phosphate stones, form only when the upper urinary tract is
intake to <2.5 g/d may decrease urinary excretion of calcium. Sucrose infected with urease-producing bacteria such as Proteus mirabilis,
and fructose intake should be minimized. Klebsiella pneumoniae, or Providencia species. Urease produced by these
For adherence to a dietary pattern that is more manageable for bacteria hydrolyzes urea and may elevate the urine pH to a supraphys-
patients than manipulating individual nutrients, the DASH (Dietary iologic level (>8.0). Struvite stones may grow quickly and fill the renal
Approaches to Stop Hypertension) diet provides an appropriate and pelvis (staghorn calculi).
readily available option. Randomized trials have conclusively shown Struvite stones require complete removal by a urologist. New stone
the DASH diet to reduce blood pressure. At present, only data from formation can be avoided by the prevention of UTIs. In patients with
observational studies are available, but these demonstrate a strong and recurrent upper UTIs (e.g., some individuals with surgically altered

urinary drainage or spinal cord injury), the urease inhibitor acetohy- TABLE 313-1 Common Mechanical Causes of Urinary Tract 2173
droxamic acid can be considered; however, this agent should be used Obstruction
with caution because of potential side effects. URETER BLADDER OUTLET URETHRA
■■LONG-TERM FOLLOW-UP Congenital
In general, the preventive regimens described above do not cure the Ureteropelvic junction Bladder neck obstruction Posterior urethral
underlying pathophysiologic process. Thus these recommendations narrowing or obstruction Ureterocele valves
typically need to be followed for the patient’s lifetime, and it is essen- Ureterovesical junction Anterior urethral
tial to tailor recommendations in a way that is acceptable to the patient. narrowing or obstruction valves
and reflux Stricture
Because the memory of the acute stone event fades and patients often
return to old habits (e.g., insufficient fluid intake), long-term follow-up, Ureterocele Meatal stenosis
including repeat 24-h urine collections, is important to ensure that the Retrocaval ureter Phimosis
preventive regimen has been implemented and has resulted in the Acquired Intrinsic Defects
desired reduction in the risk of new stone formation. Calculi Benign prostatic hyperplasia Stricture
Follow-up imaging should be planned thoughtfully. Many patients Inflammation Cancer of prostate Tumor
with recurrent episodes of renal colic that lead to emergency room
Infection Cancer of bladder Calculi
visits often undergo repeat CT studies. While CT does provide the
Trauma Calculi Trauma
best information, the radiation dose is substantially higher than that
with plain abdominal radiography (KUB). Small stones may be missed Sloughed papillae Diabetic neuropathy Phimosis
by KUB, and ultrasound has a limited ability to determine size and Tumor Spinal cord disease
number of stones. Minimizing radiation exposure should be a goal of Blood clots Anticholinergic drugs and
the long-term follow-up plan and must be balanced against the gain in α-adrenergic antagonists
diagnostic information. Acquired Extrinsic Defects
CHAPTER 313 Urinary Tract Obstruction

Pregnant uterus Carcinoma of cervix, colon Trauma
■■FURTHER READING Retroperitoneal fibrosis
Pearle MS et al: Medical management of kidney stones: AUA guide-
Aortic aneurysm Trauma
line. J Urol 192:316, 2014.
Uterine leiomyomata
Prochaska ML et al: Insights into nephrolithiasis from the Nurses’
Health Studies. Am J Public Health 106:1638, 2016. Carcinoma of uterus,
prostate, bladder, colon,
rectum
Lymphoma
Pelvic inflammatory
313 Urinary Tract Obstruction

disease, endometriosis
Accidental surgical ligation
Julian L. Seifter
is severe and unlikely to improve spontaneously, if renal function dete-

Obstruction to the flow of urine, with attendant stasis and elevation riorates, or if urinary tract infections recur despite chronic antimicro-
in urinary tract pressure, impairs renal and urinary conduit functions bial therapy. Vesicoureteral reflux may cause prenatal hydronephrosis
and is a common cause of acute and chronic kidney disease (obstruc- and, if severe, can lead to recurrent urinary infections, hypertension
tive nephropathy). Early recognition and prompt treatment of urinary and renal scarring in childhood. Posterior urethral valves are the most
tract obstruction (UTO) can prevent or reverse devastating effects on common cause of bilateral hydronephrosis in boys. In adults, UTO is
kidney structure and function, and decrease susceptibility to hyperten- due mainly to acquired defects. Pelvic tumors, calculi, and urethral stric-
sion, infection, and stone formation. Chronic obstruction may lead to ture predominate. Ligation of, or injury to, the ureter during pelvic or
permanent loss of renal mass (renal atrophy) and excretory capability. colonic surgery can lead to hydronephrosis which, if unilateral, may
Since obstructive disease may be secondary to serious underlying remain undetected. Obstructive uropathy may also result from extrin-
inflammatory, vascular, or malignant disease, familiarity with clinical sic neoplastic (carcinoma of cervix or colon) or inflammatory disorders.
findings, appropriate diagnostic testing, and therapeutic approach is of Lymphomas and pelvic or colonic neoplasms with retroperitoneal
great importance to the clinician. involvement are causes of ureteral obstruction. As many as 50% of men
aged >40 years may have lower urinary tract symptoms associated
■■ETIOLOGY with benign prostatic hypertrophy, but these symptoms may occur
Obstruction to urine flow can result from intrinsic or extrinsic mechan- without bladder outlet obstruction.
ical blockade as well as from functional defects not associated with fixed Functional impairment of urine flow occurs when voiding is altered
occlusion of the urinary drainage system. Mechanical obstruction can by abnormal pontine or sacral centers of micturition control. It may be
occur at any level of the urinary tract, from within the renal tubules, or asymptomatic or associated with lower urinary tract symptoms such
the renal calyces to the external urethral meatus (obstructive uropathy). as frequency, urgency, and postmicturition incontinence, nocturia,
Normal points of narrowing, such as the ureteropelvic and ureterove- straining to void, slow stream, hesitancy, or a feeling of incomplete
sical junctions, bladder neck, and urethral meatus, are common sites emptying. A history should be sought for trauma, back injury, sur-
of obstruction. When lower UTO is above the level of the bladder, gery, diabetes, neurologic or psychiatric conditions, and medications.
unilateral dilatation of the ureter (hydroureter) and renal pyelocalyceal Causes include neurogenic bladder, often with adynamic ureter, and
system (hydronephrosis) occurs; lesions at or below the level of the blad- vesicoureteral reflux. Reflux in children may result in severe unilat-
der cause bilateral involvement. eral or bilateral hydroureter and hydronephrosis. Overflow urinary
Common forms of obstruction are listed in Table 313-1. Childhood incontinence combined with fecal incontinence may require an urgent
causes include congenital malformations, such as narrowing of the ure- evaluation for cauda equina syndrome. Urinary retention may be the
teropelvic junction (UPJ) and abnormal insertion of the ureter into the consequence of α-adrenergic and anticholinergic agents, as well as
bladder, the most common cause. Vesicoureteral reflux in the absence opiates. Hydronephrosis in pregnancy is due to relaxational effects of
of urinary tract infection or bladder neck obstruction often resolves progesterone on smooth muscle of the renal pelvis, as well as ureteral
with age. Reinsertion of the ureter into the bladder is indicated if reflux compression by the enlarged uterus, more often on the right side.

2174 Diagnostic tools to identify anatomic obstruction include urinary nephrolithiasis, hematuria, diabetes mellitus, prostatic enlargement,
flow measurements and a postvoid residual. Bladder volume may pelvic surgery, trauma, or tumor should be evaluated for UTO.
be readily assessed by bedside ultrasound. Cystourethroscopy and In the acute setting, partial, bilateral obstruction may mimic prerenal
urodynamic studies may be reserved for the symptomatic patient to azotemia with a high blood urea nitrogen-to-creatinine ratio, concen-
assess the filling phase (cystometry), pressure-volume relationship of trated urine and sodium retention. Renal vascular resistance may be
the bladder, bladder compliance, and capacity. Pressure-flow analysis increased. However, with more prolonged obstruction, symptoms of
evaluates bladder contractility and bladder outlet resistance during polyuria and nocturia commonly accompany partial UTO and result
voiding. Bladder obstruction is characterized by high pressures in from loss of medullary hypertonicity with diminished renal concen-
women, whereas in men, a diagnosis of bladder outlet obstruction is trating ability. Failure to produce urine free of salt (natriuresis) is due
based on flow rate and voiding pressures. A voiding cystourethrogram to downregulation of salt reabsorption in the proximal tubule and of
may be useful in evaluating incomplete emptying and bladder neck transport proteins including the Na+, K+ adenosine triphosphatase
and urethral pathology. (ATPase), NaK2Cl cotransporter (NaK2Cl) in the thick ascending limb,
and the epithelial Na+ channel (ENaC) in collecting duct cells. In addi-
■■CLINICAL FEATURES AND PATHOPHYSIOLOGY tion to direct effects on renal transport mechanisms, increased pros-
The pathophysiology and clinical features of UTO are summarized in taglandin E2 (PGE2) (due to induction of cyclooxygenase-2 [COX-2]),
Table 313-2. Flank pain, the symptom that most commonly leads to angiotensin II (with its downregulation of Na+ transporters), and atrial
medical attention, is due to distention of the collecting system or renal or B-type natriuretic peptides (ANP or BNP) (due to volume expansion
capsule. Pain severity is influenced more by the rate at which disten- in the azotemic patient) contribute to decreased salt reabsorption along
tion develops than by the degree of distention. Acute supravesical the nephron.
obstruction, as from a stone lodged in a ureter (Chap. 312), is associated Dysregulation of aquaporin-2 water channels in the collecting duct
with excruciating, sometimes intermittent, pain, known as renal colic. contributes to the polyuria. The defect usually does not improve with
This pain often radiates to the lower abdomen, testes, or labia. By con- administration of vasopressin and is therefore a form of acquired neph-
trast, more insidious causes of obstruction, such as chronic narrowing rogenic diabetes insipidus.
of the UPJ, may produce little or no pain and yet result in total destruc-
PART 9
Wide fluctuations in urine output in a patient with azotemia should

tion of the affected kidney. Flank pain that occurs only with micturition always raise the possibility of intermittent or partial UTO. If fluid
is pathognomonic of vesicoureteral reflux. intake is inadequate, severe dehydration and hypernatremia may
Obstruction of urine flow results in an increase in hydrostatic pres- develop. However, as with other causes of poor renal function, excesses
sures proximal to the site of obstruction. It is this buildup of pressure of salt and water intake may result in edema and hyponatremia.
that leads to the accompanying pain, the distention of the collecting Partial bilateral UTO often results in acquired distal renal tubular aci-
system in the kidney, and elevated intratubular pressures that initiate dosis, hyperkalemia, and renal salt wasting. The H+-ATPase, situated on
tubular dysfunction. In the first days of obstruction, the dilatation the apical membrane of the intercalated cells of the collecting duct, is
of the poorly compliant collecting system may be minimal. As the critical for distal H+ secretion. The trafficking of intracellular H+ pumps
increased hydrostatic pressure is expressed in the urinary space of the from the cytoplasm to the cell membrane is disrupted in UTO. The
glomeruli, further filtration decreases or stops completely. decreased function of the ENaC, in the apical membrane of neighbor-
Azotemia develops when overall excretory function is impaired, ing collecting duct principal cells, contributes to decreased Na+ reab-
often in the setting of bladder outlet obstruction, bilateral renal pel- sorption (salt-wasting), and, therefore, decreased K+ secretion via K+
vic or ureteric obstruction, or unilateral disease in a patient with a channels. Ammonium (NH4 +) excretion important to the elimination of
solitary functioning kidney. Complete bilateral obstruction should be H+ is impaired. These defects in tubule function are often accompanied
suspected when acute renal failure is accompanied by anuria. Any by renal tubulointerstitial damage. Azotemia with hyperkalemia and
patient with renal failure otherwise unexplained, or with a history of metabolic acidosis should prompt consideration of UTO.
The renal interstitium becomes edematous and infiltrated with
mononuclear inflammatory cells early in UTO. Later, interstitial fibro-
TABLE 313-2 Pathophysiology of Bilateral Ureteral Obstruction sis and atrophy of the papillae and medulla occur and precede these
HEMODYNAMIC processes in the cortex. The increase in angiotensin II noted in UTO
EFFECTS TUBULE EFFECTS CLINICAL FEATURES contributes to the inflammatory response and fibroblast accumulation
Acute through mechanisms involving profibrotic cytokines. With time, this
process leads to chronic kidney damage.
↑ Renal blood flow ↑ Ureteral and tubule Pain (capsule distention)
pressures Azotemia UTO must always be considered in patients with urinary tract
↓ GFR
Oliguria or anuria infections or urolithiasis. Urinary stasis encourages the growth of
↓ Medullary blood flow ↑ Reabsorption of Na+,
urea, water organisms. Urea-splitting bacteria are associated with magnesium
↑ Vasodilator ammonium phosphate (struvite) calculi that may take on a staghorn
prostaglandins, nitric
appearance. Hypertension is frequent in acute and subacute unilateral
oxide
obstruction and is usually a consequence of increased release of renin
Chronic by the involved kidney. Chronic kidney disease from bilateral UTO,
↓ Renal blood flow ↓ Medullary osmolarity Azotemia often associated with extracellular volume expansion, may result in
↓↓ GFR ↓ Concentrating ability Hypertension significant hypertension. Erythrocytosis, an infrequent complication
AVP-insensitive polyuria
↑ Vasoconstrictor Structural damage; Natriuresis
of obstructive uropathy, is secondary to increased erythropoietin
prostaglandins parenchymal atrophy Hyperkalemic, production.
↑ Renin-angiotensin ↓ Transport functions for hyperchloremic acidosis
production Na+, K+, H+ ■■DIAGNOSIS
Release of Obstruction A history of difficulty in voiding, pain, infection, or change in urinary
Slow ↑ in GFR (variable) ↓ Tubule pressure Postobstructive diuresis volume is common. Evidence for distention of the kidney or urinary
↑ Solute load per Potential for volume bladder can often be obtained by palpation and percussion of the abdo-
nephron (urea, NaCl) depletion and electrolyte men. A careful rectal and genital examination may reveal enlargement
Natriuretic factors imbalance due to losses or nodularity of the prostate, abnormal rectal sphincter tone, or a rectal
present of Na+, K+, PO42–, Mg2+, or pelvic mass.
and water Urinalysis may reveal hematuria, pyuria, and bacteriuria. The urine
Abbreviations: AVP, arginine vasopressin; GFR, glomerular filtration rate. sediment is often normal, even when obstruction leads to marked

2175
ALGORITHM OF THE DIAGNOSTIC APPROACH FOR
URINARY TRACT OBSTRUCTION IN UNEXPLAINED RENAL FAILURE
Unexplained renal failure
Insert bladder catheter
No diuresis: do
Diuresis
ultrasound
Obstruction below No
Hydronephrosis
bladder neck hydronephrosis
Do CT scan to identify
Urologic site and etiology of High suspicion Low suspicion
evaluation obstruction
Positive or negative No further workup

Negative
but still high suspicion for obstruction
CHAPTER 313 Urinary Tract Obstruction

Retrograde urography Antegrade urography
and ureteral stent and percutaneous
considered nephrostomy considered
FIGURE 313-1 Diagnostic approach for urinary tract obstruction in unexplained renal failure. CT, computed tomography.
azotemia and extensive structural damage. An abdominal scout film, whereas the antegrade technique necessitates percutaneous placement
although insensitive, may detect nephrocalcinosis or a radiopaque of a catheter into the renal pelvis. Although the antegrade approach
stone. As indicated in Fig. 313-1, if UTO is suspected, a bladder may provide immediate decompression of a unilateral obstructing
catheter should be inserted. Abdominal ultrasonography should be lesion, many urologists initially attempt the retrograde approach
performed to evaluate renal and bladder size, as well as pyelocalyceal unless the catheterization is unsuccessful.
contour. Ultrasonography is ~90% specific and sensitive for detection Voiding cystourethrography is of value in the diagnosis of
of hydronephrosis. False-positive results are associated with diuresis, vesicoureteral reflux and bladder neck and urethral obstructions.
renal cysts, or the presence of an extrarenal pelvis, a normal congenital Postvoiding films reveal residual urine. Endoscopic visualization by
variant. Congenital UPJ obstruction may be mistaken for renal cystic the urologist often permits precise identification of lesions involving
disease. Hydronephrosis may be absent on ultrasound when obstruc- the urethra, prostate, bladder, and ureteral orifices.
tion is less than 48 h in duration or associated with volume contraction,
staghorn calculi, retroperitoneal fibrosis, or infiltrative renal disease.
Duplex Doppler ultrasonography may detect an increased resistive TREATMENT
index in urinary obstruction.
Recent advances in technology have led to alternatives and have
Urinary Tract Obstruction
largely replaced the once standard intravenous urogram in the further UTO complicated by infection requires immediate relief of obstruc-
evaluation of UTO. The high-resolution multidetector row computed tion to prevent development of generalized sepsis and progressive
tomography (CT) scan in particular has advantages of visualizing the renal damage. Sepsis necessitates prompt urologic intervention.
retroperitoneum, as well as identifying both intrinsic and extrinsic Drainage may be achieved by nephrostomy, ureterostomy, or ure-
sites of obstruction. Noncontrast CT scans improve visualization of teral, urethral, or suprapubic catheterization. Prolonged antibiotic
the urinary tract in the patient with renal impairment and are safer for treatment may be necessary. Chronic or recurrent infections in a
patients at risk for contrast nephropathy. Magnetic resonance urography poorly functioning obstructed kidney may necessitate nephrectomy.
is a promising technique but, at this time, not superior to the CT scan When infection is not present, surgery is often delayed until acid-
and carries the risk of certain gadolinium agents in patients with renal base, fluid, and electrolyte status is restored. Nevertheless, the site
insufficiency. CT scanning may define the site of obstruction, identify of obstruction should be ascertained as soon as feasible. Elective
and characterize kidney stones, and demonstrate dilatation of the relief of obstruction is usually recommended in patients with uri-
calyces, renal pelvis, and ureter above the obstruction. The ureter may nary retention, recurrent urinary tract infections, persistent pain, or
be tortuous in chronic obstruction. Radionuclide scans are able to give progressive loss of renal function. Benign prostatic hypertrophy may
differential renal function but give less anatomic detail than CT scans. be treated medically with α-adrenergic blockers and 5α-reductase
Furosemide is sometimes given to increase detection with imaging, inhibitors. Renal colic may be treated with anti-inflammatory med-
and to distinguish functional from anatomic obstruction. The increase ication as edema often contributes to an obstructing ureteral stone,
in urinary flow may bring out the pain of an acute obstructive process. and α-adrenergic blockers may also be of benefit. Use of opiates
To facilitate visualization of a suspected lesion in a ureter or renal in patients with decreased renal function may be dangerous and
pelvis, retrograde or antegrade urography should be attempted. These should be used with caution. Functional obstruction secondary to
procedures do not carry risk of contrast-induced acute kidney injury neurogenic bladder may be decreased with the combination of fre-
in patients with renal insufficiency. The retrograde approach involves quent voiding and cholinergic drugs.
catheterization of the involved ureter under cystoscopic control,

2176 ■■PROGNOSIS responsible for, or sustains, the diuresis observed in the postobstructive
With relief of obstruction, the prognosis regarding return of renal period. Replacement with intravenous fluids in amounts less than uri-
function depends largely on whether irreversible renal damage has nary losses usually prevents this complication. More aggressive fluid
occurred. When obstruction is not relieved, the course will depend management is required in the setting of hypovolemia, hypotension, or
mainly on whether the obstruction is complete or incomplete and disturbances in serum electrolyte concentrations.
bilateral or unilateral, as well as whether or not urinary tract infection The loss of electrolyte-free water with urea may result in hyper-
is also present. Complete obstruction with infection can lead to total natremia. Measured urinary output and serum and urine sodium,
destruction of the kidney within days. Partial return of glomerular fil- potassium and osmolal concentrations should guide the use of appro-
tration rate may follow relief of complete obstruction of 1 and 2 weeks’ priate intravenous replacement. Often replacement with 0.45% saline
duration, but after 8 weeks of obstruction, recovery is unlikely. In the is required. Relief of obstruction may be followed by urinary salt and
absence of definitive evidence of irreversibility, every effort should water losses severe enough to provoke profound dehydration and vas-
be made to decompress the obstruction in the hope of restoring renal cular collapse. In these patients, decreased tubule reabsorptive capacity
function at least partially. A renal radionuclide scan, performed after a is probably responsible for the marked diuresis. Appropriate therapy
prolonged period of decompression, may be used to predict the revers- in such patients includes intravenous administration of salt-containing
ibility of renal dysfunction. solutions to replace sodium and volume deficits.
■■POSTOBSTRUCTIVE DIURESIS
Relief of bilateral, but not unilateral, complete obstruction commonly ■■FURTHER READING
results in polyuria, which may be massive. The urine is usually hypo- Frokiaer J, Zeidel ML: Urinary tract obstruction, in Brenner and
tonic and may contain large amounts of sodium chloride, potassium, Rector’s The Kidney, 10th ed, BM Brenner (ed). Philadelphia, Saunders,
phosphate, and magnesium. The natriuresis is due in part to the correc- 2015, pp 1257–1282.
tion of extracellular volume expansion, the increase in natriuretic fac- Meldrum KK: Pathophysiology of urinary tract obstruction, in
tors accumulated during the period of renal failure, and depressed salt Campbell-Walsh Urology, 11th ed, AJ Wein et al (eds). Philadelphia,
and water reabsorption when urine flow is reestablished. The retained Elsevier; 2016, pp 1089–1103.
PART 9
urea is excreted with improved GFR, resulting in an osmotic diuresis Smith-Bindman R et al: Ultrasonography versus computed tomogra-
which increases the urine volume of electrolyte-free water. The urinary phy for suspected nephrolithiasis. N Engl J Med 371:1100, 2014.
concentrations of sodium and potassium that when added are less than Stoller ML: Urinary obstruction & stasis, in Smith and Tanagho’s
the serum sodium is evidence of electrolyte free-water excretion. In the General Urology, 18th ed, JW McAninch, TF Lue (eds). New York,
majority of patients, this diuresis results in the appropriate excretion McGraw-Hill, 2013, pp. 170–182.
of the excesses of retained salt and water. When extracellular volume Tanagho EA, Nguyen HT: Vesicoureteral reflux, in Smith and
and composition return to normal, the diuresis usually abates sponta- Tanagho’s General Urology, 18th ed, WJ McAninch, TF Lue (eds).
neously. Occasionally, iatrogenic expansion of extracellular volume is New York, McGraw-Hill, 2013, pp. 182–197.

Disorders of the Gastrointestinal System PART 10
modulation of immune and physiologic activity. Transit in the esopha-
Section 1 Disorders of the Alimentary Tract gus takes seconds and times in the stomach and small intestine range
from minutes to a few hours, but colon propagation requires more than
1 day in most individuals. Colon contractions exhibit a to-and-fro char-
314 Approach to the Patient acter that promotes fecal desiccation. The proximal colon mixes and
absorbs fluid, while the distal colon exhibits peristaltic contractions and
with Gastrointestinal Disease mass movements to expel the stool. The colon terminates in the anus,
which possesses volitional and involuntary controls to permit fecal
William L. Hasler, Chung Owyang retention until it can be released in a convenient setting.
EXTRINSIC MODULATION OF GUT

ANATOMIC CONSIDERATIONS FUNCTION
The gastrointestinal (GI) tract extends from the mouth to the anus GI function is modified by influences outside the gut. Unlike other
and is composed of several organs with distinct functions. Special- organs, the gut is in continuity with the outside environment. Protective
ized sphincters that assist in gut compartmentalization separate the mechanisms are vigilant against damage from foods, medications, tox-
organs. The gut wall is organized into distinct layers that contribute to ins, and infectious organisms. Mucosal immune mechanisms include
regional activities. The mucosa is a barrier to luminal contents or a site epithelial and lamina propria lymphocyte and plasma cell populations
for fluid and nutrient transfer. Gut smooth muscle in association with supported by lymph node chains to prevent noxious agents from
the enteric nervous system mediates propulsion from one region to the entering the circulation. Antimicrobial peptides secreted by intestinal
next. Many GI organs possess a serosal layer that provides a supportive Paneth cells also defend against luminal pathogens. All drugs and
foundation and permits external input. toxins absorbed into the bloodstream are filtered and detoxified in the
Interactions with other systems serve the needs of the gut and the liver via the portal venous circulation. Although intrinsic nerves con-
body. Pancreaticobiliary conduits deliver bile and enzymes into the trol most basic gut activities, extrinsic neural input modulates many
duodenum. The vascular supply is modulated by GI activity. Lym- functions. Many GI reflexes involve extrinsic vagus or splanchnic nerve
phatic channels assist in gut immune activities. Intrinsic nerves provide pathways. The brain-gut axis alters function in regions not under voli-
the controls for propulsion and fluid regulation. Extrinsic neural input tional regulation. As an example, stress has potent effects on gut motor,
provides volitional or involuntary control that is specific for each gut secretory, and sensory functions.
region.
OVERVIEW OF GI DISEASES
FUNCTIONS OF THE GI TRACT GI diseases develop as a result of abnormalities within or outside of the
The GI tract serves two main functions—assimilating nutrients and gut and range in severity from those that produce mild symptoms and
eliminating waste. In the mouth, food is processed, mixed with salivary no long-term morbidity to those with intractable symptoms or adverse
amylase, and delivered to the gut lumen. The esophagus propels the outcomes. Diseases may be localized to one organ or exhibit diffuse
bolus into the stomach; the lower esophageal sphincter prevents oral involvement at many sites.
reflux of gastric contents. The squamous esophageal mucosa protects
against significant diffusion or absorption. Aboral esophageal contrac- ■■CLASSIFICATION OF GI DISEASES
tions coordinate with relaxation of the upper and lower esophageal GI diseases are manifestations of alterations in nutrient assimilation or
sphincters on swallowing. waste evacuation or in the activities supporting these main functions.
The stomach triturates and mixes the food bolus with pepsin and
Impaired Digestion and Absorption Diseases of the stom-
acid. Gastric acid also sterilizes the upper gut. The proximal stomach
ach, intestine, biliary tree, and pancreas can disrupt digestion and
serves a storage function by relaxing to accommodate the meal. Phasic
absorption. The most common intestinal maldigestion syndrome,
contractions in the distal stomach propel food residue against the pylo-
lactase deficiency, produces gas and diarrhea after ingestion of dairy
rus, where it is ground and thrust proximally for further mixing before
products and has no adverse outcomes. Other intestinal enzyme
it is emptied into the duodenum. The stomach secretes intrinsic factor
deficiencies produce similar symptoms after ingestion of other simple
for vitamin B12 absorption.
sugars. Conversely, celiac disease, bacterial overgrowth, infectious
Most nutrient absorption occurs in the small intestine. The intes-
enteritis, Crohn’s ileitis, and radiation damage, which affect digestion
tinal mucosal villus architecture provides maximal surface area for
and/or absorption more diffusely, produce anemia, dehydration, elec-
absorption and is endowed with specialized enzymes and transporters.
trolyte disorders, or malnutrition. Gastric hypersecretory conditions
Triturated food from the stomach mixes with pancreatic juice and bile
such as Zollinger-Ellison syndrome damage the intestinal mucosa,
in the duodenum. Pancreatic juice contains enzymes for carbohydrate,
impair pancreatic enzyme activation, and accelerate transit due to
protein, and fat digestion as well as bicarbonate to optimize the pH for
excess gastric acid. Biliary obstruction from stricture or neoplasm
enzyme activation. Bile secreted by the liver and stored in the gallblad-
impairs fat digestion. Impaired pancreatic enzyme release in chronic
der is essential for lipid digestion. The proximal intestine is optimized
pancreatitis or pancreatic cancer decreases intraluminal digestion and
for rapid absorption of most nutrients and minerals, whereas the ileum
can lead to malnutrition.
is better suited for absorbing vitamin B12 and bile acids. Bile contains
by-products of erythrocyte degradation, toxins, medications, and cho- Altered Secretion Selected GI diseases result from dysregulation
lesterol for fecal evacuation. Small intestinal motor function delivers of gut secretion. Gastric acid hypersecretion occurs in Zollinger-Ellison
indigestible residue into the colon for processing. The ileocecal junction syndrome, G cell hyperplasia, retained antrum syndrome, and some
is a sphincteric structure that prevents coloileal reflux, maintaining individuals with duodenal ulcers. Conversely, patients with atrophic
small-intestinal sterility. gastritis or pernicious anemia release little or no gastric acid. Inflam-
The colon prepares waste for evacuation. The colonic mucosa dehy- matory and infectious small-intestinal and colonic diseases produce
drates the stool, decreasing daily volumes of 1000–1500 mL in the ileum fluid loss through impaired absorption or enhanced secretion. Common
to 100–200 mL expelled from the rectum. The colon possesses a dense intestinal and colonic hypersecretory conditions cause diarrhea and
bacterial colonization that ferments undigested carbohydrates and include acute bacterial or viral infection, chronic Giardia or cryptospo-
short-chain fatty acids. Additional roles for the gut microbiome include ridia infections, small-intestinal bacterial overgrowth, bile salt diarrhea,

2178 microscopic colitis, diabetic diarrhea, and abuse of certain laxatives. arteries. More commonly encountered are intestinal and colonic
Less common causes include large colonic villus adenomas and endo- ischemia that are consequences of arterial embolus, arterial thrombo-
crine neoplasias with tumor overproduction of secretagogue transmit- sis, venous thrombosis, or hypoperfusion from dehydration, sepsis,
ters like vasoactive intestinal polypeptide. hemorrhage, or reduced cardiac output. These may produce mucosal
injury, hemorrhage, or even perforation. Chronic ischemia may result
Altered Gut Transit Impaired gut transit may be secondary to in intestinal stricture. Some cases of radiation enterocolitis exhibit
mechanical obstruction. Esophageal occlusion most often results from reduced mucosal blood flow.
stricture (due to acid exposure or eosinophilic esophagitis) or neo-
plasm. Gastric outlet obstruction develops from peptic ulcer disease Neoplastic Degeneration All GI regions are susceptible to
or gastric cancer. Small-intestinal obstruction most commonly results malignant degeneration to varying degrees. In the United States, col-
from adhesions but may also occur with Crohn’s disease, radiation- or orectal cancer is most common and usually presents after age 50 years.
drug-induced strictures, and less likely malignancy. The most common Worldwide, gastric cancer is prevalent especially in certain Asian
cause of colonic obstruction is colon cancer, although inflammatory regions. Esophageal cancer develops with chronic acid reflux or after
strictures develop in patients with inflammatory bowel disease (IBD), an extensive alcohol or tobacco use history. Small-intestinal neoplasms
after certain infections such as diverticulitis, or with some drugs. are rare and occur with underlying inflammatory disease. Anal cancers
Retardation of propulsion also develops from disordered motor arise after prior anal infection or inflammation. Pancreatic and biliary
function. Achalasia is characterized by impaired esophageal body cancers elicit severe pain, weight loss, and jaundice and have poor
peristalsis and incomplete lower esophageal sphincter relaxation. prognoses. Hepatocellular carcinoma usually arises in the setting of
Gastroparesis is the symptomatic delay in gastric emptying of meals chronic viral hepatitis or cirrhosis secondary to other causes. Most GI
due to impaired gastric motility. Intestinal pseudoobstruction causes cancers exhibit carcinomatous histology; however, lymphomas and
marked delays in small-bowel transit due to enteric nerve or intestinal other cell types also are observed.
smooth-muscle injury. Slow-transit constipation is produced by dif-
Disorders without Obvious Organic Abnormalities The
fusely impaired colonic propulsion. Constipation also is produced by
most common GI disorders show no abnormalities on biochemical or
outlet abnormalities such as rectal prolapse, intussusception, or dys-
structural testing and include IBS, functional dyspepsia, and functional
synergia—a failure of anal or puborectalis relaxation upon attempted
heartburn. These disorders exhibit altered gut motor function; however,
defecation.
the pathogenic relevance of these abnormalities is uncertain. Exag-
Disorders of rapid propulsion are less common than those with
gerated visceral sensory responses to noxious stimulation may cause
delayed transit. Rapid gastric emptying occurs in postvagotomy
discomfort in these disorders. Symptoms in other patients result from
dumping syndrome, with gastric hypersecretion, and in some cases
altered processing of visceral pain sensations in the central nervous
of functional dyspepsia and cyclic vomiting syndrome. Exaggerated
PART 10
system. Functional bowel patients with severe symptoms may exhibit

intestinal or colonic motor patterns may be responsible for diarrhea in
significant emotional disturbances on psychometric testing. Subtle
irritable bowel syndrome (IBS). Accelerated transit with hyperdefeca-
immunologic defects may contribute to functional symptoms as well.
tion is noted in hyperthyroidism.
Genetic Influences Although many GI diseases result from
Immune Dysregulation Many inflammatory GI conditions are
Disorders of the Gastrointestinal System
environmental factors, others exhibit hereditary components. Family

consequences of altered gut immune function. The mucosal inflamma-
members of IBD patients show a genetic predisposition to disease
tion of celiac disease results from dietary ingestion of gluten-containing
development themselves. Colonic, esophageal, and pancreatic malig-
grains. Some patients with food allergy also exhibit altered immune
nancies arise in certain inherited disorders. Rare genetic dysmotility
populations. Eosinophilic esophagitis and eosinophilic gastroenteritis
syndromes are described. Familial clustering is observed in the func-
are inflammatory disorders with prominent mucosal eosinophils.
tional bowel disorders, although this may be secondary learned famil-
Ulcerative colitis and Crohn’s disease are disorders of uncertain etiol-
ial illness behavior rather than a true hereditary factor.
ogy that produce mucosal injury primarily in the lower gut. The micro-
scopic colitides, lymphocytic and collagenous colitis, exhibit colonic ■■SYMPTOMS OF GI DISEASE
subepithelial infiltrates without visible mucosal damage. Bacterial, Symptoms of GI disease include abdominal pain, heartburn, nausea
viral, and protozoal organisms may produce ileitis or colitis in selected and vomiting, altered bowel habits, GI bleeding, jaundice, and other
patient populations. Furthermore, alterations in the gut microbiome manifestations (Table 314-1).
(termed dysbiosis) are postulated to trigger flares of IBD, celiac disease,
and IBS. Abdominal Pain Abdominal pain results from GI disease and
extra-intestinal conditions involving the genitourinary tract, abdomi-
Impaired Gut Blood Flow Different GI regions are at variable nal wall, thorax, or spine. Visceral pain generally is midline in location
risk for ischemic damage from impaired blood flow. Rare cases of gas- and vague in character, whereas parietal pain is localized and pre-
troparesis result from blockage of the celiac and superior mesenteric cisely described. Painful inflammatory diseases include peptic ulcer,
TABLE 314-1 Common Causes of Common Gastrointestinal (GI) Symptoms

ABDOMINAL PAIN NAUSEA AND VOMITING DIARRHEA GI BLEEDING OBSTRUCTIVE JAUNDICE
Appendicitis Medications Infection Ulcer disease Bile duct stones
Gallstone disease GI obstruction Poorly absorbed sugars Esophagitis Cholangiocarcinoma
Pancreatitis Motor disorders Inflammatory bowel disease Varices Cholangitis
Diverticulitis Functional bowel disorder Microscopic colitis Vascular lesions Sclerosing cholangitis
Ulcer disease Enteric infection Functional bowel disorder Neoplasm Ampullary stenosis
Esophagitis Pregnancy Celiac disease Diverticula Ampullary carcinoma
GI obstruction Endocrine disease Pancreatic insufficiency Hemorrhoids Pancreatitis
Inflammatory bowel disease Motion sickness Hyperthyroidism Fissures Pancreatic tumor
Functional bowel disorder Central nervous system disease Ischemia Inflammatory bowel disease
Vascular disease Endocrine tumor Infectious colitis
Gynecologic causes
Renal stone

appendicitis, diverticulitis, IBD, pancreatitis, cholecystitis, and infec- symptom profiles are used to confidently diagnose a functional bowel 2179
tious enterocolitis. Noninflammatory visceral sources include biliary disorder.
colic, mesenteric ischemia, and neoplasia. The most common causes of
abdominal pain are IBS and functional dyspepsia. ■■HISTORY
The history in suspected GI disease has several components. Symptom
Heartburn Heartburn, a burning substernal sensation, is reported timing, patterns, and duration suggest specific etiologies. Short dura-
intermittently by 40% of the population. Classically, heartburn results
tion symptoms commonly result from acute infection or inflammation,
from excess gastroesophageal acid reflux, but some cases exhibit nor-
toxin exposure, or ischemia. Long-standing symptoms point to chronic
mal esophageal acid exposure and are caused by reflux of nonacidic
inflammation, neoplasia, or functional bowel disorders. Symptoms
material or heightened sensitivity of esophageal nerves.
from mechanical obstruction, ischemia, IBD, and functional bowel dis-
Nausea and Vomiting Nausea and vomiting are caused by GI orders are worsened by meals, while ulcer symptoms may be relieved
diseases, medications, toxins, infection, endocrine disorders, laby- by eating or antacids. Ulcer pain occurs intermittently over weeks to
rinthine conditions, and central nervous system disease. Mechanical months, whereas biliary colic has a sudden onset and lasts up to several
obstructions of the upper gut are commonly excluded as causes of hours. Acute pancreatitis pain is severe and persists for days to weeks.
chronic nausea and vomiting, but disorders of propulsion including Meals elicit diarrhea while defecation relieves discomfort in some
gastroparesis and intestinal pseudoobstruction elicit similar symptoms. cases of IBD and IBS. Functional bowel disorders are exacerbated by
Nausea and vomiting also are commonly reported by patients with IBS stress. Sudden awakening from sound sleep by pain suggests organic
and functional disorders of the upper gut (including chronic nausea rather than functional disease. Diarrhea from malabsorption usually
vomiting syndrome and cyclic vomiting syndrome). improves with fasting, whereas secretory diarrhea persists without
oral intake.
Altered Bowel Habits Altered bowel habits are common com- Symptom relation to other factors narrows the list of diagnostic
plaints of patients with GI disease. Constipation may be reported as
possibilities. Obstructive symptoms with prior abdominal surgery
infrequent defecation, straining with defecation, passage of hard stools,
raise concern for adhesions. Loose stools after gastrectomy or chole-
or a sense of incomplete fecal evacuation and is caused by obstruction,
cystectomy suggest dumping syndrome or postcholecystectomy diar-
colonic motor disorders, medications, and endocrine diseases like
rhea. Symptom onset after travel prompts consideration of infection.
hypothyroidism and hyperparathyroidism. Diarrhea may be reported
Medications produce pain, altered bowel habits, or GI bleeding. Celiac
as frequent defecation, passage of loose or watery stools, fecal urgency,
disease is prevalent in people of northern European descent, whereas
or a similar sense of incomplete evacuation. The differential diagnosis
IBD is more common in Jewish populations. A sexual history may raise
of diarrhea includes infections, inflammatory causes, malabsorption,
CHAPTER 314 Approach to the Patient with Gastrointestinal Disease

concern for infection or immunodeficiency.
and medications. IBS produces constipation, diarrhea, or an alternating
For nearly 40 years, working groups have devised symptom criteria
bowel pattern. Fecal mucus is common in IBS, whereas pus and blood
to improve diagnosis of functional bowel disorders and to minimize
characterize IBD. Steatorrhea develops with malabsorption.
the numbers of unnecessary diagnostic tests performed. The best
GI Bleeding Hemorrhage may develop from any gut organ. accepted symptom-based criteria are the Rome criteria. However,
Upper GI bleeding presents with melena or hematemesis, whereas when tested against findings of structural investigations in IBS and
lower GI bleeding produces passage of bright red or maroon stools. functional dyspepsia, the Rome criteria exhibit sensitivities and spec-
However, briskly bleeding upper sites can elicit voluminous red rectal ificities of only 55–75% indicating the need for careful test selection in
bleeding, whereas slowly bleeding ascending colon sites may produce patients at high risk of organic disease.
melena. Chronic occult GI bleeding may present with iron deficiency
anemia. Causes of upper GI bleeding include ulcer disease, gastro- ■■PHYSICAL EXAMINATION
duodenitis, esophagitis, portal hypertensive etiologies, malignancy, The physical examination complements information from the his-
tears across the gastroesophageal junction, and vascular lesions. Lower tory. Abnormal vital signs provide diagnostic clues and determine
GI sources of hemorrhage include hemorrhoids, anal fissures, diver- the need for acute intervention. Fever suggests inflammation or
ticula, ischemic colitis, neoplasm, IBD, infectious colitis, drug-induced neoplasm. Orthostasis is produced by significant blood loss, dehy-
colitis, arteriovenous malformations, and other vascular lesions. dration, sepsis, or autonomic neuropathy. Skin, eye, or joint findings
may point to specific diagnoses. Neck examination with swallowing
Jaundice Jaundice results from prehepatic, intrahepatic, or post- assessment evaluates dysphagia. Lung and cardiac examinations
hepatic disease. Posthepatic causes of jaundice include biliary diseases, evaluate for cardiopulmonary disease as causes of abdominal pain or
like choledocholithiasis, acute cholangitis, primary sclerosing cholangi- nausea. Pelvic examination tests for a gynecologic source of abdom-
tis, other strictures, and neoplasm, and pancreatic disorders, like acute inal pain. Rectal examination may detect blood, indicating mucosal
and chronic pancreatitis, stricture, and malignancy. injury or neoplasm or a palpable inflammatory mass in appendici-
Other Symptoms Other symptoms are manifestations of GI dis- tis. Metabolic conditions and gut motor disorders have associated
ease. Dysphagia, odynophagia, and unexplained chest pain suggest peripheral neuropathy.
esophageal disease. A globus sensation is reported with esophagophar- Abdominal inspection may reveal distention from obstruction,
yngeal conditions, but also occurs with functional GI disorders. Weight tumor, or ascites or vascular abnormalities with liver disease. Ecchy-
loss, anorexia, and fatigue present with neoplastic, inflammatory, motil- moses develop with severe pancreatitis. Auscultation detects bruits or
ity, pancreatic, and psychiatric conditions. IBD is associated with hepa- friction rubs from vascular disease or hepatic tumors. Loss of bowel
tobiliary dysfunction, skin and eye lesions, and arthritis. Celiac disease sounds signifies ileus, whereas high-pitched, hyperactive sounds
may present with dermatitis herpetiformis. Jaundice can produce characterize intestinal obstruction. Percussion assesses liver size and
pruritus. Conversely, systemic diseases have GI consequences. Systemic detects shifting dullness from ascites. Palpation assesses for hepato-
lupus may cause gut ischemia, presenting with pain or bleeding. Severe splenomegaly and neoplastic or inflammatory masses. Intestinal ische-
burns may lead to gastric ulcer formation. mia elicits severe pain but little tenderness. Patients with visceral pain
may exhibit generalized discomfort, whereas those with parietal pain
or peritonitis have localized pain with involuntary guarding, rigidity,
EVALUATION OF THE PATIENT WITH or rebound. Patients with musculoskeletal abdominal wall pain may
GI DISEASE note tenderness exacerbated by Valsalva or leg lift maneuvers.
Evaluation of the patient with suspected GI disease begins with a careful
history and examination. Subsequent investigation with tools to test gut ■■TOOLS FOR PATIENT EVALUATION
structure or function and luminal constituents are indicated in selected Laboratory, radiographic, and functional tests assist in diagnosis of sus-
cases. In patients with normal findings on diagnostic testing, validated pected GI disease. The GI tract also is amenable to internal evaluation

2180 using endoscopy and to examination of luminal contents. Histopatho- Endoscopy The gut is accessible with endoscopy, which can
logic examinations of GI tissues complement these tests. diagnose causes of bleeding, pain, nausea and vomiting, weight loss,
altered bowel function, and fever. Table 314-2 lists common indications
Laboratory Laboratory tests facilitate diagnosis of GI disease. for endoscopic procedures. Upper endoscopy evaluates the esophagus,
Iron-deficiency anemia suggests mucosal blood loss, whereas vitamin B12 stomach, and duodenum, whereas colonoscopy assesses the colon
deficiency results from intestinal, gastric, or pancreatic disease. Either and distal ileum. Upper endoscopy is advocated as the initial test
can result from inadequate oral intake. Leukocytosis and increased performed for suspected ulcer disease, esophagitis, neoplasm, malab-
sedimentation rates and C-reactive proteins are found in inflamma- sorption, and Barrett’s metaplasia because of its abilities to visualize
tion, whereas leukopenia is seen in viremic illness. Severe vomiting and biopsy any abnormality. Colonoscopy is the preferred procedure
or diarrhea elicits electrolyte disturbances, acid-base abnormalities, for colon cancer screening and surveillance and to biopsy colitis
and elevated blood urea nitrogen. Pancreaticobiliary or liver disease secondary to IBD, infection, ischemia, and radiation. Sigmoidoscopy
produce elevated pancreatic or liver chemistries. Thyroid chemistries, examines the colon to the splenic flexure and excludes distal inflam-
cortisol, and calcium levels evaluate for endocrinologic causes of symp- mation or obstruction in young patients not at significant risk for colon
toms. Pregnancy testing is considered for women with unexplained cancer. For elusive GI bleeding from arteriovenous malformations
nausea. Serologic tests screen for celiac disease, IBD, connective tissue or superficial ulcers, small-intestinal examination is performed with
diseases, and paraneoplastic dysmotility syndromes. Hormone levels push enteroscopy, capsule endoscopy, or double-balloon enteroscopy.
are obtained for suspected endocrine neoplasia. Intraabdominal malig- Capsule endoscopy also visualizes small-intestinal Crohn’s disease in
nancies produce tumor markers including the carcinoembryonic anti- individuals with negative radiography. Endoscopic retrograde cholan-
gen CA 19-9 and α-fetoprotein. Blood testing also monitors medication giopancreaticography (ERCP) provides diagnoses of pancreatic and
therapy, as with thiopurine metabolite levels in IBD. Pharmacogenetic biliary disease. Endoscopic ultrasound (EUS) diagnoses and stages GI
methods are being adopted to determine optimal patient populations malignancy, excludes choledocholithiasis, evaluates pancreatitis, and
for GI medication use. In areas including IBD, research into novel assesses anal continuity.
biomarkers is being conducted to predict longitudinal course and treat- A newer area involves development of novel imaging protocols
ment response. Other body fluids are sampled under certain circum- which permit optical biopsies to define mucosal histology and detect
stances. Ascitic fluid is analyzed for infection, malignancy, or findings dysplasia in selected settings. Methods employed include narrow band
of portal hypertension. Urine samples screen for carcinoid, porphyria, imaging and chromoendoscopy in colitis and confocal laser endomi-
and heavy metal intoxication. croscopy and optical coherence tomography in Barrett’s esophagus and
gastric cancer surveillance.
Luminal Contents Luminal contents can provide diagnostic
clues. Stool samples are cultured for bacterial pathogens, examined Radiography/Nuclear Medicine Radiographic tests evaluate
PART 10
for leukocytes and parasites, or tested for Giardia antigen. Duodenal gut diseases and extraluminal structures. Contrast radiography with
aspirates can be examined for parasites or cultured for bacterial over- barium provides mucosal definition and can assess gut transit and
growth. Fecal fat is quantified in possible malabsorption. Elevations in pelvic floor dysfunction. Barium swallow is the initial procedure to
fecal calprotectin or lactoferrin are found in inflammatory conditions exclude subtle rings, strictures, or achalasia as causes of dysphagia,
like IBD. Stool electrolytes can be measured in diarrheal conditions. whereas small-bowel contrast radiology detects intestinal tumors
Laxative screens are performed for suspected laxative abuse. Fecal and Crohn’s ileitis. Contrast enemas are performed when colonos-
immunochemical and DNA tests are assuming emerging roles in colon copy is unsuccessful or contraindicated. Ultrasound and computed
cancer screening in low risk populations. Gastric acid is quantified tomography (CT) evaluate regions not accessible by endoscopy or
to exclude gastrinoma. Esophageal pH testing is done for refractory contrast studies, including the liver, pancreas, gallbladder, kidneys,
symptoms of acid reflux, whereas impedance techniques quantify and retroperitoneum and are useful for diagnosing mass lesions,
nonacidic reflux. Pancreatic juice is analyzed for enzyme or bicarbonate fluid collections, organ enlargement, and, in the case of ultrasound,
content to exclude exocrine insufficiency. gallstones. CT and magnetic resonance (MR) colonography have been
TABLE 314-2 Common Indications for Endoscopy

DOUBLE-
ENDOSCOPIC RETROGRADE ENDOSCOPIC CAPSULE BALLOON
UPPER ENDOSCOPY COLONOSCOPY CHOLANGIOPANCREATOGRAPHY ULTRASOUND ENDOSCOPY ENDOSCOPY
Dyspepsia despite treatment Cancer screening Jaundice Staging of malignancy Obscure Ablation of
Dyspepsia with signs of organic Lower GI bleeding Postbiliary surgery complaints Characterize and biopsy gastrointestinal small-intestinal
disease submucosal mass (GI) bleeding bleeding sources
Anemia Cholangitis
Refractory vomiting Bile duct stones Suspected Crohn’s Biopsy of
Diarrhea Gallstone pancreatitis
disease of the suspicious
Dysphagia Polypectomy Pancreatic/biliary/ampullary Chronic pancreatitis
small intestine small-intestinal
Upper GI bleeding Obstruction tumor Drain pseudocyst masses/ulcers
Anemia Biopsy radiologic Unexplained pancreatitis Anal continuity
Weight loss abnormality Pancreatitis with unrelenting pain
Malabsorption Cancer surveillance: Fistulas
Biopsy radiologic abnormality family history prior polyp/ Biopsy radiologic abnormality
cancer, colitis
Polypectomy Pancreaticobiliary drainage
Palliate neoplasm
Place gastrostomy Sample bile
Remove foreign body
Barrett’s surveillance Sphincter of Oddi manometry
Place stent across
Palliate neoplasm
stenosis
Sample duodenal tissue/fluid
Remove foreign body
Endoscopic mucosal resection
or ablation of dysplastic
Barrett’s mucosa
Place stent across stenosis

considered as alternatives to colonoscopy for colon cancer screening. elimination diets may improve histology in some cases of eosino- 2181
MR methods image the pancreaticobiliary ducts to exclude neoplasm, philic esophagitis. Medium-chain triglycerides replace normal fats
stones, and sclerosing cholangitis, and the liver to characterize benign in short-gut syndrome or severe ileal disease. Perfusing liquid meals
and malignant tumors. Specialized CT or MR enterography quantifies through a gastrostomy is performed in those who cannot swal-
IBD intensity. Angiography excludes mesenteric ischemia and deter- low safely. Enteral jejunostomy feedings are considered for gastric
mines spread of malignancy. Angiographic techniques also access the dysmotility syndromes that preclude feeding into the stomach.
biliary tree in obstructive jaundice. CT and MR techniques screen for Intravenous hyperalimentation is used for generalized gut malfunc-
mesenteric occlusion, thereby limiting exposure to angiographic dyes. tion which does not permit enteral nutrition.
Positron emission tomography can distinguish malignant from benign
disease in several organ systems. PHARMACOTHERAPY
Scintigraphy evaluates structural abnormalities and quantifies lumi- Several medications can treat GI diseases. Considerable resources
nal transit. Radionuclide scans localize bleeding sites in patients with are expended on over-the-counter remedies. Many prescription
brisk hemorrhage to direct therapy with endoscopy, angiography, drug classes are offered as short-term or continuous therapy of GI
or surgery. Radiolabeled leukocyte scans search for intraabdominal illness. Alternative treatments have gained popularity in conditions
abscesses not visualized on CT. Biliary scintigraphy complements for which traditional therapies provide incomplete relief.
ultrasound in assessing for cholecystitis. Scintigraphy to quantify Over-the-Counter Agents Over-the-counter agents are reserved for
esophageal and gastric emptying is well established, whereas tech- mild GI symptoms. Antacids and histamine H2 antagonists decrease
niques to measure small-intestinal or colonic transit are less widely symptoms in gastroesophageal reflux disease (GERD) and dyspep-
used. sia. Potent acid inhibitors are available over the counter for treat-
Histopathology Endoscopic mucosal biopsies evaluate for inflam- ment of more persistent GERD. Fiber supplements, stool softeners,
matory, infectious, and neoplastic disease. Deep rectal biopsies facil- enemas, and laxatives are used for constipation. Laxatives are cat-
itate diagnosis of Hirschsprung’s disease or amyloid. Liver biopsy is egorized as stimulants, osmotic agents (including isotonic prepara-
performed for abnormal liver chemistries, in unexplained jaundice, tions containing polyethylene glycol), and poorly absorbed sugars.
following liver transplant to exclude rejection, and to characterize Nonprescription antidiarrheal agents include bismuth subsalicy-
inflammation in chronic viral hepatitis prior to initiating antiviral late, kaolin-pectin combinations, and loperamide. Supplemental
therapy. Biopsies obtained during CT or ultrasound evaluate for enzymes include lactase pills for lactose intolerance and bacterial
intraabdominal conditions not accessible by endoscopy. α-galactosidase to treat excess gas. Capsules containing peppermint
oil are available over the counter for treating discomfort in IBS and
CHAPTER 314 Approach to the Patient with Gastrointestinal Disease

Functional Testing Tests of gut function provide important data dyspepsia, while antiflatulents and adsorbents reduce gaseous
when structural testing is nondiagnostic. Functional testing of motor symptoms. In general, using a nonprescription preparation for
activity is provided by newer high resolution manometric techniques. more than a short time for chronic persistent symptoms should be
Esophageal manometry is useful for suspected achalasia, whereas supervised by a health care provider.
small-intestinal manometry tests for pseudoobstruction and colon Prescription Drugs Prescription drugs are approved for a broad
manometry evaluates for colonic inertia. A wireless motility capsule range of GI diseases. Higher dose prescription proton pump inhib-
measures transit and contractile activity in the stomach, small intestine, itors are advocated for GERD when over-the-counter preparations
and colon in a single test. Anorectal manometry with balloon expulsion are inadequate. Cytoprotective agents are available for upper gut
testing is used for unexplained incontinence or constipation from outlet ulcers but are less frequently prescribed. Prokinetic drugs stimulate
dysfunction. Biliary manometry tests for sphincter of Oddi dysfunction GI propulsion in gastroparesis and pseudoobstruction. Prosecretory
with unexplained biliary pain. A novel endoluminal functional lumen drugs are prescribed for constipation refractory to other agents,
imaging probe is available to measure heightened distensibility in the while peripheral opiate antagonists are offered for opiate-induced
lower esophageal sphincter in achalasia and pylorus in gastroparesis. constipation. Prescription antidiarrheals include opiate drugs,
Measurement of breath hydrogen while fasting and after oral mono- or anticholinergic antispasmodics, tricyclics, bile acid binders, and
oligosaccharide challenge can screen for carbohydrate intolerance and serotonin antagonists. Antispasmodics and antidepressants also are
small-intestinal bacterial overgrowth. Urea breath testing assesses for useful for functional GI disorders, whereas narcotics are used for
persistent Helicobacter pylori infection, while a recently approved gastric pain control in organic conditions such as disseminated malignancy
emptying breath test is an alternative to scintigraphy for gastroparesis and chronic pancreatitis. Antiemetics reduce nausea and vomiting.
diagnosis. Potent pancreatic enzymes decrease malabsorption and pain from
pancreatic disease. Antisecretory drugs such as the somatostatin
analogue octreotide treat hypersecretory states. Antibiotics treat
TREATMENT Helicobacter pylori-induced ulcers, infectious diarrhea, diverticu-
Gastrointestinal Disease litis, intestinal bacterial overgrowth, and Crohn’s disease. Anti-
inflammatory and immunomodulatory drugs are used in IBD,
Management options for GI diseases depend on the cause of symp- microscopic colitis, refractory celiac disease, and gut vasculitis.
toms. Available treatments include modifications in dietary intake, Over the past decade, several newer biologic agents including those
medications, treatment of gut dysbiosis, interventional endoscopy with anti-tumor necrosis factor activity have had dramatic impact
or radiology techniques, surgery, and therapies directed to external in Crohn’s disease and ulcerative colitis. Chemotherapy with or
influences. Given the hereditary predisposition of many GI diseases, without radiotherapy is offered for GI malignancies. Most GI car-
genetic testing may be indicated in some patients. cinomas respond poorly to such therapy, whereas lymphomas may
NUTRITIONAL MANIPULATION be cured with such intervention.
Dietary modifications for GI disease include treatments that only Complementary and Alternative Medicine Treatments Alternative
reduce symptoms, therapies correct pathologic defects, or replace treatments are marketed to treat selected GI symptoms. Ginger,
normal food intake with enteral or parenteral formulations. Changes acupressure, and acustimulation have been advocated for nausea,
that improve symptoms but do not reverse organic abnormalities whereas pyridoxine has been investigated for nausea of first-
include lactose restriction for lactase deficiency, liquid meals in trimester pregnancy. Herbal preparations like STW 5 (Iberogast, a
gastroparesis, carbohydrate restrictions with dumping syndrome, mixture of nine herbs) are useful in cases of functional dyspepsia
and low-FODMAP (fermentable oligo-di-monosaccharides and and IBS. Low-potency pancreatic enzyme preparations are sold
polyols) diets in IBS. The gluten-free diet for celiac disease exempli- as general digestive aids but have little evidence to support their
fies a primary therapy to reduce mucosal inflammation. Likewise, efficacy.

2182 THERAPIES TARGETING GUT DYSBIOSIS Medication-unresponsive ulcerative colitis, diverticulitis, cholecys-
Some cases of diarrhea predominant-IBS respond to nonabsorb- titis, appendicitis, and intraabdominal abscess are curable with
able antibiotics. Oral antibiotics also are the mainstay of managing surgery, whereas symptom control without cure is only possible
intestinal bacterial overgrowth. Probiotics containing active bac- with Crohn’s disease. Surgery is mandated for ulcer complica-
terial cultures and prebiotics that selectively nourish non-noxious tions such as bleeding, obstruction, or perforation and intestinal
commensal bacteria are used as adjuncts in some cases of infectious obstructions that persist after conservative care. Fundoplication of
diarrhea and IBS. Transplantation of donor feces into the colon by the gastroesophageal junction is performed for severe ulcerative
colonoscopy or enema has become accepted and effective treatment esophagitis and drug-refractory symptomatic acid reflux. Achala-
for recurrent, refractory Clostridium difficile colitis. sia responds to operations to reduce lower esophageal sphincter
tone. Operations for motor disorders have been introduced includ-
INTERVENTIONAL ENDOSCOPY AND RADIOLOGY ing implanted electrical stimulators for gastroparesis and electrical
Gut luminal intubations are performed in some situations. Nasogas- devices and artificial sphincters for fecal incontinence. Surgery may
tric tube suction decompresses the upper gut in ileus or mechanical be needed to place a jejunostomy for long-term enteral feedings. The
obstruction. Nasogastric lavage of saline or water in the patient with threshold for performing surgery depends on the clinical setting.
upper GI hemorrhage determines the rate of bleeding and helps In all cases, the benefits of operation must be weighed against the
evacuate blood before therapeutic endoscopy. Enteral feedings can be potential for postoperative complications.
delivered through nasogastric or nasoenteric tubes. Enemas relieve
fecal impaction or assist in gas evacuation in acute colonic pseu- THERAPY DIRECTED TO EXTERNAL INFLUENCES
doobstruction. A rectal tube can be placed to vent the distal colon In some conditions, GI symptoms respond to treatments directed
in colonic pseudoobstruction and other colonic distention disorders. outside the gut. Psychological therapies including psychother-
In addition to its diagnostic role, endoscopy has therapeutic apy, behavior modification, and hypnosis, have shown efficacy in
capabilities in many settings. Cautery techniques and injection of functional bowel disorders. Patients with significant psychological
vasoconstrictor substances can stop hemorrhage from ulcers and dysfunction and those with little response to treatments targeting
vascular malformations. Endoscopic encirclement of varices and the gut are likely to benefit from this form of therapy. Biofeed-
hemorrhoids with constricting bands stops hemorrhage from these back methods administered by physical therapies are accepted for
sites, whereas endoscopically placed clips can occlude arterial bleed- treating refractory fecal incontinence or constipation secondary to
ing sites. Cyanoacrylate and hemostatic powder sprays have been dyssynergia.
evaluated for abilities to stop brisk GI bleeding. Endoscopy can
remove polyps or debulk lumen-narrowing malignancies. Colonos- ■■FURTHER READING
copy is used to withdraw luminal gas in some cases of acute colonic
PART 10
Beg S et al: The use of optical imaging techniques in the gastrointestinal

pseudoobstruction. Endoscopic mucosal resection, submucosal dis- tract. Frontline Gastroenterol 7:207, 2016.
section, and radiofrequency techniques can ablate some cases of Goodman RP, Chung DC: Clinical genetic testing in gastroenterology.
Barrett’s esophagus with dysplasia or superficial cancer and early Clin Transl Gastroenterol 7:e167, 2016.
gastric malignancies. Obstructions of the gut lumen and pancreatic- Panes J et al: Advances in use of endoscopy, radiology, and biomarkers
obiliary tree are relieved by endoscopic dilation or placing plastic or to monitor inflammatory bowel diseases. Gastroenterology 152:362,
expandable metal stents. Endoscopic sphincterotomy of the ampulla 2017.
of Vater relieves symptoms of choledocholithiasis. Cholangioscopy Peery AF et al: Burden of gastrointestinal, liver, and pancreatic diseases
can help with stone lithotripsy in the common bile duct, ablation of in the United States. Gastroenterology 149:1731, 2015.
small ductal tumors, and placement of gallbladder stents to facilitate Schreuders EH et al: Advances in fecal tests for colorectal cancer
drainage in non-operative candidates. Endoscopic methods have screening. Curr Treat Options Gastroenterol 14:152, 2016.
been developed for pancreatic cyst gastrostomy, pancreatic necro- Weilert F, Binmoeller KF: New endoscopic technologies and pro-
sectomy, and placement of fiducial markers to direct pancreatic and cedural advances for endoscopic hemostasis. Clin Gastroenterol
rectal radiotherapy. Endoscopy is commonly used to insert gastric Hepatol 14:1234, 2016.
feeding tubes. Peroral endoscopic myotomy is now being performed
on the lower esophageal sphincter in achalasia and on the pylorus
in gastroparesis by selected endoscopists. Endoscopic treatments for
acid reflux including radiofrequency therapy, transoral fundoplica-
tion, endoscopic stapling, and antireflux mucosectomy have been
315 Gastrointestinal
devised. Similarly, endoscopic bariatric methodologies including
intragastric balloons, aspiration therapy, gastroplasty, and duodenal
bypass are in use or in development. Endoscopy
Radiologic measures also are useful in GI disease. Angiographic
embolization or vasoconstriction decreases bleeding from gut sites Louis Michel Wong Kee Song, Mark Topazian
not amenable to endoscopic intervention. Dilatation or stenting with
fluoroscopic guidance relieves luminal strictures. Contrast enemas
can reduce volvulus and evacuate air in acute colonic pseudoob- Gastrointestinal endoscopy has been attempted for over 200 years, but
struction. CT and ultrasound help drain abdominal fluid collections,
the introduction of semirigid gastroscopes in the middle of the twentieth
in many cases obviating the need for surgery. Percutaneous tran-
century marked the dawn of the modern endoscopic era. Since then
shepatic cholangiography relieves biliary obstruction when ERCP is
rapid advances in endoscopic technology have led to dramatic changes
contraindicated. Transjugular intrahepatic portosystemic shunts are
in the diagnosis and treatment of many digestive diseases. Innovative
commonly performed by interventional radiologists for variceal hem-
endoscopic devices and new endoscopic treatment modalities continue
orrhage not amenable to endoscopic therapy. Lithotripsy can fragment
to expand the use of endoscopy in patient care.
gallstones in patients who are not candidates for surgery. In some
Flexible endoscopes provide an electronic video image generated by a
instances, radiologic approaches offer advantages over endoscopy
charge-coupled device in the tip of the endoscope. Operator controls per-
for gastroenterostomy placement. Finally, central venous catheters for
mit deflection of the endoscope tip; fiberoptic bundles or light-emitting
parenteral nutrition may be placed using radiographic techniques.
diodes provide light at the tip of the endoscope; and working channels
SURGERY allow washing, suctioning, and the passage of instruments (Fig. 315-1).
Surgery is performed to cure disease, control symptoms with- Progressive changes in the diameter and stiffness of endoscopes have
out cure, maintain nutrition, or palliate unresectable neoplasm. improved the ease and patient tolerance of endoscopy.

of cases and the terminal ileum (Fig. 315-6) can often be examined. 2183
Colonoscopy is the gold standard for imaging the colonic mucosa
(Fig. 315-7). Colonoscopy has greater sensitivity than barium enema
for colitis (Fig. 315-8), polyps (Fig. 315-9), and cancer (Fig. 315-10). CT
colonography rivals the accuracy of colonoscopy for detection of some
polyps and cancer, although it is not as sensitive for the detection of
flat lesions, such as serrated polyps (Fig. 315-11). Conscious sedation is
usually given before colonoscopy in the United States, although a will-
ing patient and a skilled examiner can complete the procedure without
sedation in many cases.
■■FLEXIBLE SIGMOIDOSCOPY
Flexible sigmoidoscopy is similar to colonoscopy, but it visualizes only
the rectum and a variable portion of the left colon, typically to 60 cm
from the anal verge. This procedure causes abdominal cramping, but it is
brief and is usually performed without sedation. Flexible sigmoidoscopy
is primarily used for evaluation of diarrhea and rectal outlet bleeding.
■■SMALL BOWEL ENDOSCOPY
FIGURE 315-1 Gastrointestinal endoscope. Shown here is a conventional Three endoscopic techniques are currently used to evaluate the small
colonoscope with control knobs for tip deflection, push buttons for suction and intestine, most often in patients presenting with presumed small bowel
air insufflation (single arrows), and a working channel for passage of accessories bleeding. For capsule endoscopy, the patient swallows a disposable cap-
(double arrows). sule that contains a complementary metal oxide silicon (CMOS) chip
camera. Color still images (Fig. 315-12) are transmitted wirelessly to
ENDOSCOPIC PROCEDURES an external receiver at several frames per second until the capsule’s
battery is exhausted or it is passed into the toilet. Capsule endoscopy
■■UPPER ENDOSCOPY enables visualization of the small bowel mucosa beyond the reach of
Upper endoscopy, also referred to as esophagogastroduodenoscopy a conventional endoscope, and at present it is solely a diagnostic pro-
(EGD), is performed by passing a flexible endoscope through the mouth cedure. Patients with a history of prior intestinal surgery or Crohn’s
CHAPTER 315 Gastrointestinal Endoscopy

into the esophagus, stomach, and duodenum. The procedure is the best disease are at risk for capsule retention at the site of a clinically unsus-
method for examining the upper gastrointestinal mucosa (Fig. 315-2). pected small bowel stricture, and ingestion of a “patency capsule”
While the upper gastrointestinal radiographic series has similar accu- composed of radiologically opaque biodegradable material may be
racy for diagnosis of duodenal ulcer (Fig. 315-3), EGD is superior for indicated prior to capsule endoscopy in such patients.
detection of gastric ulcers (Fig. 315-4) and flat mucosal lesions, such Push enteroscopy is performed with a long endoscope similar in
as Barrett’s esophagus (Fig. 315-5), and it permits directed biopsy and design to an upper endoscope. The enteroscope is pushed down
endoscopic therapy. Intravenous conscious sedation is given to most the small bowel, sometimes with the help of a stiffening overtube
patients in the United States to ease the anxiety and discomfort of the that extends from the mouth to the small intestine. The proximal to
procedure, although in many countries EGD is routinely performed with mid-jejunum is usually reached, and the instrument channel of the
topical pharyngeal anesthesia only. Patient tolerance of unsedated EGD endoscope allows for biopsy or endoscopic therapy.
is improved by the use of an ultrathin, 5-mm diameter endoscope that Deeper insertion into the small bowel can be accomplished by
can be passed transorally or transnasally. device-assisted enteroscopy, which may utilize inflatable balloons at the
tip of the enteroscope and/or an overtube (single- or double-balloon ent-
■■COLONOSCOPY eroscopy) or a rotating, screw-like overtube (spiral enteroscopy) to pleat
Colonoscopy is performed by passing a flexible colonoscope through the small intestine onto the endoscope (Fig. 315-13, Video V5-1). Using
the anal canal into the rectum and colon. The cecum is reached in >95% device-assisted enteroscopy the entire small intestine can be visualized
A B
FIGURE 315-2 Normal upper endoscopic examination. A. Esophagus. B. Gastroesophageal junction. C. Gastric fundus. D. Gastric body. E. Gastric antrum. F. Pylorus.
G. Duodenal bulb. H. Second portion of the duodenum.

2184
C D
PART 10
E F
G H

2185
A B
A B FIGURE 315-4 Gastric ulcers. A. Benign gastric ulcer. B. Malignant gastric ulcer
involving greater curvature of stomach.
FIGURE 315-3 Duodenal ulcers. A. Ulcer with a clean base. B. Ulcer with a visible
vessel (arrow) in a patient with recent hemorrhage.
of pancreatic necrosis, are well-established clinical procedures (Video

in some patients when both the oral and anal routes of insertion are V5-2); others such as peroral endoscopic myotomy (POEM) for achala-
used. Biopsies and endoscopic therapy can be performed throughout sia (Fig. 315-21), peroral endoscopic tumorectomy (POET) (Fig. 315-22),
the visualized small bowel (Fig. 315-14). and endoscopic full-thickness resection (EFTR) of gastrointestinal mural
lesions (Fig. 315-23, Video V5-3), are emerging as minimally invasive
■■ENDOSCOPIC RETROGRADE therapeutic options. NOTES is an area of continuing innovation and
CHOLANGIOPANCREATOGRAPHY (ERCP) endoscopic research.
During ERCP a side-viewing endoscope is passed through the mouth to
the duodenum, the ampulla of Vater is identified and cannulated with a ■■ENDOSCOPIC RESECTION AND CLOSURE
thin plastic catheter, and radiographic contrast material is injected into the TECHNIQUES
bile duct and pancreatic duct under fluoroscopic guidance (Fig. 315-15). Endoscopic mucosal resection (EMR) (Video V5-4) and endoscopic
When indicated, the major papilla can be opened using the technique of submucosal dissection (ESD) (Fig. 315-24, Video V5-5) are the two

endoscopic sphincterotomy (Fig. 315-16). Stones can be retrieved from the commonly used techniques for the resection of benign and early-stage
ducts, biopsies can be performed, and strictures can be dilated and/or malignant gastrointestinal neoplasms. In addition to providing larger
stented (Fig. 315-17), and ductal leaks can be treated (Fig. 315-18). ERCP specimens for more accurate histopathological assessment and diagno-
is usually performed for therapy but is also important diagnostically, and sis, these techniques can be potentially curative for certain dysplastic
facilitates tissue sampling of biliary or pancreatic ductal strictures. lesions and focal intramucosal carcinomas involving the esophagus,
stomach, and colon. Several devices are available for closure of EMR
■■ENDOSCOPIC ULTRASOUND (EUS)
EUS utilizes ultrasound transducers incorporated into
the tip of a flexible endoscope. Ultrasound images are
obtained of the gut wall and adjacent organs, vessels,
lymph nodes, and other structures. High-resolution
images are obtained by bringing a high-frequency
ultrasound transducer close to the area of interest via
endoscopy. EUS provides the most accurate preopera-
tive local staging of esophageal, pancreatic, and rectal
malignancies (Fig. 315-19), but it does not detect most
distant metastases. EUS is also useful for diagnosis
of bile duct stones, gallbladder disease, subepithe-
lial gastrointestinal lesions, and chronic pancreatitis.
Fine-needle aspirates and core biopsies of organs,
masses and lymph nodes in the posterior mediasti-
num, abdomen, pancreas, retroperitoneum, and pelvis A B
can be obtained under EUS guidance (Fig. 315-20).
EUS-guided therapeutic procedures are increasingly
performed, including drainage of abscesses, pseu-
docysts, and pancreatic necrosis into the gut lumen
(Video V5-2), celiac plexus neurolysis for treatment
of pancreatic pain, ethanol ablation of pancreatic
neuroendocrine tumors, treatment of gastrointestinal
hemorrhage, and drainage of obstructed biliary and
pancreatic ducts.
■■NATURAL ORIFICE TRANSLUMINAL

ENDOSCOPIC SURGERY (NOTES)
NOTES is an evolving collection of endoscopic meth- C D
ods that entail passage of an endoscope or its acces-
sories into or through the wall of the gastrointestinal FIGURE 315-5 Barrett’s esophagus. A. Pink tongues of Barrett’s mucosa extending proximally from
the gastroesophageal junction. B. Barrett’s esophagus with a suspicious nodule (arrow) identified
tract to perform diagnostic or therapeutic interventions. during endoscopic surveillance. C. Histologic finding of intramucosal adenocarcinoma in the
Some NOTES procedures, such as percutaneous endo- endoscopically resected nodule. Tumor extends into the esophageal submucosa (arrow). D. Barrett’s
scopic gastrostomy (PEG) or endoscopic necrosectomy esophagus with locally advanced adenocarcinoma.

2186
A B
FIGURE 315-6 Colonoscopic view of terminal ileum. A. Normal-appearing terminal ileum (TI). B. View of normal villi of TI enhanced by examination under water
immersion.
PART 10
A B
C D
FIGURE 315-7 Normal colonoscopic examination. A. Cecum with view of appendiceal orifice. B. Ileocecal valve. C. Normal-appearing colon. D. Rectum (retroflexed view).

2187
A B
FIGURE 315-10 Ulcerated colon adenocarcinoma narrowing the colonic lumen.
C D
FIGURE 315-8 Causes of colitis. A. Chronic ulcerative colitis with diffuse
ulcerations and exudates. B. Severe Crohn’s colitis with deep ulcers.
C. Pseudomembranous colitis with yellow, adherent pseudomembranes. D. Ischemic

colitis with patchy mucosal edema, subepithelial hemorrhage, and cyanosis.
A B
C
FIGURE 315-11 Flat serrated polyp in the cecum. A. Appearance of the lesion
B under conventional white-light imaging. B. Mucosal patterns and boundary of the
lesion enhanced with narrow band imaging. C. Submucosal lifting of the lesion
FIGURE 315-9 Colonic polyps. A. Pedunculated polyp on a stalk. B. Sessile polyp. with dye (methylene blue) injection prior to resection.

2188
FIGURE 315-12 Capsule endoscopy image of jejunal vascular ectasia. FIGURE 315-13 Radiograph of a double-balloon enteroscope in the small
intestine.
PART 10
A B C
FIGURE 315-14 Nonsteroidal anti-inflammatory drug (NSAID)-induced proximal ileal stricture diagnosed by double-balloon endoscopy. A. Ileal stricture causing
obstructive symptoms. B. Balloon dilation of the ileal stricture. C. Appearance of stricture after dilation.
A B
A B
FIGURE 315-15 Endoscopic retrograde cholangiopancreatography (ERCP) for
C D
bile duct stones with cholangitis. A. Faceted bile duct stones are demonstrated
in the common bile duct. B. After endoscopic sphincterotomy, the stones are FIGURE 315-16 Endoscopic sphincterotomy. A. A normal-appearing ampulla of
extracted with a Dormia basket. A small abscess communicates with the left Vater. B. Sphincterotomy is performed with electrosurgery. C. Bile duct stones
hepatic duct. are extracted with a balloon catheter. D. Final appearance of the sphincterotomy.

2189
A B
FIGURE 315-18 Bile leak (arrow) from a duct of Luschka after laparoscopic
cholecystectomy. Contrast leaks from a small right intrahepatic duct into the
gallbladder fossa, then flows into the pigtail of a percutaneous drainage catheter.
C D
FIGURE 315-17 Endoscopic diagnosis, staging, and palliation of hilar

cholangiocarcinoma. A. Endoscopic retrograde cholangiopancreatography
(ERCP) in a patient with obstructive jaundice demonstrates a malignant-appearing RISKS OF ENDOSCOPY
stricture of the biliary confluence extending into the left and right intrahepatic Medications used during conscious sedation may cause respiratory
ducts. B. Intraductal ultrasound of the biliary stricture demonstrates marked bile depression or allergic reactions. All endoscopic procedures carry some
duct wall thickening due to tumor (T) with partial encasement of the hepatic artery risk of bleeding and gastrointestinal perforation. The risk is small with
(arrow). C. Intraductal biopsy obtained during ERCP demonstrates malignant cells diagnostic upper endoscopy, flexible sigmoidoscopy, and colonoscopy
infiltrating the submucosa of the bile duct wall (arrow). D. Endoscopic placement
(<1:1000 procedures), but it ranges from 0.5 to 5% when therapeutic
of bilateral self-expanding metal stents (arrow) relieves the biliary obstruction.
GB, gallbladder. (Image C courtesy of Dr. Thomas Smyrk; with permission.) procedures such as polypectomy, EMR, ESD, control of hemorrhage, or
stricture dilation are performed. The risk of adverse events for diagnostic
EUS (without needle aspiration) is similar to that for diagnostic upper
endoscopy.
and ESD defects as well as gastrointestinal fistulas and perforations. Infectious complications are uncommon with most endoscopic pro-
Endoscopic clips deployed through the working channel of an endo- cedures. Some procedures carry a higher incidence of postprocedure
scope have been used for many years to treat bleeding lesions, and the bacteremia, and prophylactic antibiotics may be indicated (Table 315-1).
development of larger over-the-scope clips has facilitated endoscopic Management of antithrombotic agents prior to endoscopic procedures
closure of gastrointestinal fistulas and perforations not previously ame- should take into account the procedural risk of hemorrhage, the agent,
nable to endoscopic therapy (Video V5-6). Endoscopic suturing can be and the patient condition, as summarized in Table 315-2.
used to close perforations and large defects (Fig. 315-25), anastomotic ERCP carries additional risks. Pancreatitis occurs in ~5% of patients
leaks, and fistulas. Other potential indications for endoscopic suturing undergoing the procedure and in up to 30% of patients with sphincter
include stent fixation to prevent migration (Fig. 315-26, Video V5-7) of Oddi dysfunction. Young anicteric patients with normal ducts are at
and endoscopic bariatric procedures. These technologies are likely to increased risk. Post-ERCP pancreatitis is usually mild and self-limited,
have an expanding role in patient care. but it may result in prolonged hospitalization, surgery, diabetes, or
A B C
FIGURE 315-19 Local staging of gastrointestinal cancers with endoscopic ultrasound. In each example the white arrowhead marks the primary tumor and the black
arrow indicates the muscularis propria (mp) of the intestinal wall. A. T1 gastric cancer. The tumor does not invade the mp. B. T2 esophageal cancer. The tumor invades
the mp. C. T3 esophageal cancer. The tumor extends through the mp into the surrounding tissue, and focally abuts the aorta. AO, aorta.

2190 death when severe. Significant bleeding occurs after
endoscopic sphincterotomy in ~1% of cases. Ascending
cholangitis, pseudocyst infection, duodenal perforation,
and abscess formation may occur as a result of ERCP.
Percutaneous gastrostomy tube placement during EGD
is associated with a 10–15% incidence of adverse events,
most often wound infections. Fasciitis, pneumonia, bleed-
ing (Fig. 315-27), buried bumper syndrome, and colonic
injury may result from gastrostomy tube placement.
URGENT ENDOSCOPY
■■ACUTE GASTROINTESTINAL
HEMORRHAGE
Endoscopy is the primary diagnostic and therapeutic
A B technique for patients with acute gastrointestinal hemor-
FIGURE 315-20 Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). A. Ultrasound rhage. Although gastrointestinal bleeding stops sponta-
image of a 22-gauge needle passed through the duodenal wall and positioned in a neously in most cases, some patients will have persistent
hypoechoic pancreatic head mass. B. Micrograph of aspirated malignant cells. (Image B courtesy or recurrent hemorrhage that may be life-threatening.
of Dr. Michael R. Henry; with permission.)
PART 10
A B C
D E F
G H I
FIGURE 315-21 Peroral endoscopic myotomy (POEM) for achalasia. A. Dilated aperistaltic esophagus with retained secretions. B. Hypertonic lower esophageal
sphincter (LES) region. C. Mucosal incision (mucosotomy) 10 cm proximal to the LES. D. Submucosal dissection using an electrosurgical knife following endoscope
entry through the mucosotomy site into the submucosal space. E. Completion of submucosal tunnel to the cardia. F. Initiation of myotomy of the muscularis propria
distal to the mucosotomy site. G. Completion of myotomy to the cardia. H. Closure of mucosotomy site with clips. I. Patulous gastroesophageal junction following
myotomy.

2191
A B

C D
E F
G H
FIGURE 315-22 Peroral endoscopic tumorectomy (POET). A. Midesophageal subepithelial lesion. B. Mucosal incision (mucosotomy) 5 cm proximal to the lesion.
C. Submucosal dissection and tunneling to the site of the lesion. D. Dissection of the lesion from its attachment to the muscularis propria. E. Postresection defect
through the muscularis propria. F. Mucosotomy site. G. Closure of mucosotomy site with clips. H. Resected specimen (leiomyoma).

2192
A B
C D
PART 10
FIGURE 315-23 Endoscopic full-thickness resection (EFTR) of a gastrointestinal stromal tumor. A. Subepithelial lesion in the proximal stomach. B. Hypoechoic
lesion arising from the fourth layer (muscularis propria) at endoscopic ultrasound. C. Full-thickness resection defect. D. Closure of defect using an over-the-scope clip.
A B
C D
FIGURE 315-24 Endoscopic submucosal dissection (ESD). A. Large flat distal rectal adenoma with central lobulation. B. Marking the periphery of the lesion with
coagulation dots. C. Rectal defect following ESD. D. Specimen resected en bloc.

2193
A B

C D
FIGURE 315-25 Closure of large defect using an endoscopic suturing device. A. Ulcerated inflammatory fibroid polyp in the antrum. B. Large defect following
endoscopic submucosal dissection of the lesion. C. Closure of the defect using endoscopic sutures (arrows). D. Resected specimen.
A B
C D
FIGURE 315-26 Prevention of stent migration using endoscopic sutures. A. Esophagogastric anastomotic stricture refractory to balloon dilation. B. Temporary
placement of a covered esophageal stent. C. Endoscopic suturing device to anchor the stent to the esophageal wall. D. Stent fixation with endoscopic sutures (arrows).

2194 TABLE 315-1 Antibiotic Prophylaxis for Endoscopic Procedures
PERIPROCEDURAL ANTIBIOTIC
PATIENT CONDITION PROCEDURE CONTEMPLATED GOAL OF PROPHYLAXIS PROPHYLAXIS
All cardiac conditions Any endoscopic procedure Prevention of infective endocarditis Not indicated
Bile duct obstruction in the absence ERCP with complete drainage Prevention of cholangitis Not recommended
of cholangitis
Bile duct obstruction in absence of ERCP with anticipated incomplete Prevention of cholangitis Recommended; continue antibiotics
cholangitis drainage (e.g., sclerosing cholangitis, after the procedure
hilar strictures)
Sterile pancreatic fluid collection ERCP Prevention of cyst infection Recommended; continue antibiotics
(e.g., pseudocyst, necrosis), which after the procedure
communicates with pancreatic duct
Sterile pancreatic fluid collection Transmural drainage Prevention of cyst infection Recommended
Solid lesion along upper GI tract EUS-FNA Prevention of local infection Not recommendeda
Solid lesion along lower GI tract EUS-FNA Prevention of local infection Not recommendeda
Cystic lesions along GI tract EUS-FNA Prevention of cyst infection Recommended
(including mediastinum and pancreas)
All patients Percutaneous endoscopic feeding tube Prevention of peristomal infection Recommendedb
placement
Cirrhosis with acute GI bleeding Required for all such patients, Prevention of infectious complications Recommended, upon admissionc
regardless of endoscopic procedures and reduction of mortality
Continuous peritoneal dialysis Lower GI tract endoscopy Prevention of bacterial peritonitis Recommended
Synthetic vascular graft and other Any endoscopic procedure Prevention of graft and device infection Not recommendedd
nonvalvular cardiovascular devices
Prosthetic joints Any endoscopic procedure Prevention of septic arthritis Not recommendede
a
Low rates of bacteremia and local infection. Cefazolin or an antibiotic with equivalent coverage of oral and skin flora. Risk for bacterial infection associated with
b c
cirrhosis and GI bleeding is well established; ceftriaxone or a quinolone antibiotic recommended. dNo reported cases of infection associated with endoscopy. eVery low
risk of infection.
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; EUS-FNA, endoscopic ultrasound–fine-needle aspiration; GI, gastrointestinal.
PART 10
Source: Adapted from MA Kashab et al: Gastrointest Endosc 81:81, 2015; with permission from Elsevier.
Clinical predictors of rebleeding help identify patients most likely coagulopathy or thrombocytopenia is usually treated before endoscopy,
to benefit from urgent endoscopy and endoscopic, angiographic, or since correction of these abnormalities may lead to resolution of bleeding,
surgical hemostasis. and techniques for endoscopic hemostasis are limited in such patients.
Metabolic derangements should also be addressed. Tracheal intubation
Initial Evaluation The initial evaluation of the bleeding patient for airway protection should be considered before upper endoscopy in
focuses on the severity of hemorrhage as reflected by the presence of patients with repeated recent hematemesis, encephalopathy and sus-
supine hypotension or tachycardia, postural vital sign changes, and pected variceal hemorrhage. A single dose of erythromycin (3–4 mg/
the frequency of hematemesis or melena. Decreases in hematocrit and kg or 250 mg) administered intravenously 30–90 min prior to upper
hemoglobin lag behind the clinical course and are not reliable gauges endoscopy increases gastric emptying and may clear blood and clots
of the magnitude of acute bleeding. Nasogastric tube aspiration and from the stomach to improve endoscopic visualization.
lavage can also be used to judge the severity of bleeding, but these are Most patients with hematochezia who are otherwise stable can
no longer routinely performed for this purpose. The bedside initial undergo semielective colonoscopy. Controlled trials have not shown
evaluation, completed well before the bleeding source is confidently a benefit to urgent colonoscopy in patients hospitalized with hema-
identified, guides immediate supportive care of the patient, triage to tochezia, although patients with massive or recurrent large-volume
the ward or intensive care unit, and timing of endoscopy. The severity episodes of hematochezia should undergo urgent colonoscopy after a
of the initial hemorrhage is the most important indication for urgent rapid colonic purge with a polyethylene glycol solution. Colonoscopy
endoscopy, since a large initial bleed increases the likelihood of ongoing has a higher diagnostic yield than radionuclide bleeding scans or angi-
or recurrent bleeding. Patients with resting hypotension or orthostatic ography in lower gastrointestinal bleeding, and endoscopic therapy
change in vital signs, repeated hematemesis, bloody nasogastric aspirate can be applied in some cases. Urgent colonoscopy can be hindered by
that does not clear with large volume lavage, or those requiring blood poor visualization due to persistent vigorous bleeding with recurrent
transfusions should be considered for urgent endoscopy. In addition, hemodynamic instability, and other techniques (such as angiography
patients with cirrhosis, coagulopathy, respiratory or renal failure, and or even emergent subtotal colectomy) must be employed. In such
those over 70 years of age are more likely to have significant rebleeding patients, massive bleeding originating from an upper gastrointestinal
and to benefit from prompt evaluation and treatment. source should also be considered and excluded promptly by upper
Bedside evaluation also suggests an upper or lower gastrointestinal endoscopy. The anal and rectal mucosa should also be visualized endo-
source of bleeding in most patients. Over 90% of patients with melena scopically early in the course of massive rectal bleeding, as bleeding
are bleeding proximal to the ligament of Treitz, and ~85% of patients lesions in or close to the anal canal may be identified that are amenable
with hematochezia are bleeding from the colon. Melena can result to endoscopic or surgical transanal hemostatic techniques.
from bleeding in the small bowel or right colon, especially in older
patients with slow colonic transit. Conversely, some patients with Peptic Ulcer The endoscopic appearance of peptic ulcers provides
massive hematochezia may be bleeding from an upper gastrointestinal useful prognostic information and guides the need for endoscopic
source, such as a gastric Dieulafoy lesion or duodenal ulcer, with rapid therapy in patients with acute hemorrhage (Fig. 315-28). A clean-based
intestinal transit. Early upper endoscopy should be considered in such ulcer is associated with a low risk (3–5%) of rebleeding; patients with
patients. melena and a clean-based ulcer are often discharged home from the
Endoscopy should be performed after the patient has been resusci- emergency room or endoscopy suite if they are young, reliable, and
tated with intravenous fluids and transfusions, as necessary. Marked otherwise healthy. Flat pigmented spots and adherent clots covering

TABLE 315-2 Management of Antithrombotic Drugs Prior to Endoscopic Procedures 2195
BLEEDING RISK OF INTERVAL BETWEEN LAST DOSE

DRUG PROCEDURE MANAGEMENT AND PROCEDURE COMMENTS
Warfarin Lowa Continue N/A Ensure that INR is not
supratherapeutic
Highb Discontinue 3–7 days (usually 5), INR Consider bridging therapy with
should be ≤1.5 for procedure heparin;c usually safe to resume
warfarin on the same or next day
Dabigatran, rivaroxaban, Lowa Continue or hold morning N/A
apixaban, edoxaban dose on day of procedure
Dabigatran Highb Discontinue 2–3 days if GFR is ≥50 mL/min, Bridging therapy not recommended;
3–4 days if GFR is 30–49 mL/ resume drug when bleeding risk is low
min
Rivaroxaban, apixaban, edoxaban Higha Discontinue 2 days if GFR is ≥60 mL/min, Bridging therapy not recommended;
3 days if GFR is 30–59 mL/min, resume drug when bleeding risk is low
4 days if GFR is <30 mL/min
Heparin Lowa Continue N/A
Highb Discontinue 4–6 h for unfractionated heparin Skip one dose if using low-molecular-
weight heparin
Aspirin Any Continue N/A Low-dose aspirin does not
substantially increase the risk of
endoscopic procedures
Aspirin with dipyridamole Lowa Continue N/A
Highb Discontinue 2–7 days Consider continuing aspirin
monotherapy
P2Y12 receptor antagonists Lowa Continue N/A
(clopidogrel, prasugrel,
ticlopidine, ticagrelor, cangrelor
Highb Coronary stent in place: 5 days (clopidogrel or ticagrelor), Risk of stent thrombosis for 12 months

discuss with cardiologist 7 days (prasugrel), 10–4 days after insertion of drug-eluting coronary
(ticlopidine) stent or 1 month after insertion of
bare metal coronary stent
No coronary stent:
Discontinue, consider
substituting to aspirin
a
Low-risk endoscopic procedures include EGD or colonoscopy with or without biopsy, EUS without FNA, ERCP with stent exchange. bHigh-risk endoscopic procedures
include EGD or colonoscopy with dilation, polypectomy, or thermal ablation; PEG; EUS with FNA; ERCP with sphincterotomy or pseudocyst drainage. cBridging therapy
with low-molecular-weight heparin should be considered for patients discontinuing warfarin who are at high risk for thromboembolism, including those with (1) atrial
fibrillation with a CHA2DS2-VASc score ≥2, mechanical valves, or history of stroke; (2) mechanical mitral valve; (3) mechanical aortic valve with other thromboembolic
risk factors or older-generation mechanical aortic valve; (4) venous thromboembolism within the past 3 months.
Abbreviations: GFR, glomerular filtration rate; INR, international normalized ratio; N/A, not applicable.
Source: Data from RD Acosta et al: Gastrointest Endosc 83:3, 2016; and AM Veitch et al: Gut 65:374, 2016.
the ulcer base have a 10% and 20% risk of rebleeding, respectively. Endoscopic therapy of ulcers with high-risk stigmata typically
Endoscopic therapy may be considered for an ulcer with an adherent lowers the rebleeding rate to 5–10%. Several hemostatic techniques are
clot. When a fibrin plug is seen protruding from a vessel wall in the available, including injection of epinephrine or a sclerosant into and
base of an ulcer (so-called sentinel clot or visible vessel), the risk of around the vessel (Fig. 315-29), “coaptive coagulation” of the vessel in
rebleeding from the ulcer is 40%. This finding generally leads to endo- the base of the ulcer using a thermal probe that is pressed against the
scopic therapy to decrease the rebleeding rate. When active spurting site of bleeding (Fig. 315-30), placement of through-the-scope hemo-
from an ulcer is seen, there is a 90% risk of ongoing bleeding without clips (Fig. 315-31) or an over-the-scope clip (Fig. 315-32), or a combina-
therapy. tion of these modalities (Video V5-8). In conjunction with endoscopic
A B
FIGURE 315-27 Bleeding from percutaneous endoscopic gastrostomy (PEG) tube placement. A. Patient with melena from a recently placed PEG tube. B. Loosening
of the internal disk bumper of the PEG tube revealed active bleeding from within the PEG tract.

2196
A B
PART 10
C D E
FIGURE 315-28 Stigmata of hemorrhage in peptic ulcers. A. Gastric antral ulcer with a clean base. B. Duodenal ulcer with flat pigmented spots (arrows). C. Duodenal
ulcer with a dense adherent clot. D. Gastric ulcer with a pigmented protuberance/visible vessel. E. Duodenal ulcer with active spurting (arrow).
therapy, the administration of a proton pump inhibitor decreases the After treatment of the acute hemorrhage, an elective course of
risk of rebleeding and improves patient outcome. endoscopic therapy can be undertaken with the goal of eradicating
esophageal varices and preventing rebleeding months to years later.
Varices Two complementary strategies guide therapy of bleeding However, this chronic therapy is less successful, preventing long-term
varices: local treatment of the bleeding varices and treatment of the
rebleeding in ~50% of patients. Pharmacologic therapies that decrease
underlying portal hypertension. Local therapies, including endoscopic
variceal band ligation, endoscopic variceal sclerotherapy (EVS), stent
placement and balloon tamponade with a Sengstaken-Blakemore tube,
effectively control acute hemorrhage in most patients, although thera-
pies that decrease portal pressure (pharmacologic treatment, surgical
shunts, or radiologically placed intrahepatic portosystemic shunts) also
play an important role.
Endoscopic variceal ligation (EVL) is indicated for the prevention
of a first bleed (primary prophylaxis) from large esophageal varices
(Fig. 315-33), particularly in patients in whom nonselective beta
blockers are contraindicated or not tolerated. EVL is also the preferred
endoscopic therapy for control of active esophageal variceal bleeding
and for subsequent eradication of esophageal varices (secondary pro-
phylaxis). During EVL a varix is suctioned into a cap fitted on the end
of the endoscope, and a rubber band is released from the cap, ligating
the varix (Fig. 315-34, Video V5-9). EVL controls acute hemorrhage
in up to 90% of patients. Complications of EVL, such as postligation
ulcer bleeding and esophageal stenosis, are uncommon. EVS involves
the injection of a sclerosing, thrombogenic solution into or next to
esophageal varices. EVS also controls acute hemorrhage in most
patients, but it is generally used as salvage therapy when band liga-
tion fails because of its higher complication rate. Bleeding from large
gastric fundic varices (Fig. 315-35) is best treated with endoscopic
cyanoacrylate (“glue”) injection (Video V5-10), since EVL or EVS of
these varices is associated with a high rebleeding rate. Complications
of cyanoacrylate injection include infection and glue embolization to FIGURE 315-29 Epinephrine injection into a duodenal ulcer with visible vessel
other organs, such as the lungs, brain, and spleen. (arrow) and adherent clot.

2197
FIGURE 315-30 Treated duodenal ulcer by contact coagulation with a thermal

probe.
portal pressure have similar efficacy, and the two modalities are usually
combined.
Dieulafoy’s Lesion This lesion, also called persistent caliber

artery, is a large-caliber arteriole that runs immediately beneath the
gastrointestinal mucosa and bleeds through a focal mucosal erosion
(Fig. 315-36). Dieulafoy’s lesion is seen most commonly on the lesser
B
curvature of the proximal stomach, causes impressive arterial hemor-
rhage, and may be difficult to diagnose when not actively bleeding; it is FIGURE 315-32 Endoscopic hemostasis of ulcer bleeding. A. Pyloric channel
often recognized only after repeated endoscopy for recurrent bleeding. ulcer with visible vessel (arrow). B. Ulcer hemostasis with placement of an over-
the-scope clip.
Endoscopic therapy, such as thermal coagulation, band ligation, or

endoscopic suturing, is typically effective for control of bleeding and
sealing of the underlying vessel once the lesion has been identified
(Video V5-11). Rescue therapies, such as angiographic embolization
or surgical oversewing, are considered in situations where endoscopic
therapy has failed.
Mallory-Weiss Tear A Mallory-Weiss tear is a linear mucosal
rent near or across the gastroesophageal junction that is often associ-
ated with retching or vomiting (Fig. 315-37). When the tear disrupts
a submucosal arteriole, brisk hemorrhage may result. Endoscopy is
the best method for diagnosis, and an actively bleeding tear can be
treated endoscopically with epinephrine injection, coaptive coagula-
tion, band ligation, or hemoclips (Video V5-12). Unlike peptic ulcer, a
A Mallory-Weiss tear with a nonbleeding sentinel clot in its base rarely
rebleeds and thus does not necessitate endoscopic therapy.
B
FIGURE 315-31 Ulcer hemostasis using through-the-scope clips. A. Superficial
duodenal ulcer with visible vessel (arrow). B. Hemostasis secured following
placement of multiple clips. FIGURE 315-33 Esophageal varices.

2198
A A
PART 10
B B
FIGURE 315-34 Endoscopic band ligation of esophageal varices. A. Large FIGURE 315-35 Gastric varices. A. Large gastric fundal varices. B. Stigmata of
esophageal varices with stigmata of recent bleeding characterized by a fibrin plug
recent bleeding from the same gastric varices (arrow).

(arrow). B. Band ligation of varices.
or treated endoscopically. Esophageal, gastroduodenal, and colonic

Vascular Ectasias Vascular ectasias are flat mucosal vascular obstruction or pseudoobstruction can all be diagnosed and often man-
anomalies that are best diagnosed by endoscopy. They usually cause aged endoscopically.
slow intestinal blood loss and occur either in a sporadic fashion or in a
well-defined pattern of distribution (e.g., gastric antral vascular ectasia Acute Esophageal Obstruction Esophageal obstruction by
[GAVE] or “watermelon stomach”) (Fig. 315-38). Cecal vascular ecta- impacted food (Fig. 315-41) or an ingested foreign body (Fig. 315-42) is
sias, GAVE, and radiation-induced rectal ectasias are often responsive a potentially life-threatening event and represents an endoscopic emer-
to local endoscopic ablative therapy, such as argon plasma coagulation gency. Left untreated, the patient may develop esophageal ulceration,
(Video V5-13). Patients with diffuse small bowel vascular ectasias ischemia, and perforation. Patients with persistent esophageal obstruc-
(associated with chronic renal failure and with hereditary hemorrhagic tion often have hypersalivation and are usually unable to swallow
telangiectasia) may continue to bleed despite endoscopic treatment of water. Sips of a carbonated beverage, sublingual nifedipine or nitrates,
easily accessible lesions by conventional endoscopy. These patients or intravenous glucagon may resolve an esophageal food impaction,
may benefit from device-assisted enteroscopy with endoscopic therapy but in most patients an underlying web, ring, or stricture is present
or pharmacologic treatment with octreotide or estrogen/progesterone. and endoscopic removal of the obstructing food bolus is necessary.
Colonic Diverticula Diverticula form where
nutrient arteries penetrate the muscular wall of the
colon en route to the colonic mucosa (Fig. 315-39).
The artery found in the base of a diverticulum may
bleed, causing painless and impressive hematochezia.
Colonoscopy is indicated in patients with hematoc-
hezia and suspected diverticular hemorrhage, since
other causes of bleeding (such as vascular ectasias,
colitis, and colon cancer) must be excluded. In addition
an actively bleeding diverticulum may be seen and
treated during colonoscopy (Fig. 315-40, Video V5-14).
■■GASTROINTESTINAL OBSTRUCTION
AND PSEUDOOBSTRUCTION
Endoscopy is useful for evaluation and treatment A B
of some forms of gastrointestinal obstruction. An FIGURE 315-36 Dieulafoy’s lesion. A. Actively spurting jejunal Dieulafoy’s lesion. There is no
important exception is small-bowel obstruction due to underlying mucosal lesion. B. Histology of a gastric Dieulafoy’s lesion. A persistent caliber artery
surgical adhesions, which is generally not diagnosed (arrows) is present in the gastric submucosa, immediately beneath the mucosa.

appearance may be characteristic of a particular condition, such as 2199
sigmoid volvulus (Fig. 315-44). Both obstruction and pseudoobstruc-
tion may lead to colonic perforation if left untreated. Acute colonic
pseudoobstruction is a form of colonic ileus that is usually attributable
to electrolyte disorders, narcotic and anticholinergic medications, immo-
bility (as after surgery), or retroperitoneal hemorrhage or mass. Multiple
causative factors are often present. Colonoscopy, water-soluble contrast
enema, or CT may be used to assess for an obstructing lesion and dif-
ferentiate obstruction from pseudoobstruction. One of these diagnostic
studies should be strongly considered if the patient does not have clear
risk factors for pseudoobstruction, if radiographs do not show air in
the rectum, or if the patient fails to improve when underlying causes of
pseudoobstruction have been addressed. The risk of cecal perforation
in pseudoobstruction rises when the cecal diameter exceeds 12 cm,
and decompression of the colon may be achieved using intravenous
neostigmine or via colonoscopic decompression (Fig. 315-45). Most
patients should receive a trial of conservative therapy (with correction of
electrolyte disorders, removal of offending medications, and increased
mobilization) before undergoing an invasive decompressive procedure
for colonic pseudoobstruction.
Colonic obstruction is an indication for urgent intervention. In the
past, emergent diverting colostomy was usually performed with a sub-
FIGURE 315-37 Mallory-Weiss tear at the gastroesophageal junction. sequent second operation after bowel preparation to treat the under-
lying cause of obstruction. Colonoscopic placement of an expandable
stent is an alternative treatment option that can relieve malignant
Endoscopy is generally the best initial test in such patients since endo- colonic obstruction without emergency surgery and permit bowel
scopic removal of the obstructing material is usually possible, and the preparation for an elective one-stage operation (Fig. 315-46, Video
presence of an underlying esophageal pathology can often be deter- V5-17).

mined. Radiographs of the chest and neck should be considered before
endoscopy in patients with fever, obstruction for ≥24 h, or ingestion of ■■ACUTE BILIARY OBSTRUCTION
a sharp object, such as a fishbone. Radiographic contrast studies inter- The steady, severe pain that occurs when a gallstone acutely obstructs
fere with subsequent endoscopy and are not advisable in most patients the common bile duct often brings patients to a hospital. The diag-
with a clinical picture of esophageal obstruction. nosis of a ductal stone is suspected when the patient is jaundiced or
when serum liver tests or pancreatic enzyme levels are elevated; it is
Gastric Outlet Obstruction Obstruction of the gastric outlet confirmed by EUS, magnetic resonance cholangiography (MRCP), or
is commonly caused by gastric, duodenal, or pancreatic malignancy, direct cholangiography (performed endoscopically, percutaneously,
or chronic peptic ulceration with stenosis of the pylorus (Fig. 315-43). or during surgery). ERCP is the primary means of treating common
Patients vomit partially digested food many hours after eating. Gastric bile duct stones (Figs. 315-15 and 315-16), although they can also be
decompression with a nasogastric tube and subsequent lavage for removed by laparoscopic bile duct exploration at the time of cholecys-
removal of retained material is the first step in treatment. The diagnosis tectomy. Radiologic percutaneous biliary drainage may be required in
can then be confirmed with a saline load test, if desired. Endoscopy some cases.
is useful for diagnosis and treatment. Patients with benign pyloric
stenosis may be treated with endoscopic balloon dilation of the pylo- Bile Duct Imaging While transabdominal ultrasound diagnoses
rus, and a course of endoscopic dilation results in long-term relief only a minority of bile duct stones, MRCP and EUS are >90% accurate
of symptoms in ~50% of patients. Removable, fully covered lumen- and have an important role in diagnosis. Examples of these modalities
apposing metal stents (LAMS) may also be used to treat benign pylo- are shown in Fig. 315-47.
ric stenosis (Video V5-15). Malignant gastric outlet obstruction can be If the suspicion for a bile duct stone is high and urgent treatment is
relieved with endoscopically placed expandable stents in patients with required (as in a patient with obstructive jaundice and biliary sepsis),
inoperable malignancy (Video V5-16). ERCP is the procedure of choice since it remains the gold standard
for diagnosis and allows for immediate treatment (Video V5-18). If a
Colonic Obstruction and Pseudoobstruction These condi- persistent bile duct stone is relatively unlikely (as in a patient with gall-
tions both present with abdominal distention and discomfort, tympany, stone pancreatitis), ERCP may be supplanted by less invasive imaging
and a dilated colon on plain abdominal radiography. The radiographic techniques, such as EUS, MRCP, or intraoperative cholangiography
A B C
FIGURE 315-38 Gastrointestinal vascular ectasias. A. Gastric antral vascular ectasia (“watermelon stomach”) characterized by stripes of prominent flat or raised
vascular ectasias. B. Cecal vascular ectasias. C. Radiation-induced vascular ectasias of the rectum in a patient previously treated for prostate cancer.

2200
FIGURE 315-41 Esophageal food (meat) impaction.

FIGURE 315-39 Colonic diverticula.
acute biliary obstruction. Medical management usually improves the

performed during cholecystectomy, sparing some patients the risk and patient’s clinical status, providing a window of ~24 h during which
discomfort of ERCP. biliary drainage should be established, typically by ERCP. Undue delay
can result in recrudescence of overt sepsis and increased morbidity and
Ascending Cholangitis Charcot’s triad of jaundice, abdominal mortality rates. In addition to Charcot’s triad, the additional presence
pain, and fever is present in ~70% of patients with ascending cholan- of shock and confusion (Reynolds’s pentad) is associated with a high
PART 10
gitis and biliary sepsis. These patients are managed initially with fluid mortality rate and should prompt urgent intervention to restore biliary
resuscitation and intravenous antibiotics. Abdominal ultrasound is drainage.
often performed to assess for gallbladder stones and bile duct dila-
tion. However, the bile duct may not be dilated early in the course of Gallstone Pancreatitis Gallstones may cause acute pancreatitis
as they pass through the ampulla of Vater. The occurrence of gallstone
pancreatitis usually implies passage of a stone into the duodenum,

and only ~20% of patients harbor a persistent stone in the ampulla or
the common bile duct. Retained stones are more common in patients
with jaundice, rising serum liver tests following hospitalization, severe
pancreatitis, or superimposed ascending cholangitis.
Urgent ERCP decreases the morbidity rate of gallstone pancreatitis in
a subset of patients with retained bile duct stones. It is unclear whether
the benefit of ERCP is mainly attributable to treatment and prevention
of ascending cholangitis or to relief of pancreatic ductal obstruction.
ERCP is warranted early in the course of gallstone pancreatitis if
ascending cholangitis is suspected, especially in a jaundiced patient.
B
FIGURE 315-40 Diverticular hemorrhage. A. Actively bleeding sigmoid diverticulum.
B. Hemostasis achieved using endoscopic clips. FIGURE 315-42 Impacted nail in the esophagus.

2201
FIGURE 315-44 Sigmoid volvulus with the characteristic radiologic appearance

of a “bent inner tube.”
a heterogeneous category that includes disorders of motility, sensation

and somatization. Gastric and esophageal malignancies are less common
causes of dyspepsia. Careful history-taking allows accurate differential
diagnosis of dyspepsia in only about half of patients. In the remainder,

endoscopy can be a useful diagnostic tool, especially in patients whose
symptoms are not resolved by Helicobacter pylori treatment or an empir-
ical trial of acid-reducing therapy. Endoscopy should be performed
B at the outset in patients with dyspepsia and alarm features, such as
weight loss or iron-deficiency anemia.
■■GASTROESOPHAGEAL REFLUX DISEASE (GERD)

When classic symptoms of gastroesophageal reflux are present, such
as water brash and substernal heartburn, presumptive diagnosis and
C
FIGURE 315-43 Gastric outlet obstruction due to pyloric stenosis. A. Nonsteroidal
anti-inflammatory agent-induced ulcer disease with severe stenosis of the pylorus
(arrow). B. Balloon dilation of the stenosis. C. Appearance of pyloric ring post A
dilation.
Urgent ERCP may also benefit patients predicted to have severe

pancreatitis using a clinical index of severity, such as the Glasgow or
Ranson score. Since the benefit of ERCP is limited to patients with a
retained bile duct stone, a strategy of initial MRCP or EUS for diag-
nosis decreases the utilization of ERCP in gallstone pancreatitis and
improves clinical outcomes by limiting the occurrence of ERCP-related
adverse events.
ELECTIVE ENDOSCOPY
■■DYSPEPSIA B
Dyspepsia is a chronic or recurrent burning discomfort or pain in the FIGURE 315-45 Acute colonic pseudoobstruction. A. Acute colonic dilation
upper abdomen that may be caused by diverse processes, such as gas- occurring in a patient soon after knee surgery. B. Colonoscopic placement of
troesophageal reflux, peptic ulcer disease, and “nonulcer dyspepsia,” decompression tube with marked improvement in colonic dilation.

2202
A B C
FIGURE 315-46 Obstructing colonic carcinoma. A. Colonic adenocarcinoma causing marked luminal narrowing of the distal transverse colon. B. Endoscopic placement
of a self-expandable metal stent. C. Radiograph of expanded stent across the obstructing tumor with a residual waist (arrow).
empirical treatment are often sufficient. Endoscopy is a sensitive test be considered in patients with a chronic (≥10 year) history of GERD
for diagnosis of esophagitis (Fig. 315-48), but it will miss nonerosive symptoms. Endoscopic biopsy is the gold standard for confirmation
reflux disease (NERD) since some patients have symptomatic reflux of Barrett’s esophagus and for dysplasia or cancer arising in Barrett’s
without esophagitis. The most sensitive test for diagnosis of GERD is mucosa.
24-h ambulatory pH monitoring. Endoscopy is indicated in patients Periodic EGD with biopsies is recommended for surveillance of
with reflux symptoms refractory to antisecretory therapy; in those with patients with Barrett’s esophagus. Endoscopic resection (EMR or ESD)
alarm symptoms, such as dysphagia, weight loss, or gastrointestinal and/or ablation are performed when high-grade dysplasia or intramu-
PART 10
bleeding; and in those with recurrent dyspepsia after treatment that is cosal cancer are found in the Barrett’s mucosa. Although guidelines
not clearly due to reflux on clinical grounds alone. Endoscopy should be recommend observation and surveillance of low-grade dysplasia in
considered in patients with long-standing (≥10 years) GERD, as they Barrett’s mucosa, recent evidence suggests that endoscopic treatment
have a sixfold increased risk of harboring Barrett’s esophagus com- may be appropriate in select patients. Radiofrequency ablation (RFA)
pared to patients with <1 year of reflux symptoms. is the commonest ablative modality used for endoscopic treatment of
Barrett’s Esophagus Barrett’s esophagus is specialized columnar Barrett’s esophagus, and other modalities, such as cryotherapy, are also
metaplasia that replaces the normal squamous mucosa of the distal available.
esophagus in some persons with GERD. Barrett’s epithelium is a major
risk factor for adenocarcinoma of the esophagus and is readily detected ■■PEPTIC ULCER
endoscopically, due to proximal displacement of the squamocolumnar Peptic ulcer classically causes epigastric gnawing or burning, often
junction (Fig. 315-5). A screening EGD for Barrett’s esophagus should occurring nocturnally and promptly relieved by food or antacids.
A B C
FIGURE 315-47 Methods of bile duct imaging. Arrows mark bile duct stones. A. Endoscopic ultrasound (EUS). B. Magnetic resonance cholangiopancreatography
(MRCP). C. Helical computed tomography (CT).

(feline esophagus) should raise suspicion for eosinophilic 2203
esophagitis, an increasingly recognized cause for recur-
rent dysphagia and food impaction (Fig. 315-51). Blind or
forceful passage of an endoscope may lead to perforation
in a patient with stenosis of the cervical esophagus or a
Zenker’s diverticulum, but gentle passage of an endo-
scope under direct visual guidance is reasonably safe.
Endoscopy can miss a subtle stricture or ring in some
patients.
When transfer dysphagia is evident or an esopha-
geal motility disorder is suspected, esophageal radiog-
A B raphy and/or a video-swallow study are the best initial
diagnostic tests. The oropharyngeal swallowing mecha-
nism, esophageal peristalsis, and the lower esophageal
sphincter can all be assessed. In some disorders, subse-
quent esophageal manometry may also be important for
diagnosis.
Various causes of dysphagia are amenable to endo-
scopic therapy. Benign strictures, rings, and webs can be
dilated using a through-the-scope balloon (Fig. 315-52)
or a polyvinyl dilator passed over a guide wire. In some
instances, thin fibrotic strictures may respond to needle-
knife electroincision (Fig. 315-53) when they prove
refractory to dilation. Esophageal covered stents can
be used to palliate dysphagia from malignant obstruc-
tion (Fig. 315-54), and flexible endoscopic myotomy
C D
is an option for Zenker’s diverticulum (Video V5-19).
FIGURE 315-48 Causes of esophagitis. A. Severe reflux esophagitis with mucosal ulceration Recent advances in submucosal endoscopy have

and friability. B. Cytomegalovirus esophagitis. C. Herpes simplex virus esophagitis with target- enabled the development of procedures, such as POEM
type shallow ulcerations. D. Candida esophagitis with white plaques adherent to the esophageal
mucosa.
(Video V5-20) and POET (Video V5-21) for the man-
agement of achalasia and select subepithelial esopha-
geal tumors, respectively.
Although endoscopy is the most sensitive diagnostic test for peptic ■■ENDOSCOPIC TREATMENT OF OBESITY
ulcer, it is not a cost-effective strategy in young patients with ulcer-like The majority of Americans are overweight or obese, and obesity-
dyspeptic symptoms unless endoscopy is available at low cost. Patients associated diabetes has become a major public health problem. Bariatric
with suspected peptic ulcer should be evaluated for H. pylori infection. surgery is the most effective weight-loss intervention, and it has been
Serology (past or present infection), urea breath testing (current infec- shown to decrease long-term mortality in obese persons, but many
tion), and stool tests are noninvasive and less costly than endoscopy patients do not undergo surgery. Endoscopic treatments for obesity
with biopsy. Patients aged >50 and those with alarm symptoms or have been developed and include insertion of an intragastric balloon
persistent symptoms despite treatment should undergo endoscopy to or duodenojejunal bypass liner, placement of a percutaneous gastric
exclude malignancy. tube for aspiration of gastric contents after meals, or endoscopic sleeve
gastroplasty, which utilizes endoscopic suturing to narrow the lumen
■■NONULCER DYSPEPSIA of the gastric body (Video V5-22). Prospective trials show that these
Nonulcer dyspepsia may be associated with bloating and, unlike peptic treatments induce total body weight loss of 7–20% and varying degrees
ulcer, tends not to remit and recur. Most patients describe persistent of glycemic control. Additional endoscopic modalities are undergoing
symptoms despite acid-reducing, prokinetic, or anti-Helicobacter ther-
apy, and are referred for endoscopy to exclude a refractory ulcer and
assess for other causes. Although endoscopy is useful for excluding
other diagnoses, its impact on the treatment of patients with nonulcer
dyspepsia is limited.
■■DYSPHAGIA
About 50% of patients presenting with difficulty swallowing have a
mechanical obstruction; the remainder has a motility disorder, such
as achalasia or diffuse esophageal spasm. Careful history-taking often
points to a presumptive diagnosis and leads to the appropriate use of
diagnostic tests. Esophageal strictures (Fig. 315-49) typically cause pro-
gressive dysphagia, first for solids, then for liquids; motility disorders
often cause intermittent dysphagia for both solids and liquids. Some
underlying disorders have characteristic historic features: Schatzki’s
ring (Fig. 315-50) causes episodic dysphagia for solids, typically at the
beginning of a meal; oropharyngeal motor disorders typically present
with difficulty initiating deglutition (transfer dysphagia) and nasal reflux
or coughing with swallowing; and achalasia may cause nocturnal regur-
gitation of undigested food.
When mechanical obstruction is suspected, endoscopy is a use-
ful initial diagnostic test, since it permits immediate biopsy and/or
dilation of strictures, masses, or rings. The presence of linear furrows
and multiple corrugated rings throughout a narrowed esophagus FIGURE 315-49 Peptic esophageal stricture associated with esophagitis.

2204 endoscopically is often made in collaboration with a surgeon and/
or oncologist.
Endoscopic palliation of gastrointestinal malignancies relieves
symptoms and in many cases prolongs survival. Malignant obstruction
can be relieved by endoscopic stent placement (Figs. 315-17, 315-54,
and 315-55; Videos V5-16, V5-17), and malignant gastrointestinal bleed-
ing can often be palliated endoscopically as well. EUS-guided celiac
plexus neurolysis may relieve pancreatic cancer pain.
■■ANEMIA AND OCCULT BLOOD IN THE STOOL

Iron-deficiency anemia may be attributed to poor iron absorption
(as in celiac sprue) or, more commonly, chronic blood loss. Intestinal
bleeding should be strongly suspected in men and postmenopausal
women with iron-deficiency anemia, and colonoscopy is indicated in
such patients, even in the absence of detectable occult blood in the
stool. Approximately 30% will have large colonic polyps, 10% will have
colorectal cancer, and a few patients will have colonic vascular lesions.
When a convincing source of blood loss is not found in the colon, upper
gastrointestinal endoscopy should be considered; if no lesion is found,
duodenal biopsies should be obtained to exclude sprue (Fig. 315-56).
Small bowel evaluation with capsule endoscopy (Fig. 315-57), CT or
MR enterography, or device-assisted enteroscopy may be appropriate
FIGURE 315-50 Schatzki’s ring at the gastroesophageal junction.
if both EGD and colonoscopy are unrevealing.
Tests for occult blood in the stool detect hemoglobin or the heme
moiety and are most sensitive for colonic blood loss, although they will
initial clinical trials. The long-term efficacy of endoscopic bariatric
also detect larger amounts of upper gastrointestinal bleeding. Patients
treatment is currently unknown.
with occult blood in normal-appearing stool should undergo colonos-
■■TREATMENT OF MALIGNANCIES copy to diagnose or exclude colorectal neoplasia, especially if they
Endoscopy plays an important role in the treatment of gastrointesti- are over 50 years of age or have a family history of colonic neoplasia.
PART 10
nal malignancies. Early-stage malignancies limited to the superficial Whether upper endoscopy is also indicated depends on the patient’s
layers of the gastrointestinal mucosa may be resected using the symptoms.
techniques of EMR (Video V5-4) or ESD (Video V5-5). Photodynamic The small intestine may be the source of chronic intestinal bleed-
therapy (PDT) and RFA are effective modalities for ablative treatment ing, especially if colonoscopy and upper endoscopy are not diag-
of high-grade dysplasia and intramucosal cancer in Barrett’s esopha- nostic. The utility of small bowel evaluation varies with the clinical
gus (Video V5-23). Gastrointestinal stromal tumors can be removed setting and is most important in patients in whom bleeding causes
en bloc by EFTR (Video V5-3). In general, endoscopic techniques chronic or recurrent anemia. In contrast to the low diagnostic yield of
offer the advantage of a minimally invasive approach to treatment small bowel radiography, positive findings on capsule endoscopy are
but rely on other imaging techniques (such as CT, MRI, positron seen in 50–70% of patients with suspected small intestinal bleeding.
emission tomography [PET], and EUS) to exclude distant metastases The most common finding is mucosal vascular ectasia. CT or MR
or locally advanced disease better treated by surgery or other modal- enterography accurately detects small bowel masses and inflam-
ities. The decision to treat an early-stage gastrointestinal malignancy mation, and are also useful for initial small bowel evaluation. Deep
enteroscopy may follow capsule endoscopy for biopsy of lesions or to
provide specific therapy, such as argon plasma coagulation of vascu-
lar ectasias (Fig. 315-58).
■■COLORECTAL CANCER SCREENING

The majority of colon cancers develop from preexisting colonic ade-
nomas, and colorectal cancer can be largely prevented by the detection
and removal of adenomatous polyps (Video V5-24). The choice of
screening strategy for an asymptomatic person depends on personal
and family history. Individuals with inflammatory bowel disease, a
history of colorectal polyps or cancer, family members with adenoma-
tous polyps or cancer, or certain familial cancer syndromes (Fig. 315-59)
are at increased risk for colorectal cancer. An individual without these
factors is generally considered at average risk.
Screening strategies are summarized in Table 315-3. While stool
tests for occult blood have been shown to decrease mortality rate from
colorectal cancer, they do not detect some cancers and many polyps,
and direct visualization of the colon is a more effective screening
strategy. Either sigmoidoscopy or colonoscopy may be used for cancer
screening in asymptomatic average-risk individuals. The use of sig-
moidoscopy was based on the historical finding that the majority
of colorectal cancers occurred in the rectum and left colon, and that
patients with right-sided colon cancers had left-sided polyps. Over the
past several decades, however, the distribution of colon cancers has
FIGURE 315-51 Eosinophilic esophagitis with multiple circular rings of the
esophagus creating a corrugated appearance, and an impacted grape at the changed in the United States, with proportionally fewer rectal and left-
narrowed esophagogastric junction. The diagnosis requires biopsy with histologic sided cancers than in the past. Large American studies of colonoscopy
finding of >15–20 eosinophils/high-power field. for screening of average-risk individuals show that cancers are roughly

2205
A B C
FIGURE 315-52 Endoscopic management of peptic stricture. A. Peptic stricture. B. Through-the-scope balloon dilation of stricture. C. Improvement in luminal diameter
postdilation.
equally distributed between left and right colon and half of patients
with right-sided lesions have no polyps in the left colon. Visualization
of the entire colon thus appears to be the optimal strategy for colorectal
cancer screening and prevention.
Virtual colonoscopy (VC) is a radiologic technique that images the
colon with CT following rectal insufflation of the colonic lumen.
Computer rendering of CT images generates an electronic display of
a virtual “flight” along the colonic lumen, simulating colonoscopy
(Fig. 315-60). Findings detected during VC often require subsequent

conventional colonoscopy for confirmation and treatment.
■■DIARRHEA
Most cases of diarrhea are acute, self-limited, and due to infections or
medication. Chronic diarrhea (lasting >6 weeks) is more often due to a
A
B
A
C
FIGURE 315-53 Endoscopic management of an esophagogastric anastomotic
B
stricture. A. Recurrent anastomotic stricture despite periodic balloon dilation.
B. Needle-knife electroincision of stricture. C. Improvement in luminal opening FIGURE 315-54 Palliation of malignant dysphagia. A. Obstructing distal
post therapy. esophageal cancer. B. Palliative stent placement.

2206
A B
PART 10
C D
FIGURE 315-55 Biliary and duodenal self-expanding metal stents (SEMS) for obstruction caused by pancreatic cancer. A. Endoscopic retrograde cholangiopancreatography
(ERCP) demonstrates a distal bile duct stricture (arrow). B. A biliary SEMS is placed. C. Contrast injection demonstrates a duodenal stricture (arrow). D. Biliary and
duodenal SEMS in place.
primary inflammatory, malabsorptive, or motility disorder, is less likely Patients with colonic symptoms and findings such as bloody diar-
to resolve spontaneously, and generally requires diagnostic evaluation. rhea, tenesmus, fever, or leukocytes in stool generally undergo sigmoi-
Patients with chronic diarrhea or severe, unexplained acute diarrhea doscopy or colonoscopy to assess for colitis (Fig. 315-8). Sigmoidoscopy
often undergo endoscopy if stool tests for pathogens are unrevealing. is an appropriate initial test in most patients. Conversely, patients
The choice of endoscopic testing depends on the clinical setting. with symptoms and findings suggesting small bowel disease, such as
large-volume watery stools, substantial weight loss, and malabsorption
of iron, calcium, or fat, may undergo upper endoscopy with duode-
nal aspirates for assessment of bacterial overgrowth and biopsies for
assessment of mucosal diseases, such as celiac sprue.
FIGURE 315-57 Capsule endoscopy images of a mildly scalloped jejunal fold

(left) and an ileal tumor (right) in a patient with celiac sprue. (Images courtesy of
FIGURE 315-56 Scalloped duodenal folds in a patient with celiac sprue. Dr. Elizabeth Rajan; with permission.)

colon. Patients reporting red blood on the toilet tissue only, without 2207
blood in the toilet or on the stool, are generally bleeding from a lesion
in the anal canal; careful external inspection, digital examination, and
proctoscopy with anoscopy may be sufficient for diagnosis in such
cases.
■■PANCREATITIS
About 20% of patients with pancreatitis have no identified cause after
routine clinical investigation (including a review of medication and
alcohol use, measurement of serum triglyceride and calcium levels,
abdominal ultrasonography, and CT or MR). Endoscopic assessment
A leads to a specific diagnosis in the majority of such patients, often
altering clinical management. Endoscopic investigation is particu-
larly appropriate if the patient has had more than one episode of
pancreatitis.
Microlithiasis, or the presence of microscopic crystals in bile, is
a leading cause of previously unexplained acute pancreatitis and is
sometimes seen during abdominal ultrasonography as layering sludge
or flecks of floating, echogenic material in the gallbladder. EUS may
identify previously undetected microlithiasis.
Previously undetected chronic pancreatitis, pancreatic malignancy, or
pancreas divisum may be diagnosed by either ERCP or EUS. Autoimmune
pancreatitis is often suspected on the basis of CT, MR, or serologic findings,
B
but it may first become apparent during EUS and may require EUS-guided
pancreatic biopsy for histologic diagnosis.
FIGURE 315-58 A. Mid-jejunal vascular ectasia identified by double-balloon Severe pancreatitis often results in pancreatic fluid collections.
endoscopy. B. Ablation of vascular ectasia with argon plasma coagulation.
Symptomatic pseudocysts and areas of walled-off pancreatic necro-
sis can be drained into the stomach or duodenum endoscopically,

using transpapillary and transmural endoscopic techniques. Pancreatic
Many patients with chronic diarrhea do not fit either of these patterns.
necrosis can be treated by direct endoscopic necrosectomy (Video V5-2)
In the setting of a long-standing history of alternating constipation and
via an endoscopically created transmural drainage site.
diarrhea dating to early adulthood, without findings such as blood in the
stool or anemia, a diagnosis of irritable bowel syndrome may be made
without direct visualization of the bowel. Steatorrhea and upper abdom- ■■CANCER STAGING
inal pain may prompt evaluation of the pancreas rather than the gut. Local staging of esophageal, gastric, pancreatic, bile duct, and rectal
Patients whose chronic diarrhea is not easily categorized often undergo cancers can be obtained with EUS (Fig. 315-19). EUS with fine-needle
initial colonoscopy to examine the entire colon and terminal ileum for aspiration (Fig. 315-20) currently provides the most accurate pre-
inflammatory or neoplastic disease (Fig. 315-61). operative assessment of local tumor and nodal staging, but it does
not detect many distant metastases. Details of the local tumor stage
can guide treatment decisions including resectability and need for
■■MINOR HEMATOCHEZIA neoadjuvant therapy. EUS with transesophageal needle biopsy may
Bright red blood passed with or on formed brown stool usually has a
also be used to assess the presence of non-small-cell lung cancer in
rectal, anal, or distal sigmoid source (Fig. 315-62). Patients with even
mediastinal nodes.
trivial amounts of hematochezia should be investigated with flexible
sigmoidoscopy and anoscopy to exclude polyps or cancers in the distal
OPEN-ACCESS ENDOSCOPY
Direct scheduling of endoscopic procedures by primary care physicians
without preceding gastroenterology consultation, or open-access endos-
copy, is common. When the indications for endoscopy are clear-cut and
appropriate, the procedural risks are low, and the patient understands
what to expect, open-access endoscopy streamlines patient care and
decreases costs.
Patients referred for open-access endoscopy should have a recent
history, physical examination, and medication review. A copy of such
an evaluation should be available when the patient comes to the
endoscopy suite. Patients with unstable cardiovascular or respiratory
conditions should not be referred directly for open-access endoscopy.
Patients with particular conditions and undergoing certain procedures
should be prescribed prophylactic antibiotics prior to endoscopy
(Table 315-1). In addition, patients taking anticoagulants and/or anti-
platelet drugs may require adjustment of these agents before endos-
copy based on the procedural risk for bleeding and their underlying
risk for a thromboembolic event (Table 315-2).
Common indications for open-access EGD include dyspepsia
resistant to a trial of appropriate therapy, dysphagia, gastrointesti-
nal bleeding, and persistent anorexia or early satiety. Open-access
colonoscopy is often requested in men or postmenopausal women
FIGURE 315-59 Numerous colon polyps in a patient with familial adenomatous with iron-deficiency anemia, in patients age >50 with occult blood in
polyposis syndrome. the stool, in patients with a previous history of colorectal adenomatous

2208 TABLE 315-3 Colorectal Cancer Screening Strategies
CHOICES/RECOMMENDATIONS COMMENTS
Average-Risk Patients
Asymptomatic individuals ≥50 years of age Colonoscopy every 10 yearsa Preferred cancer prevention strategy
(≥45 years of age for African Americans)
Annual FIT or FOBT, multiple take-home Cancer detection strategy, does not detect most polyps;
specimen cards colonoscopy if results are positive
CT colonography every 5 years Colonoscopy if results are positive
Flexible sigmoidoscopy every 5 years Does not detect proximal colon polyps and cancers;
colonoscopy if results are positive
Double-contrast barium enema every Less sensitive than colonoscopy or CT colonography,
5 years misses some cancers and polyps; colonoscopy if results
Stool DNA test every 3 years are positive
Does not detect many polyps; colonoscopy if results are
positive
Personal History of Polyps or CRC
1 or 2 small (<1 cm) adenomas with low-grade Repeat colonoscopy in 5–10 years Assuming complete polyp resection. Interval may vary based
dysplasia on prior history, family history
3–10 adenomas, or any high-risk adenomab Repeat colonoscopy in 3 years; subsequent Assuming complete polyp resection
colonoscopy based on findings
>10 adenomas Repeat colonoscopy in <3 years based on Consider evaluation for FAP or HNPCC; see recommendations
clinical judgment below
Piecemeal removal of a sessile polyp Exam in 2–6 months to verify complete
removal
Small (<1 cm) hyperplastic polyps of sigmoid and Repeat colonoscopy in 10 years Those with hyperplastic polyposis syndrome merit more
rectum frequent follow-up
Sessile serrated adenoma/polyp <10 mm, without Repeat colonoscopy in 5 years
dysplasia
Sessile serrated adenoma/polyp ≥10 mm or with Repeat colonoscopy in 3 years Serrated polyposis syndrome merits more frequent follow-up
PART 10
dysplasia, or ≥2 serrated polyps

Incompletely removed serrated polyp ≥1 cm Exam in 2–6 months to verify complete
removal
Colon cancer Evaluate entire colon around the time of Subsequent colonoscopy in 3 years if the 1-year examination
resection, then repeat colonoscopy in 1 year is normal
Inflammatory Bowel Disease

Long-standing (>8 years) ulcerative pancolitis or Colonoscopy with biopsies every 1–2 years Consider chromoendoscopy or other advanced imaging
Crohn’s colitis, or left-sided ulcerative colitis of techniques for detection of flat dysplasia during colonoscopy
>15 years’ duration
Family History of Polyps or CRC
First-degree relatives with only small tubular Same as average risk
adenomas
Single first-degree relative with CRC or advanced Colonoscopy every 10 years starting at
adenoma at age ≥60 years age 40
Single first-degree relative with CRC or advanced Colonoscopy every 5 years beginning at age
adenoma at age <60 years, OR two first-degree 40 years or 10 years younger than age at
relatives with CRC or advanced adenomas at any age diagnosis of the youngest affected relative,
whichever is earlier
FAP Sigmoidoscopy or colonoscopy annually, Consider genetic counseling and testing
beginning at age 10–12 years
HNPCC Colonoscopy every 2 years beginning at age Consider histologic evaluation for microsatellite instability in
20–25 years (or 10 years younger than the tumor specimens of patients who meet modified Bethesda
youngest affected first-degree relative) until criteria; consider genetic counseling and testing
age 40, then annually thereafter
a
Assumes good colonic preparation and complete examination to cecum. bHigh-risk adenoma: any adenoma ≥ 1 cm in size, or containing high-grade dysplasia or villous
features
Abbreviations: CRC, colorectal cancer; FAP, familial adenomatous polyposis; FIT, fecal immunochemical test; FOBT, fecal occult blood test; HNPCC, hereditary
nonpolyposis colorectal cancer.
Source: Adapted from United States Preventative Services Task Force Guidelines released in 2016 (https://www.uspreventiveservicestaskforce.org/Page/Document/
UpdateSummaryFinal/colorectal-cancer-screening2?ds=1&s=colorectal) accessed on Jan 2, 2017, and American Cancer Society Guidelines updated in 2016 (http://www.cancer
.org/cancer/colonandrectumcancer/moreinformation/colonandrectumcancerearlydetection/colorectal-cancer-early-detection-acs-recommendations) accessed Jan 2, 2017.
polyps or cancer, and for colorectal cancer screening. Flexible sigmoi- solution, with or without citric acid. A “split-dose” regimen improves
doscopy is commonly performed as an open-access procedure. the quality of colonic preparation. Sodium phosphate purgatives may
When patients are referred for open-access colonoscopy, the cause fluid and electrolyte abnormalities and renal toxicity, especially
primary care provider may need to choose a colonic preparation. in patients with renal failure or congestive heart failure and those
Commonly used oral preparations include polyethylene glycol lavage >70 years of age.

■■FURTHER READING 2209
ASGE Standards of Practice Committee et al: Appropriate use of
GI endoscopy. Gastrointest Endosc 75:1127, 2012.
ASGE Standards of Practice Committee et al: Antibiotic
prophylaxis for GI endoscopy. Gastrointest Endosc 81:81, 2015.
ASGE Standards of Practice Committee et al: Open-access
endoscopy. Gastrointest Endosc 81:1326, 2015.
Garcia-Tsao G et al: Portal hypertensive bleeding in cirrhosis: Risk
stratification, diagnosis, and management: 2016 practice guidance by
the American Association for the study of liver diseases. Hepatology
65:310, 2017.
Gralnek IM et al: Diagnosis and management of nonvariceal upper
gastrointestinal hemorrhage: European Society of Gastrointestinal
Endoscopy (ESGE) Guideline. Endoscopy 47:a1, 2015.
Lin JS et al: Screening for colorectal cancer: Updated evidence report
and systematic review. JAMA 315:2576, 2016.
Shaheen NJ et al: ACG Clinical Guideline: Diagnosis and management
of Barrett’s esophagus. Am J Gastroenterol 111:30, 2016.
Strate LL et al: ACG Clinical Guideline: Management of patients with
acute lower gastrointestinal bleeding. Am J Gastroenterol 111:459,
FIGURE 315-60 Virtual colonoscopy image of a colon polyp (arrow). (Image 2016.
courtesy of Dr. Jeff Fidler; with permission.)
316 Diseases of the Esophagus
CHAPTER 316 Diseases of the Esophagus

Peter J. Kahrilas, Ikuo Hirano
ESOPHAGEAL STRUCTURE AND FUNCTION

The esophagus is a hollow, muscular tube coursing through the pos-
terior mediastinum joining the hypopharynx to the stomach with a
sphincter at each end. It functions to transport food and fluid between
these ends, otherwise remaining empty. The physiology of swallowing,
esophageal motility, and oral and pharyngeal dysphagia are described
in Chap. 40. Esophageal diseases can be manifested by impaired func-
tion or pain. Key functional impairments are swallowing disorders
and excessive gastroesophageal reflux. Pain, sometimes indistinguish-
able from cardiac chest pain, can result from inflammation, infection,
dysmotility, or neoplasm.
FIGURE 315-61 Crohn’s ileitis. SYMPTOMS OF ESOPHAGEAL DISEASE
The clinical history remains central to the evaluation of esophageal
symptoms. A thoughtfully obtained history will often expedite man-
agement. Important details include weight gain or loss, gastrointestinal
bleeding, dietary habits including the timing of meals, smoking, and
alcohol consumption. The major esophageal symptoms are heart-
burn, regurgitation, chest pain, dysphagia, odynophagia, and globus
sensation.
Heartburn (pyrosis), the most common esophageal symptom, is char-
acterized by a discomfort or burning sensation behind the sternum that
arises from the epigastrium and may radiate toward the neck. Heart-
burn is an intermittent symptom, most commonly experienced after
eating, during exercise, and while lying recumbent. The discomfort is
relieved with drinking water or antacid but can occur frequently inter-
fering with normal activities including sleep. The association between
heartburn and gastroesophageal reflux disease (GERD) is so strong that
empirical therapy for GERD has become accepted management. How-
ever, the term “heartburn” is often misused and/or referred to with
other terms such as “indigestion” or “repeating,” making it important
to clarify the intended meaning.
Regurgitation is the effortless return of food or fluid into the pharynx
without nausea or retching. Patients report a sour or burning fluid
in the throat or mouth that may also contain undigested food parti-
FIGURE 315-62 Internal hemorrhoids with bleeding (arrow) as seen on a cles. Bending, belching, or maneuvers that increase intraabdominal
retroflexed view of the rectum. pressure can provoke regurgitation. A clinician needs to discriminate

2210 among regurgitation, vomiting, and rumination. Vomiting is preceded radiography compared with endoscopy for detecting reflux esophagitis
by nausea and accompanied by retching. Rumination is a behavior in reportedly ranges from 22 to 95%, with higher grades of esophagitis
which recently swallowed food is regurgitated and then reswallowed (i.e., ulceration or stricture) exhibiting greater detection rates. Con-
repetitively for up to an hour. Although there is some linkage between versely, the sensitivity of barium radiography for detecting esophageal
rumination and cognitive deficiency, the behavior is also exhibited by strictures is greater than that of endoscopy, especially when the study
unimpaired individuals. is done in conjunction with a 13-mm barium tablet. Barium studies
Chest pain is a common esophageal symptom with characteristics also provide an assessment of esophageal function and morphology
similar to cardiac pain, sometimes making this distinction difficult. that may be undetected on endoscopy. Tracheoesophageal fistula,
Esophageal pain is usually experienced as a pressure type sensation in altered postsurgical anatomy, and extrinsic esophageal compression
the mid chest, radiating to the mid back, arms, or jaws. The similarity to are conditions where radiographic imaging complements endoscopic
cardiac pain is likely because the two organs share a nerve plexus and assessment. Hypopharyngeal pathology and disorders of the cri-
the nerve endings in the esophageal wall have poor discriminative abil- copharyngeus muscle are better appreciated on radiographic exami-
ity among stimuli. Esophageal distention or even chemostimulation nation than with endoscopy, particularly with rapid sequence or video
(e.g., with acid) will often be perceived as chest pain. Gastroesophageal fluoroscopic recording. The major shortcoming of barium radiography
reflux is the most common cause of esophageal chest pain. is that it rarely obviates the need for endoscopy. Either a positive or a
Esophageal dysphagia (Chap. 40) is often described as a feeling of negative study is usually followed by an endoscopic evaluation either
food “sticking” or even lodging in the chest. Important distinctions are to obtain biopsies, provide therapy, or clarify findings in the case of
between uniquely solid food dysphagia as opposed to liquid and solid, a positive examination or to add a level of certainty in the case of a
episodic versus constant dysphagia, and progressive versus static dys- negative one.
phagia. If the dysphagia is for liquids as well as solid food, it suggests
a motility disorder such as achalasia. Conversely, uniquely solid food
■■ENDOSCOPIC ULTRASOUND
dysphagia is suggestive of a stricture, ring, or tumor. Of note, a patient’s
Endoscopic ultrasound (EUS) instruments combine an endoscope
localization of food hang-up in the esophagus is notoriously imprecise.
with an ultrasound transducer to create a transmural image of the
Approximately 30% of distal esophageal obstructions are perceived
tissue surrounding the endoscope tip. The key advantage of EUS over
as cervical dysphagia. In such instances, the absence of concomitant
alternative radiologic imaging techniques is much greater resolution
symptoms generally associated with oropharyngeal dysphagia such as
attributable to the proximity of the ultrasound transducer to the area
aspiration, nasopharyngeal regurgitation, cough, drooling, or obvious
being examined. Available devices can provide either radial imaging
neuromuscular compromise should suggest an esophageal etiology.
(360-degree, cross-sectional) or a curved linear image that can guide
Odynophagia is pain either caused by or exacerbated by swallowing.
fine-needle aspiration of imaged structures such as lymph nodes or
PART 10
Although typically considered distinct from dysphagia, odynophagia

tumors. Major esophageal applications of EUS are to stage esophageal
may manifest concurrently with dysphagia. Odynophagia is more com-
cancer, to evaluate dysplasia in Barrett’s esophagus, and to assess
mon with pill or infectious esophagitis than with reflux esophagitis and
submucosal lesions.
should prompt a search for these entities. When odynophagia does occur
in GERD, it is likely related to an esophageal ulcer or extensive erosions.
Globus sensation, also known as globus pharyngeus, is the perception ■■ESOPHAGEAL MANOMETRY
of a lump or fullness in the throat that is felt irrespective of swallowing. Esophageal manometry, or motility testing, entails positioning a
Although such patients are frequently referred for an evaluation of dys- pressure-sensing catheter within the esophagus and then observing
phagia, globus sensation is often relieved by the act of swallowing. As the contractility following test swallows. The upper and lower esoph-
implied by its alternative name, “globus hystericus,” globus sensation ageal sphincters (LESs) appear as zones of high pressure that relax
often occurs in the setting of anxiety or obsessive-compulsive disor- on swallowing, while the intersphincteric esophagus exhibits peri-
ders. Clinical experience teaches that it is often attributable to GERD. staltic contractions. Manometry is used to diagnose motility disorders
Water brash is excessive salivation resulting from a vagal reflex trig- (achalasia, diffuse esophageal spasm [DES]) and to assess peristaltic
gered by acidification of the esophageal mucosa. This is not a common integrity prior to the surgery for reflux disease. Technologic advances
symptom. Afflicted individuals will describe the unpleasant sensation have enhanced esophageal manometry as high-resolution esophageal
of the mouth rapidly filling with salty thin fluid, often in the setting of pressure topography (Fig. 316-1). Manometry can also be combined
concomitant heartburn. with intraluminal impedance monitoring. Impedance recordings use a
series of paired electrodes added to the manometry catheter. Esopha-
DIAGNOSTIC STUDIES geal luminal contents in contact with the electrodes decrease (liquid) or
increase (air) the impedance signal, allowing detection of anterograde
■■ENDOSCOPY or retrograde esophageal bolus transit.
Endoscopy, also known as esophagogastroduodenoscopy (EGD), is the
most useful test for the evaluation of the proximal gastrointestinal tract.
Modern instruments produce high-quality, color images of the esoph- ■■REFLUX TESTING
ageal, gastric, and duodenal lumen. Endoscopes also have an instru- GERD is often diagnosed in the absence of endoscopic esophagitis,
mentation channel through which biopsy forceps, injection catheters which would otherwise define the disease. This occurs in the settings of
for local delivery of therapeutic agents, balloon dilators, or hemostatic partially treated disease, an abnormally sensitive esophageal mucosa,
devices can be used. The key advantages of endoscopy over barium or without obvious explanation. In such instances, reflux testing can
radiography are: (1) increased sensitivity for the detection of mucosal demonstrate excessive esophageal exposure to refluxed gastric juice,
lesions, (2) vastly increased sensitivity for the detection of abnormali- the physiologic abnormality of GERD. This can be done by ambu-
ties mainly identifiable by color such as Barrett’s metaplasia or vascular latory 24- to 96-h esophageal pH recording using either a wireless
lesions, (3) the ability to obtain biopsy specimens for histologic exami- pH-sensitive transmitter that is affixed to the esophageal mucosa or a
nation of suspected abnormalities, and (4) the ability to dilate strictures transnasally positioned wire electrode with the tip stationed in the dis-
during the examination. The main disadvantages of endoscopy are low tal esophagus. Either way, the outcome is expressed as the percentage
sensitivity for detection of diffuse, non-focal esophageal strictures, cost, of the day that the pH was <4 (indicative of recent acid reflux), with
and the utilization of sedatives or anesthetics. values exceeding 5% indicative of GERD. Reflux testing is useful in the
evaluation of patients presenting with atypical symptoms or an inex-
■■RADIOGRAPHY plicably poor response to therapy. Intraluminal impedance monitoring
Contrast radiography of the esophagus, stomach, and duodenum can be added to pH monitoring to detect reflux events irrespective of
can demonstrate reflux of the contrast media, hiatal hernia, mucosal whether or not they are acidic, potentially increasing the sensitivity of
granularity, erosions, ulcerations, and strictures. The sensitivity of the study.

2211
FIGURE 316-1 High-resolution esophageal pressure topography (right) and conventional manometry (left) of a normal swallow. E, esophageal body; LES, lower
esophageal sphincter; UES, upper esophageal sphincter.
STRUCTURAL DISORDERS intermittent dysphagia to solids similar to Schatzki rings and are sim-
ilarly treated with dilation. The combination of symptomatic proximal
■■HIATAL HERNIA esophageal webs and iron-deficiency anemia in middle-aged women
Hiatus hernia is a herniation of viscera, most commonly the stomach, constitutes Plummer-Vinson syndrome.
into the mediastinum through the esophageal hiatus of the diaphragm.
Four types of hiatus hernia are distinguished with type I, or sliding hia- ■■DIVERTICULA
tal hernia, comprising at least 95% of the overall total. A sliding hiatal Esophageal diverticula are categorized by location with the most

hernia is one in which the gastroesophageal junction and gastric cardia common being epiphrenic, hypopharyngeal (Zenker’s), and midesoph-
translocate cephalad as a result of weakening of the phrenoesophageal ageal. Epiphrenic and Zenker’s diverticula are false diverticula involv-
ligament attaching the gastroesophageal junction to the diaphragm at ing herniation of the mucosa and submucosa through the muscular
the hiatus and dilatation of the diaphragmatic hiatus. The incidence layer of the esophagus. These lesions result from increased intralumi-
of sliding hernia increases with age. True to its name, sliding hernias nal pressure associated with distal obstruction. In the case of Zenker’s,
enlarge with increased intraabdominal pressure, swallowing, and res- the obstruction is a stenotic cricopharyngeus muscle (upper esophageal
piration. Conceptually, sliding hernias are the result of wear and tear: sphincter), and the hypopharyngeal herniation most commonly occurs
increased intraabdominal pressure from abdominal obesity, pregnancy, in an area of natural weakness proximal to the cricopharyngeus known
etc., along with hereditary factors predisposing to the condition. The as Killian’s triangle (Fig. 316-3). Small Zenker’s diverticula are usually
main significance of sliding hernias is the propensity of affected indi- asymptomatic, but when they enlarge sufficiently to retain food and
viduals to have GERD. saliva they can be associated with dysphagia, halitosis, and aspira-
Type II, III, and IV hiatal hernias are all subtypes of paraesophageal tion. Treatment is by surgical diverticulectomy and cricopharyngeal
hernia in which the herniation into the mediastinum includes a visceral
structure other than the gastric cardia. With type II and III paraesoph-
ageal hernias, the gastric fundus also herniates with the distinction Tubular
being that in type II, the gastroesophageal junction remains fixed at esophagus
Eso tibule
ves
the hiatus, whereas type III is a combined sliding and paraesophageal

pha
hernia. With type IV hiatal hernias, viscera other than the stomach
gea
herniate into the mediastinum, most commonly the colon. With type II
Phrenic
l Sli ernia
and III paraesophageal hernias, the stomach inverts as it herniates and ampulla
large paraesophageal hernias can lead to an “upside down stomach,” A ring
ding
h
gastric volvulus, and even strangulation of the stomach. Because of this

hiat
risk, surgical repair is often advocated for large paraesophageal hernias

al
particularly when they are symptomatic.
■■RINGS AND WEBS

A lower esophageal mucosal ring, also called a B ring, is a thin membra- B ring
nous narrowing at the squamocolumnar mucosal junction (Fig. 316-2). squamo-columnar
Its origin is unknown, but B rings are demonstrable in about 10–15% of junction
the general population and are usually asymptomatic. When the lumen
diameter is <13 mm, distal rings are usually associated with episodic
solid food dysphagia and are called Schatzki rings. Patients typically Diaphragmatic Rugal folds
present older than 40 years, consistent with an acquired rather than impression traversing hiatus
congenital origin. Schatzki ring is one of the most common causes of
intermittent food impaction, also known as “steakhouse syndrome”
because meat is a typical instigator. Symptomatic rings are readily
treated by dilation.
Web-like constrictions higher in the esophagus can be of congenital
or inflammatory origin. Asymptomatic cervical esophageal webs are
demonstrated in about 10% of people and typically originate along the
anterior aspect of the esophagus. When circumferential, they can cause FIGURE 316-2 Radiographic anatomy of the gastroesophageal junction.

2212
A B C
FIGURE 316-3 Examples of small (A) and large (B, C) Zenker’s diverticula arising from Killian’s triangle in the distal hypopharynx. Smaller diverticula are evident
only during the swallow, whereas larger ones retain food and fluid.
myotomy or a marsupialization procedure in which an endoscopic These generally become symptomatic only when they are associated
stapling device is used to divide the cricopharyngeus. with dysphagia and merit removal only under the same circumstances.
Epiphrenic diverticula are often associated with achalasia, esoph-
ageal hypercontractile disorders, or a distal esophageal stricture. CONGENITAL ANOMALIES
Midesophageal diverticula may be caused by traction from adjacent The most common congenital esophageal anomaly is esophageal
PART 10
inflammation (classically tuberculosis) in which case they are true atresia, occurring in about 1 in 5000 live births. Atresia can occur in
diverticula involving all layers of the esophageal wall, or by pulsion several permutations, the common denominator being developmental
associated with esophageal motor disorders. Midesophageal and
epiphrenic diverticula are usually asymptomatic until they enlarge suf-
ficiently to retain food and cause dysphagia and regurgitation. Symp-
toms attributable to the diverticula tend to correlate more with the

underlying esophageal disorder than the size of the diverticula. Large
diverticula can be removed surgically, usually in conjunction with
a myotomy if the underlying motility disorder is identified. Diffuse
intramural esophageal pseudodiverticulosis is a rare entity that results
from dilatation of the excretory ducts of submucosal esophageal glands
(Fig. 316-4). Esophageal candidiasis and proximal esophageal strictures
are commonly found in association with this disorder.
■■TUMORS
Esophageal cancer occurs in about 4.5:100,000 people in the
United States with the associated mortality being only slightly less at
4.4:100,000. It is about 10 times less common than colorectal cancer but
kills about one-quarter as many patients. These statistics emphasize
both the rarity and lethality of esophageal cancer. One notable trend
is the shift of dominant esophageal cancer type from squamous cell
to adenocarcinoma, strongly linked to reflux disease and Barrett’s
metaplasia. Other distinctions between cell types are the predilection
for adenocarcinoma to affect the distal esophagus in white males and
squamous cell to affect the more proximal esophagus in black males
with the added risk factors of smoking, alcohol consumption, caustic
injury, and human papilloma virus infection (Chap. 76).
The typical presentation of esophageal cancer is of progressive solid
food dysphagia and weight loss. Associated symptoms may include
odynophagia, iron deficiency, and, with midesophageal tumors,
hoarseness from left recurrent laryngeal nerve injury. Generally, these
are indications of locally invasive or even metastatic disease manifest
by tracheoesophageal fistulas and vocal cord paralysis. Even when
detected as a small lesion, esophageal cancer has poor survival because
of the abundant esophageal lymphatics leading to regional lymph node
metastases.
Benign esophageal tumors are uncommon and usually discovered
incidentally. In decreasing frequency of occurrence, cell types include FIGURE 316-4 Intramural esophageal pseudodiverticulosis associated with
leiomyoma, fibrovascular polyps, squamous papilloma, granular cell chronic obstruction. Invaginations of contrast into the esophageal wall outline
tumors, lipomas, neurofibromas, and inflammatory fibroid polyps. deep esophageal glands.

failure of fusion between the proximal and distal esophagus associated 2213
with a tracheoesophageal fistula, most commonly with the distal seg-
ment excluded. Alternatively, there can be an H-type configuration in
which esophageal fusion has occurred, but with a tracheoesophageal
fistula. Esophageal atresia is usually recognized and corrected surgi-
cally within the first few days of life. Later life complications include
dysphagia from anastomotic strictures or absent peristalsis and reflux,
which can be severe. Less common developmental anomalies include
congenital esophageal stenosis, webs, and duplications.
Dysphagia can also result from congenital abnormalities that cause
extrinsic compression of the esophagus. In dysphagia lusoria, the
esophagus is compressed by an aberrant right subclavian artery arising
from the descending aorta and passing behind the esophagus. Alterna-
tively, vascular rings may surround and constrict the esophagus.
Heterotopic gastric mucosa, also known as an esophageal inlet
patch, is a focus of gastric type epithelium in the proximal cervical
esophagus; the estimated prevalence is 4–5%. The inlet patch is thought
to result from incomplete replacement of embryonic columnar epi- FIGURE 316-5 Achalasia with esophageal dilatation, tapering at the gastro-
esophageal junction, and an air-fluid level within the esophagus. The example
thelium with squamous epithelium. The majority of inlet patches are
on the left shows sigmoid deformity with very advanced disease.
asymptomatic, but acid production can occur as most contain fundic
type gastric epithelium with parietal cells.
is more likely with advanced age, abrupt onset of symptoms (<1 year),
ESOPHAGEAL MOTILITY DISORDERS and weight loss. Hence, endoscopy is a necessary part of the evaluation
Esophageal motility disorders are diseases attributable to esophageal of achalasia. When the clinical suspicion for pseudoachalasia is high
neuromuscular dysfunction commonly associated with dysphagia, and endoscopy nondiagnostic, computed tomography (CT) scanning
chest pain, or heartburn. The major entities are achalasia, DES, and or EUS may be of value. Rarely, pseudoachalasia can result from a para-
GERD. Motility disorders can also be secondary to broader disease neoplastic syndrome with circulating antineuronal antibodies.
processes as is the case with pseudoachalasia, Chagas’ disease, and Achalasia is diagnosed by barium swallow x-ray and/or esopha-

scleroderma. Not included in this discussion are diseases affecting the geal manometry; endoscopy has a relatively minor role other than to
pharynx and proximal esophagus, the impairment of which is almost exclude pseudoachalasia. The barium swallow x-ray appearance is of a
always part of a more global neuromuscular disease process. dilated esophagus with poor emptying, an air-fluid level, and tapering
at the LES giving it a beak-like appearance (Fig. 316-5). Occasionally,
■■ACHALASIA an epiphrenic diverticulum is observed. In long-standing achalasia,
Achalasia is a rare disease caused by loss of ganglion cells within the the esophagus may assume a sigmoid configuration. The diagnostic
esophageal myenteric plexus with a population incidence estimated to criteria for achalasia with esophageal manometry are impaired LES
be 1–3 per 100,000 and usually presenting between age 25 and 60. With relaxation and absent peristalsis. High-resolution manometry has
long-standing disease, aganglionosis is noted. The disease involves somewhat advanced this diagnosis; three subtypes of achalasia are dif-
both excitatory (cholinergic) and inhibitory (nitric oxide) ganglionic ferentiated based on the pattern of pressurization in the nonperistaltic
neurons. Functionally, inhibitory neurons mediate deglutitive LES esophagus (Fig. 316-6). Because manometry identifies early disease
relaxation and the sequential propagation of peristalsis. Their absence before esophageal dilatation and food retention, it is the most sensitive
leads to impaired deglutitive LES relaxation and absent peristalsis. diagnostic test.
Increasing evidence suggests that the ultimate cause of ganglion cell There is no known way of preventing or reversing achalasia.
degeneration in achalasia is an autoimmune process attributable to Therapy is directed at reducing LES pressure so that gravity and
a latent infection with human herpes simplex virus 1 combined with esophageal pressurization promote esophageal emptying. Peristalsis
genetic susceptibility. does not recover. However, in many instances, remnants of peristalsis
Long-standing achalasia is characterized by progressive dilatation masked by esophageal pressurization and dilatation prior to therapy
and sigmoid deformity of the esophagus with hypertrophy of the are demonstrable following effective treatment. LES pressure can be
LES. Clinical manifestations may include dysphagia, regurgitation, reduced by pharmacologic therapy, pneumatic balloon dilation, or
chest pain, and weight loss. Most patients report solid and liquid food surgical myotomy. No large, controlled trials of the therapeutic alter-
dysphagia. Regurgitation occurs when food, fluid, and secretions are natives exist, and the optimal approach is debated. Pharmacologic
retained in the dilated esophagus. Patients with advanced achalasia are therapies are relatively ineffective but are often used as temporizing
at risk for bronchitis, pneumonia, or lung abscess from chronic regur- therapies. Nitrates or calcium channel blockers are administered before
gitation and aspiration. Chest pain is frequent early in the course of eating, advising caution because of their effects on blood pressure. Bot-
achalasia, thought to result from esophageal spasm. Patients describe ulinum toxin, injected into the LES under endoscopic guidance, inhibits
a squeezing, pressure-like retrosternal pain, sometimes radiating to the acetylcholine release from nerve endings and improves dysphagia in
neck, arms, jaw, and back. Paradoxically, some patients complain of about 66% of cases for at least 6 months. Sildenafil and alternative
heartburn that may be a chest pain equivalent. Treatment of achalasia phosphodiesterase inhibitors effectively decrease LES pressure, but
is less effective in relieving chest pain than it is in relieving dysphagia practicalities limit their clinical use in achalasia.
or regurgitation. The only durable therapies for achalasia are pneumatic dilation and
The differential diagnosis of achalasia includes DES, Chagas’ dis- Heller myotomy. Pneumatic dilation, with a reported efficacy ranging
ease, and pseudoachalasia. Chagas’ disease is endemic in areas of cen- from 32 to 98%, is an endoscopic technique using a noncompliant,
tral Brazil, Venezuela, and northern Argentina and spread by the bite cylindrical balloon dilator positioned across the LES and inflated to
of the reduviid (kissing) bug that transmits the protozoan, Trypanosoma a diameter of 3–4 cm. The major complication is perforation with a
cruzi. The chronic phase of the disease develops years after infection reported incidence of 0.5–5%. The most common surgical procedure
and results from destruction of autonomic ganglion cells throughout for achalasia is laparoscopic Heller myotomy, usually performed in
the body, including the heart, gut, urinary tract, and respiratory tract. conjunction with an antireflux procedure (partial fundoplication);
Tumor infiltration, most commonly seen with carcinoma in the gastric good to excellent results are reported in 62–100% of cases. A European-
fundus or distal esophagus, can mimic idiopathic achalasia. The resul- randomized controlled trial demonstrated an equivalent response rate
tant “pseudoachalasia” accounts for up to 5% of suspected cases and of ~90% for both pneumatic dilation and laparoscopic Heller myotomy

2214 A. Classic achalasia is the likely explanation for the association between achalasia and
0 Pharynx esophageal squamous cell cancer. Tumors develop after years of acha-
150
125 5 lasia, usually in the setting of extreme esophageal dilatation with the
overall squamous cell cancer risk increased seventeenfold compared
100 10 to controls.
75
50
15 ■■DIFFUSE ESOPHAGEAL SPASM
Cm
20
DES is manifested by episodes of dysphagia and chest pain attribut-
25 able to abnormal esophageal contractions with normal deglutitive LES
0 25 relaxation. Beyond that, there is little consensus. The pathophysiology
–10 and natural history of DES are ill defined. Radiographically, DES has
30
mmHg been characterized by tertiary contractions or a “corkscrew esophagus”
35 Stomach (Fig. 316-7), but in many instances, these abnormalities are actually
0 1 2 3 4 5 6 7 8 9 10 indicative of achalasia. Manometrically, a variety of defining features
Seconds have been proposed including uncoordinated (“spastic”) activity in
the distal esophagus, spontaneous and repetitive contractions, or high-
B. Achalasia with compression
75 0 Pharynx amplitude and prolonged contractions. The current consensus, derived
70 from high-resolution manometry studies, is to define spasm by the
5 occurrence of contractions in the distal esophagus with short latency
60
relative to the time of the pharyngeal contraction, a dysfunction indic-
50 10
ative of impairment of inhibitory myenteric plexus neurons. When
40 15 defined in this restrictive fashion (Fig. 316-8), DES is actually much less
Cm common than achalasia.
30 20 Esophageal chest pain closely mimics angina pectoris. Features
20 suggesting esophageal pain include pain that is nonexertional, pro-
15 25
10 longed, interrupts sleep, meal-related, relieved with antacids, and
5 30 accompanied by heartburn, dysphagia, or regurgitation. However, all
0 of these features exhibit overlap with cardiac pain, which still must be
–5
35 Stomach the primary consideration. Furthermore, even within the spectrum of
–10
mmHg 0 5 10 15 20 25 esophageal diseases, both chest pain and dysphagia are also character-
PART 10
Seconds
istic of peptic or infectious esophagitis. Only after these more common
mmHg C. Spastic achalasia entities have been excluded by evaluation and/or treatment should a
100 0 Pharynx diagnosis of DES be pursued.
90 Although DES is diagnosed by manometry, endoscopy is useful to
5 identify alternative structural and inflammatory lesions that may cause

80
70 10
chest pain. Radiographically, a “corkscrew esophagus,” “rosary bead
60
esophagus,” pseudodiverticula, or curling can be indicative of DES,
15 but these are also found with spastic achalasia. Given these vagaries of
50
Cm defining DES, and the resultant heterogeneity of patients identified for
40 20 inclusion in therapeutic trials, it is not surprising that trial results have
30 been disappointing. Only small, uncontrolled trials exist, reporting
25
20 response to nitrates, calcium channel blockers, hydralazine, botulinum
15
10 30 toxin, and anxiolytics. The only controlled trial showing efficacy was
5
0
35 Stomach
–10
0 10 20 30 40 50
Seconds
FIGURE 316-6 Three subtypes of achalasia: classic (A), with esophageal
compression (B), and spastic achalasia (C) imaged with pressure topography.
All are characterized by impaired lower esophageal sphincter (LES) relaxation
and absent peristalsis. However, classic achalasia has minimal pressurization
of the esophageal body, whereas substantial fluid pressurization is observed in
achalasia with esophageal compression, and spastic esophageal contractions
are observed with spastic achalasia.
at 5-year follow-up. Occasionally, patients with advanced disease fail

to respond to pneumatic dilation or Heller myotomy. In such refrac-
tory cases, esophageal resection with gastric pull-up or interposition
of a segment of transverse colon may be the only option other than
gastrostomy feeding.
An endoscopic approach to LES myotomy has been introduced,
referred to as per oral esophageal myotomy (POEM). This technique
involves the creation of a submucosal tunnel within the esophageal
wall through which the circular muscle of the LES and distal esoph-
agus are transected with electrocautery. Short-term studies of efficacy
have been favorable. Potential advantages over the conventional
laparoscopic approach include avoidance of surgical disruption of the
FIGURE 316-7 Diffuse esophageal spasm. The characteristic “corkscrew” esophagus
diaphragmatic hiatus and more rapid recovery. results from spastic contraction of the circular muscle in the esophageal wall;
In untreated or inadequately treated achalasia, esophageal dilata- more precisely, this is actually a helical array of muscle. These findings are also
tion predisposes to stasis esophagitis. Prolonged stasis esophagitis seen with spastic achalasia.

mmHg with the mechanism of belching (transient 2215
150 LES relaxation), but esophagitis results
Jackhammer esophagus Diffuse esophageal spasm from excessive reflux, often accompanied
by impaired clearance of the refluxed gas-
tric juice. Restricting reflux to that which
is physiologically intended depends on
100 the anatomic and physiologic integrity of
the esophagogastric junction, a complex
sphincter comprised of both the LES and
the surrounding crural diaphragm. Three
Latency= 3.5 s dominant mechanisms of esophagogas-
50 tric junction incompetence are recognized:
(1) transient LES relaxations (a vagovagal
reflex in which LES relaxation is elicited by
0 5 10 15 0 10 20 30 gastric distention), (2) LES hypotension, or
Time (s) Time (s) (3) anatomic distortion of the esophagogas-
0 tric junction inclusive of hiatus hernia. Of
Normal latency with hypercontractility Short latency, premature contraction
note, the third factor, esophagogastric junc-
FIGURE 316-8 Esophageal pressure topography of the two major variants of esophageal spasm: jackhammer tion anatomic disruption, is both significant
esophagus (left) and diffuse esophageal spasm (right). Jackhammer esophagus is defined by the extraordinarily unto itself and also because it interacts
vigorous and repetitive contractions with normal peristaltic onset and normal latency of the contraction. Diffuse
esophageal spasm is similar but primarily defined by a short latency (premature) contraction.
with the first two mechanisms. Transient
LES relaxations account for about 90% of
reflux in normal subjects or GERD patients
with an anxiolytic. Surgical therapy (long myotomy or even esophagec- without hiatus hernia, but patients with hiatus hernia have a more
tomy) should be considered only with severe weight loss or unbearable heterogeneous mechanistic profile. Factors tending to exacerbate reflux
pain. These indications are extremely rare. regardless of mechanism are abdominal obesity, pregnancy, gastric
hypersecretory states, delayed gastric emptying, disruption of esopha-
■■NONSPECIFIC MANOMETRIC FINDINGS geal peristalsis, and gluttony.

Manometric studies done to evaluate chest pain and/or dysphagia After acid reflux, peristalsis returns the refluxed fluid to the stomach
often report minor abnormalities (e.g., hypertensive or hypotensive and acid clearance is completed by titration of the residual acid by
peristalsis, hypertensive LES) that are insufficient to diagnose either bicarbonate contained in swallowed saliva. Consequently, two causes
achalasia or DES. These findings are of unclear significance. Reflux of prolonged acid clearance are impaired peristalsis and reduced sali-
and psychiatric diagnoses, particularly anxiety and depression, are vation. Impaired peristaltic emptying can be attributable to disrupted
common among such individuals. A lower visceral pain threshold and peristalsis or superimposed reflux associated with a hiatal hernia.
symptoms of irritable bowel syndrome are noted
in more than half of such patients. Consequently,
therapy for these individuals should either target the
most common esophageal disorder, GERD, or more
global conditions such as depression or somatization
neurosis that are found to be coexistent.
GASTROESOPHAGEAL REFLUX
DISEASE
The current conception of GERD is to encompass a
family of conditions with the commonality that they
are caused by gastroesophageal reflux resulting in
either troublesome symptoms or an array of potential
esophageal and extraesophageal manifestations. It is
estimated that 10–15% of adults in the United States
are affected by GERD, although such estimates are A Erosive esophagitis B Esophageal stricture with chronic
erosive esophagitis
based only on population studies of self-reported
chronic heartburn. With respect to the esophagus, the
spectrum of injury includes esophagitis, stricture, Bar-
rett’s esophagus, and adenocarcinoma (Fig. 316-9). Of
particular concern is the rising incidence of esophageal
adenocarcinoma, an epidemiologic trend that parallels
the increasing incidence of GERD. There were about
8000 incident cases of esophageal adenocarcinoma
in the United States in 2013 (half of all esophageal
cancers); it is estimated that this disease burden has
increased two- to sixfold in the last 20 years.
■■PATHOPHYSIOLOGY
The best-defined subset of GERD patients, albeit
a minority overall, have esophagitis. Esophagitis
occurs when refluxed gastric acid and pepsin cause C Barrett’s esophagus D Esophageal adenocarcinoma
necrosis of the esophageal mucosa causing erosions with Barrett’s esophagus
and ulcers. Note that some degree of gastroesoph- FIGURE 316-9 Endoscopic appearance of (A) peptic esophagitis, (B) a peptic stricture, (C) Barrett’s
ageal reflux is normal, physiologically intertwined metaplasia, and (D) adenocarcinoma developing within an area of Barrett’s esophagus.

2216 With superimposed reflux, fluid retained within a sliding hiatal hernia eosinophilic esophagitis (EoE), peptic ulcer disease, dyspepsia, biliary
refluxes back into the esophagus during swallow-related LES relax- colic, coronary artery disease, and esophageal motility disorders. It is
ation, a phenomenon that does not normally occur. especially important that coronary artery disease be given early con-
Inherent in the pathophysiologic model of GERD is that gastric sideration because of its potentially lethal implications. The remaining
juice is harmful to the esophageal epithelium. However, gastric acid elements of the differential diagnosis can be addressed by endoscopy,
hypersecretion is usually not a dominant factor in the development of upper gastrointestinal series, or esophageal manometry as appropriate.
esophagitis. An obvious exception is with Zollinger-Ellison syndrome, Erosive esophagitis at the esophagogastric junction is the endoscopic
which is associated with severe esophagitis in about 50% of patients. hallmark of GERD, but identified in only about one third of patients with
Another caveat is with chronic Helicobacter pylori gastritis, which may GERD. The distinction among etiologies of esophagitis is readily made
have a protective effect by inducing atrophic gastritis with concomi- by endoscopic appearance but mucosal biopsies may be helpful to eval-
tant hypoacidity. Pepsin, bile, and pancreatic enzymes within gastric uate for infectious or eosinophilic inflammation. In terms of endoscopic
secretions can also injure the esophageal epithelium, but their noxious appearance, the ulcerations seen in peptic esophagitis are usually soli-
properties are either lessened without an acidic environment or depen- tary and distal, whereas infectious ulcerations are punctate and diffuse.
dent on acidity for activation. Bile warrants attention because it persists EoE characteristically exhibits multiple esophageal rings, linear furrows,
in refluxate despite acid-suppressing medications. Bile can transverse white punctate exudate, and strictures. Esophageal ulcerations from pill
the cell membrane, imparting severe cellular injury in a weakly acidic esophagitis are usually singular and deep at points of luminal narrow-
environment, and has also been invoked as a cofactor in the pathogen- ing, especially near the carina, with sparing of the distal esophagus.
esis of Barrett’s metaplasia and adenocarcinoma. Hence, the causticity
of gastric refluxate extends beyond hydrochloric acid. ■■COMPLICATIONS
The complications of GERD are related to chronic esophagitis (bleed-
■■SYMPTOMS ing and stricture) and the relationship between GERD and esophageal
Heartburn and regurgitation are the typical symptoms of GERD. Some- adenocarcinoma. However, both erosive esophagitis and peptic stric-
what less common are dysphagia and chest pain. In each case, multiple tures have become increasingly rare in the era of potent antisecretory
potential mechanisms for symptom genesis operate that extend beyond medications. Conversely, the most severe histologic consequence of
the basic concepts of mucosal erosion and activation of afferent sensory GERD is Barrett’s metaplasia with the associated risk of esophageal
nerves. Specifically, hypersensitivity and functional pain are increas- adenocarcinoma, and the incidence of these lesions has increased, not
ingly recognized as cofactors. Nonetheless, the dominant clinical decreased, in the era of potent acid suppression. Barrett’s metaplasia,
strategy is empirical treatment with acid inhibitors, reserving further endoscopically recognized by tongues of salmon-colored mucosa
evaluation for those who fail to respond. Important exceptions to this extending proximally from the gastroesophageal junction (Fig. 316-9)
or histopathologically by the finding of specialized columnar metapla-
PART 10
are patients with chest pain or persistent dysphagia, each of which

may be indicative of more morbid conditions. With chest pain, cardiac sia, is associated with a significantly increased risk for development of
disease must be carefully considered. In the case of persistent dyspha- esophageal adenocarcinoma.
gia, chronic reflux can lead to the development of a peptic stricture or Barrett’s metaplasia can progress to adenocarcinoma through the
adenocarcinoma, each of which benefits from early detection and/or intermediate stages of low- and high-grade dysplasia (Fig. 316-10).
specific therapy. Owing to this risk, areas of Barrett’s and especially any included areas
Extraesophageal syndromes with an established association to of mucosal irregularity should be carefully inspected and extensively
GERD include chronic cough, laryngitis, asthma, and dental erosions. biopsied. The rate of cancer development is estimated at 0.1–0.3% per
A multitude of other conditions including pharyngitis, chronic bron- year, but vagaries in definitional criteria and of the extent of Barrett’s
chitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias, sleep metaplasia requisite to establish the diagnosis have contributed to vari-
apnea, and recurrent aspiration pneumonia have proposed associations ability and inconsistency in this risk assessment. The group at greatest
with GERD. However, in both cases, it is important to emphasize the risk is obese white males in their sixth decade of life. However, despite
word association as opposed to causation. In many instances, the disor- common practice, the utility of endoscopic screening and surveillance
ders likely coexist because of shared pathogenetic mechanisms rather programs intended to control the adenocarcinoma risk has not been
than strict causality. Potential mechanisms for extraesophageal GERD established. Also of note, no high-level evidence confirms that aggres-
manifestations are either regurgitation with direct contact between sive antisecretory therapy or antireflux surgery causes regression of
the refluxate and supraesophageal structures or via a vagovagal reflex Barrett’s esophagus or prevents adenocarcinoma.
wherein reflux activation of esophageal afferent nerves triggers efferent Although the management of Barrett’s esophagus remains contro-
vagal reflexes such as bronchospasm, cough, or arrhythmias. versial, the finding of dysplasia in Barrett’s, particularly high-grade
dysplasia, mandates further intervention. In addition to the high rate
■■DIFFERENTIAL DIAGNOSIS of progression to adenocarcinoma, there is also a high prevalence of
Although generally quite characteristic, symptoms from GERD need unrecognized coexisting cancer with high-grade dysplasia. Treatment
to be distinguished from symptoms related to infectious, pill, or recommendations for Barrett’s esophagus with high-grade dysplasia
Barrett’s metaplasia High grade dysplasia
Alcian blue stain H&E stain
FIGURE 316-10 Histopathology of Barrett’s metaplasia and Barrett’s with high-grade dysplasia. H&E, hematoxylin and eosin.

have evolved over the past several years. Historically, esophagectomy similar efficacy to PPI therapy. However, the benefits of fundoplica- 2217
was the gold standard treatment for high-grade dysplasia. However, tion must be weighed against potential deleterious effects, including
esophagectomy has a mortality ranging from 3 to 10%, along with surgical morbidity and mortality, postoperative dysphagia, failure
substantial morbidity and recent prospective studies have demon- or breakdown requiring reoperation, an inability to belch, and
strated the efficacy of mucosal ablation therapy with substantially less increased bloating, flatulence, and bowel symptoms after surgery.
morbidity and essentially no mortality. Consequently, current societal
guidelines endorse endoscopic mucosal ablation therapies for the ■■EOSINOPHILIC ESOPHAGITIS
management of high-grade dysplasia. EoE is increasingly recognized in adults and children around the
world. Current prevalence estimates in the United States identified 4–6
TREATMENT cases per 10,000 with a predilection for white males between 30 and
40 years of age. The increasing prevalence of EoE is attributable to a
Gastroesophageal Reflux Disease combination of an increasing incidence and a growing recognition of
the condition. There is also an incompletely understood, but important,
Lifestyle modifications are routinely advocated as GERD therapy.
overlap between EoE and GERD that may confound the diagnosis of
Broadly speaking, these fall into three categories: (1) avoidance of
the disease.
foods that reduce LES pressure, making them “refluxogenic” (these
EoE is diagnosed based on the combination of typical esophageal
commonly include fatty foods, alcohol, spearmint, peppermint, and
symptoms and esophageal mucosal biopsies demonstrating squamous
possibly coffee and tea); (2) avoidance of acidic foods that are inher-
epithelial eosinophil-predominant inflammation. Alternative etiologies
ently irritating (citrus fruits, tomato-based foods); and (3) adoption of esophageal eosinophilia include GERD, drug hypersensitivity, con-
of behaviors to minimize reflux and/or heartburn. In general, min- nective tissue disorders, hypereosinophilic syndrome, Crohn’s disease,
imal evidence supports the efficacy of these measures. However, and infection. Current evidence indicates that EoE is an immunologic
clinical experience dictates that subsets of patients are benefitted disorder induced by antigen sensitization in susceptible individuals.
by specific recommendations, based on their individual history and Dietary factors play an important role in both the pathogenesis and
symptom profile. A patient with sleep disturbance from nighttime treatment of EoE. Aeroallergens may also contribute, but the evidence
heartburn is more likely to benefit from elevation of the head of is weaker. The natural history of EoE is unclear, but an increased risk of
the bed and avoidance of eating before retiring. The most broadly esophageal stricture development paralleling the duration of untreated
applicable recommendation is for weight reduction. Even though disease has been noted.
the benefit with respect to reflux cannot be assured, the strong epi- EoE should be strongly considered in children and adults with

demiologic relationship between body mass index and GERD and dysphagia and esophageal food impactions. In preadolescent chil-
the secondary health gains of weight reduction is beyond dispute. dren, symptom presentations of EoE include chest or abdominal pain,
The dominant pharmacologic approach to GERD management is nausea, vomiting, and food aversion. Other symptoms in adults may
with inhibitors of gastric acid secretion, and abundant data support include atypical chest pain and heartburn, particularly heartburn that
the effectiveness of this approach. Pharmacologically reducing the is refractory to PPI therapy. An atopic history of food allergy, asthma,
acidity of gastric juice does not prevent reflux, but it ameliorates eczema, or allergic rhinitis is present in the majority of patients. Periph-
reflux symptoms and allows esophagitis to heal. The hierarchy of eral blood eosinophilia is demonstrable in up to 50% of patients, but the
effectiveness among pharmaceuticals parallels their antisecretory specificity of this finding is problematic in the setting of concomitant
potency. Proton pump inhibitors (PPIs) are more efficacious than atopy. The characteristic endoscopically identified esophageal findings
histamine2 receptor antagonists (H2RAs), and both are superior to include loss of vascular markings (edema), multiple esophageal rings,
placebo. No major differences exist among PPIs, and only modest longitudinally oriented furrows, and punctate exudate (Fig. 316-11).
gain is achieved by increased dosage. Histologic confirmation is made with the demonstration of esophageal
Paradoxically, the perceived frequency and severity of heartburn
correlate poorly with the presence or severity of esophagitis. When
GERD treatments are assessed in terms of resolving heartburn, both
efficacy and differences among pharmaceuticals are less clear-cut
than with the objective of healing esophagitis. Although the same
overall hierarchy of effectiveness exists, observed efficacy rates are
lower and vary widely, likely reflecting patient heterogeneity.
Reflux symptoms tend to be chronic, irrespective of esophagitis.
Thus, a common management strategy is indefinite treatment with
PPIs or H2RAs as necessary for symptom control. The side effects of
PPI therapy are generally minimal. Rare cases of interstitial nephritis
and severe, reversible hypomagnesemia have been reported. Vita-
min B12 and iron absorption may be compromised and susceptibility
to enteric infections, particularly Clostridium difficile colitis, increased A B
with treatment. Observational data have also noted an association
between PPI exposure and renal disease, dementia, and cardiovas-
cular disease, but the hazard ratios reported in these studies were
small and potential for unrecognized residual confounding bias
was substantial. Population studies have also suggested a slight
increased risk of bone fracture with chronic PPI use suggesting an
impairment of calcium absorption, but prospective studies have
failed to corroborate this. Nonetheless, as with any medication,
PPI dosage should be minimized to that necessary for the clinical
indication.
Laparoscopic Nissen fundoplication, wherein the proximal stom-
ach is wrapped around the distal esophagus to create an antireflux
barrier, is a surgical alternative to the management of chronic GERD. C D
Just as with PPI therapy, evidence on the utility of fundoplication FIGURE 316-11 Endoscopic features of (A) eosinophilic esophagitis (EoE),
is strongest for treating esophagitis, and controlled trials suggest (B) Candida esophagitis, (C) giant ulcer associated with HIV, and (D) a Schatzki ring.

2218 INFECTIOUS ESOPHAGITIS
With the increased use of immunosuppression for organ transplan-
tation as well as chronic inflammatory diseases and chemotherapy
along with the AIDS epidemic, infections with Candida species, herpes-
virus, and cytomegalovirus (CMV) have become relatively common.
Although rare, infectious esophagitis also occurs among the non-
immunocompromised, with herpes simplex and Candida albicans being
the most common pathogens. Among AIDS patients, infectious esoph-
agitis becomes more common as the CD4 count declines; cases are rare
with a CD4 count >200 and common when <100. HIV itself may also be
associated with a self-limited syndrome of acute esophageal ulceration
with oral ulcers and a maculopapular skin rash at the time of serocon-
version. Additionally, some patients with advanced disease have deep,
persistent esophageal ulcers treated with oral glucocorticoids or thalid-
omide. However, with the widespread use of highly effective anti-viral
therapies, a reduction in these HIV complications has been noted.
Regardless of the infectious agent, odynophagia is a characteristic
symptom of infectious esophagitis; dysphagia, chest pain, and hem-
orrhage are also common. Odynophagia is uncommon with reflux
esophagitis, so its presence should always raise suspicion of an alter-
native etiology.
■■CANDIDA ESOPHAGITIS
Candida is normally found in the throat, but can become pathogenic and
produce esophagitis in a compromised host; C. albicans is most com-
mon. Candida esophagitis also occurs with esophageal stasis secondary
to esophageal motor disorders and diverticula. Patients complain of
odynophagia and dysphagia. If oral thrush is present, empirical ther-
apy is appropriate, but co-infection is common, and persistent symp-
PART 10
toms should lead to prompt endoscopy with biopsy, which is the most
useful diagnostic evaluation. Candida esophagitis has a characteristic
FIGURE 316-12 Histopathology of eosinophilic esophagitis (EoE) showing appearance of white plaques with friability. Rarely, Candida esophagitis
infiltration of the esophageal squamous epithelium with eosinophils. Additional is complicated by bleeding, perforation, stricture, or systemic invasion.
features of basal cell hyperplasia and lamina propria fibrosis are present. Oral fluconazole (200–400 mg on the first day, followed by 100–200 mg
Eosinophilic inflammation can also be seen with gastroesophageal reflux disease.

daily) for 14–21 days is the preferred treatment. Patients refractory to
fluconazole may respond to voriconazole, or posaconazole. Alterna-
tively, poorly responsive patients or those who cannot swallow medi-
mucosal eosinophilia (peak density ≥15 eosinophils per high-power cations can be treated with an intravenous echinocandin.
field) (Fig. 316-12). Complications of EoE include esophageal stricture,
narrow-caliber esophagus, food impaction, and esophageal perforation. ■■HERPETIC ESOPHAGITIS
The goals of EoE management are symptom control and the preven- Herpes simplex virus type 1 or 2 may cause esophagitis. Vesicles on
tion of complications. Once esophageal eosinophilia is demonstrated, the nose and lips may coexist and are suggestive of a herpetic etiology.
patients typically undergo a trial of PPI therapy as a means of exclud- Varicella-zoster virus can also cause esophagitis in children with chick-
ing a contribution of GERD to the symptoms and esophageal mucosal enpox or adults with zoster. The characteristic endoscopic findings are
inflammation. PPI-responsive esophageal eosinophilia, characterized vesicles and small, punched-out ulcerations. Because herpes simplex
by elimination of mucosal eosinophilia, occurs in 30–50% of cases of infections are limited to squamous epithelium, biopsies from the ulcer
suspected EoE. Patients with persistent symptoms and eosinophilic margins are most likely to reveal the characteristic ground-glass nuclei,
inflammation following PPI therapy are subsequently considered for eosinophilic Cowdry’s type A inclusion bodies, and giant cells. Cul-
treatments such as elimination diets or swallowed topical glucocorti- ture or polymerase chain reaction (PCR) assays are helpful to identify
coids. Elemental formula diets are a highly effective therapy but are acyclovir-resistant strains. Acyclovir (200 mg orally five times a day for
limited by palatability. Notably, allergy testing by means of either 7–10 days) can be used for immunocompetent hosts, although the dis-
serum IgE or skin prick testing has demonstrated poor sensitivity ease is typically self-limited after a 1- to 2-week period in such patients.
and specificity in the identification of foods that incite the esophageal Immunocompromised patients are treated with acyclovir (400 mg
inflammatory response. Allergy testing combining skin prick and orally five times a day for 14–21 days), famciclovir (500 mg orally three
atopy patch testing has been effective in children with EoE, but addi- times a day), or valacyclovir (1 g orally three times a day). In patients
tional validation is needed. Empiric elimination of common food aller- with severe odynophagia, intravenous acyclovir, 5 mg/kg every 8 h for
gies (milk, wheat, egg, soy, nuts, and seafood) followed by systematic 7–14 days, reduces this morbidity.
reintroduction has been an effective diet therapy in both children and
adults with EoE. The intent of the elimination diet approach is the iden- ■■CYTOMEGALOVIRUS
tification of a single or a small number of food triggers. Swallowed, CMV esophagitis occurs primarily in immunocompromised patients,
topical glucocorticoids (e.g., fluticasone propionate or budesonide) are particularly organ transplant recipients. CMV is usually activated
highly effective, but recurrence of disease is common following the ces- from a latent stage. Endoscopically, CMV lesions appear as serpigi-
sation of short-term therapy. Systemic glucocorticoids are reserved for nous ulcers in an otherwise normal mucosa, particularly in the distal
severely afflicted patients refractory to less morbid treatments. Esoph- esophagus. Biopsies from the ulcer bases have the greatest diagnostic
ageal dilation is very effective at relieving dysphagia in patients with yield for finding the pathognomonic large nuclear or cytoplasmic
fibrostenosis. Dilation should be approached conservatively because of inclusion bodies. Immunohistology with monoclonal antibodies to
the risk of deep, esophageal mural laceration or perforation in the stiff- CMV and in situ hybridization tests are useful for early diagnosis.
walled esophagus that is characteristic of the disease. Data on therapy for CMV esophagitis are limited. Treatment studies of

CMV gastrointestinal disease have demonstrated effectiveness of both is attributed to poor “pill taking habits”: inadequate liquid with the 2219
ganciclovir (5 mg/kg every 12 h intravenously) and valganciclovir pill or lying down immediately after taking a pill. The most common
(900 mg orally every 12 h). Therapy is continued until healing, which location for the pill to lodge is in the mid-esophagus near the crossing
may take 3–6 weeks. Maintenance therapy may be needed for patients of the aorta or carina. Extrinsic compression from these structures halts
with relapsing disease. the movement of the pill or capsule. Since initially reported in 1970,
more than 1000 cases of pill esophagitis have been reported, suggesting
MECHANICAL TRAUMA AND IATROGENIC that this is not an unusual occurrence. A wide variety of medications
INJURY are implicated with the most common being doxycycline, tetracycline,
quinidine, phenytoin, potassium chloride, ferrous sulfate, nonsteroidal
■■ESOPHAGEAL PERFORATION anti-inflammatory drugs (NSAIDs), and bisphosphonates.
Most cases of esophageal perforation are from instrumentation of the Typical symptoms of pill esophagitis are the sudden onset of chest
esophagus or trauma. Alternatively, forceful vomiting or retching can pain and odynophagia. Characteristically, the pain will develop over
lead to spontaneous rupture at the gastroesophageal junction (Boer- a period of hours or will awaken the individual from sleep. A classic
haave’s syndrome). More rarely, corrosive esophagitis or neoplasms history in the setting of ingestion of recognized pill offenders obviates
lead to perforation. Instrument perforation from endoscopy or nasoga- the need for diagnostic testing in most patients. When endoscopy is
stric tube placement typically occurs in the hypopharynx or at the performed, localized ulceration or inflammation is evident. Histologi-
gastroesophageal junction. Perforation may also occur at the site of a cally, acute inflammation is typical. Chest CT imaging will sometimes
stricture in the setting of endoscopic food disimpaction or esophageal reveal esophageal thickening consistent with transmural inflamma-
dilation. Esophageal perforation causes pleuritic retrosternal pain tion. Although the condition usually resolves within days to weeks,
that can be associated with pneumomediastinum and subcutaneous symptoms may persist for months and stricture can develop in severe
emphysema. Mediastinitis is a major complication of esophageal per- cases. No specific therapy is known to hasten the healing process, but
foration, and prompt recognition is key to optimizing outcome. CT antisecretory medications are frequently prescribed to remove concom-
of the chest is most sensitive in detecting mediastinal air. Esophageal itant reflux as an aggravating factor. When healing results in stricture
perforation is confirmed by a contrast swallow, usually Gastrografin formation, dilation is indicated.
followed by thin barium. Treatment includes nasogastric suction and
parenteral broad-spectrum antibiotics with prompt surgical drainage ■■FOREIGN BODIES AND FOOD IMPACTION
and repair in noncontained leaks. Conservative therapy with NPO Food or foreign bodies may lodge in the esophagus causing complete
status and antibiotics without surgery may be appropriate in cases of obstruction, which in turn can cause an inability to handle secretions
(foaming at the mouth) and severe chest pain. Food impaction may

contained perforation that are detected early. Endoscopic clipping or
stent placement may be indicated in nonoperated iatrogenic perfora- occur due to peptic stricture, carcinoma, Schatzki ring, EoE, or simply
tions or nonoperable cases such as perforated tumors. inattentive eating. If it does not spontaneously resolve, impacted food
can be removed endoscopically. Use of meat tenderizer enzymes to
■■MALLORY-WEISS TEAR facilitate passage of a meat bolus is discouraged because of poten-
Vomiting, retching, or vigorous coughing can cause a nontransmural tial esophageal injury. Glucagon (1 mg IV) is sometimes tried before
tear at the gastroesophageal junction that is a common cause of upper endoscopic dislodgement. After emergent treatment, patients should
gastrointestinal bleeding. Most patients present with hematemesis. be evaluated for potential causes of the impaction with treatment ren-
Antecedent vomiting is the norm, but not always evident. Bleeding dered as indicated.
usually abates spontaneously, but protracted bleeding may respond
to local epinephrine or cauterization therapy, endoscopic clipping, or ESOPHAGEAL MANIFESTATIONS OF
angiographic embolization. Surgery is rarely needed. SYSTEMIC DISEASE
■■RADIATION ESOPHAGITIS ■■SCLERODERMA AND COLLAGEN VASCULAR
Radiation esophagitis can complicate treatment for thoracic cancers, DISEASES
especially breast and lung, with the risk proportional to radiation Scleroderma esophagus (hypotensive LES and absent esophageal
dosage. Radiosensitizing drugs such as doxorubicin, bleomycin, cyclo- peristalsis) was initially described as a manifestation of scleroderma
phosphamide, and cisplatin also increase the risk. Dysphagia and or other collagen vascular diseases and thought to be specific for these
odynophagia may last weeks to months after therapy. The esophageal disorders. However, this nomenclature subsequently proved unfortu-
mucosa becomes erythematous, edematous, and friable. Submucosal nate and has been discarded because an estimated half of qualifying
fibrosis and degenerative tissue changes and stricturing may occur patients do not have an identifiable systemic disease, and reflux disease
years after the radiation exposure. Radiation exposure in excess of 5000 is often the only identifiable association. When scleroderma esophagus
cGy has been associated with increased risk of esophageal stricture. occurs as a manifestation of a collagen vascular disease, the histopatho-
Treatment for acute radiation esophagitis is supportive. Chronic stric- logic findings are of infiltration and destruction of the esophageal mus-
tures are managed with esophageal dilation. cularis propria with collagen deposition and fibrosis. The pathogenesis
of absent peristalsis and LES hypotension in the absence of a collagen
■■CORROSIVE ESOPHAGITIS vascular disease is unknown. Regardless of the underlying cause, the
Caustic esophageal injury from ingestion of alkali or, less commonly, manometric abnormalities predispose patients to severe GERD due to
acid can be accidental or from attempted suicide. Absence of oral injury inadequate LES barrier function combined with poor esophageal clear-
does not exclude possible esophageal involvement. Thus, early endo- ance of refluxed acid. Dysphagia may also be manifest but is generally
scopic evaluation is recommended to assess and grade the injury to the mild and alleviated by eating in an upright position and using liquids
esophageal mucosa. Severe corrosive injury may lead to esophageal to facilitate solid emptying.
perforation, bleeding, stricture, and death. Glucocorticoids have not
been shown to improve the clinical outcome of acute corrosive esoph- ■■DERMATOLOGIC DISEASES
agitis and are not recommended. Healing of more severe grades of A host of dermatologic disorders (pemphigus vulgaris, bullous pem-
caustic injury is commonly associated with severe stricture formation phigoid, cicatricial pemphigoid, Behçet’s syndrome, and epidermolysis
and often requires repeated dilation. bullosa) can affect the oropharynx and esophagus, particularly the
proximal esophagus with blisters, bullae, webs, and strictures. Gluco-
■■PILL ESOPHAGITIS corticoid treatment is usually effective. Erosive lichen planus, Stevens-
Pill-induced esophagitis occurs when a swallowed pill fails to traverse Johnson syndrome, and graft-versus-host disease can also involve the
the entire esophagus and lodges within the lumen. Generally, this esophagus. Esophageal dilation may be necessary to treat strictures.

2220 ■■FURTHER READING
Dellon ES et al: ACG Clinical Guideline: Evidence based approach to
the diagnosis and management of esophageal eosinophilia and eosin-
ophilic esophagitis. Am J Gastroenterol 108:679, 2013.
Furuta GT, Katzka DA: Eosinophilic esophagitis. N Engl J Med
373:1640, 2015. Gastric pit
Kahrilas PJ: Clinical practice. Gastroesophageal reflux disease. N Engl (foveolus)
J Med 359:1700, 2008. Surface mucous cells
Kahrilas PJ, Boeckxstaens G: The spectrum of achalasia: Lessons
from studies of pathophysiology and high-resolution manometry.
Gastroenterology 145:954, 2013.
Kahrilas PJ et al: American Gastroenterological Association Institute Isthmus
technical review on the management of gastroesophageal reflux dis-
ease. Gastroenterology 135:1392, 2008.
Mucous neck cells
Pandolfino JE, Gawron AJ: Achalasia: A systematic review. JAMA
313:1841, 2015.
Shaheen NJ et al: Diagnosis and Management of Barrett’s Esophagus. Neck
Am J Gastroenterol 111:30, 2016.
Oxyntic Gland
Spechler SJ, Souza RF: Barrett’s esophagus. N Engl J Med 371:836,
2014. Parietal cells
Endocrine cell
Base
317 Peptic Ulcer Disease and

Related Disorders
(fundus)
Chief cells
PART 10
John Del Valle

FIGURE 317-1 Diagrammatic representation of the oxyntic gastric gland. (Adapted
from S Ito, RJ Winchester: J Cell Biol 16:541, 1963. © 1963 Ito and Winchester.)
PEPTIC ULCER DISEASE
A peptic ulcer is defined as disruption of the mucosal integrity of the

stomach and/or duodenum leading to a local defect or excavation due intracellular canaliculi containing short microvilli along its apical sur-
to active inflammation. Although burning epigastric pain exacerbated face (Fig. 317-2). H+,K+-adenosine triphosphatase (ATPase) is expressed
by fasting and improved with meals is a symptom complex associated in the tubulovesicle membrane; upon cell stimulation, this membrane,
with peptic ulcer disease (PUD), it is now clear that >90% patients with along with apical membranes, transforms into a dense network of api-
this symptom complex (dyspepsia) do not have ulcers and that the cal intracellular canaliculi containing long microvilli. Acid secretion, a
majority of patients with peptic ulcers may be asymptomatic. Ulcers process requiring high energy, occurs at the apical canalicular surface.
occur within the stomach and/or duodenum and are often chronic in Numerous mitochondria (30–40% of total cell volume) generate the
nature. Acid peptic disorders are very common in the United States, energy required for secretion.
with 4 million individuals (new cases and recurrences) affected per
year. Lifetime prevalence of PUD in the United States is ~12% in men Gastroduodenal Mucosal Defense The gastric epithelium
and 10% in women. PUD significantly affects quality of life by impair- is under constant assault by a series of endogenous noxious factors,
ing overall patient well-being and contributing substantially to work including hydrochloric acid (HCl), pepsinogen/pepsin, and bile salts.
absenteeism. Moreover, an estimated 15,000 deaths per year occur as a In addition, a steady flow of exogenous substances such as medica-
consequence of complicated PUD. The financial impact of these com- tions, alcohol, and bacteria encounter the gastric mucosa. A highly
mon disorders has been substantial, with an estimated burden on direct
and indirect health care costs of ~$6 billion per year in the United States,
with $3 billion spent on hospitalizations, $2 billion on physician office Resting Stimulated
visits, and $1 billion in decreased productivity and days lost from work.
■■GASTRIC PHYSIOLOGY
Gastric Anatomy The gastric epithelial lining consists of rugae Canaliculus HCl
that contain microscopic gastric pits, each branching into four or
H+,K+–ATPase KCl
five gastric glands made up of highly specialized epithelial cells. The
makeup of gastric glands varies with their anatomic location. Glands Tubulovesicles
within the gastric cardia comprise <5% of the gastric gland area and KCl
Active H3O+ Active
contain mucous and endocrine cells. The 75% of gastric glands are pump pump
found within the oxyntic mucosa and contain mucous neck, parietal,
Ca cAMP
chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL) –
cells (Fig. 317-1). Pyloric glands contain mucous and endocrine cells Gastrin
(including gastrin cells) and are found in the antrum. ACh Histamine
The parietal cell, also known as the oxyntic cell, is usually found in FIGURE 317-2 Gastric parietal cell undergoing transformation after secretagogue-
the neck, or isthmus, or in the oxyntic gland. The resting, or unstim- mediated stimulation. cAMP, cyclic adenosine monophosphate. (Adapted from SJ
ulated, parietal cell has prominent cytoplasmic tubulovesicles and Hersey, G Sachs: Physiol Rev 75:155, 1995.)

intricate biologic system is in place to provide defense from mucosal gradient ranging from 1 to 2 at the gastric luminal surface and reaching 2221
injury and to repair any injury that may occur. 6–7 along the epithelial cell surface.
The mucosal defense system can be envisioned as a three-level Surface epithelial cells provide the next line of defense through
barrier, composed of preepithelial, epithelial, and subepithelial ele- several factors, including mucus production, epithelial cell ionic trans-
ments (Fig. 317-3). The first line of defense is a mucus-bicarbonate- porters that maintain intracellular pH and bicarbonate production,
phospholipid layer, which serves as a physicochemical barrier to and intracellular tight junctions. Surface epithelial cells generate heat
multiple molecules, including hydrogen ions. Mucus is secreted in shock proteins that prevent protein denaturation and protect cells from
a regulated fashion by gastroduodenal surface epithelial cells. It certain factors such as increased temperature, cytotoxic agents, or oxi-
consists primarily of water (95%) and a mixture of phospholipids dative stress. Epithelial cells also generate trefoil factor family peptides
and glycoproteins (mucin). The mucous gel functions as a nonstirred and cathelicidins, which also play a role in surface cell protection and
water layer impeding diffusion of ions and molecules such as pep- regeneration. If the preepithelial barrier were breached, gastric epithe-
sin. Bicarbonate, secreted in a regulated manner by surface epithelial lial cells bordering a site of injury can migrate to restore a damaged
cells of the gastroduodenal mucosa into the mucous gel, forms a pH region (restitution). This process occurs independent of cell division and
CHAPTER 317 Peptic Ulcer Disease and Related Disorders
FIGURE 317-3 Components involved in providing gastroduodenal mucosal defense and repair. CCK, cholecystokinin; CRF, corticotropin-releasing factor; EGF, epidermal
growth factor; HCl, hydrochloride; IGF, insulin-like growth factor; TGFα, transforming growth factor α; TRF, thyrotropin releasing factor. (Modified and updated from
A Tarnawski: Cellular and molecular mechanisms of mucosal defense and repair, in T Yoshikawa, T Arakawa [eds]: Bioregulation and Its Disorders in the Gastrointestinal
Tract. Tokyo, Japan: Blackwell Science, 1998:3–17.)

2222 requires uninterrupted blood flow and an alkaline pH in the surround- NO is important in the maintenance of gastric mucosal integrity. The
ing environment. Several growth factors, including epidermal growth key enzyme NO synthase is constitutively expressed in the mucosa and
factor (EGF), transforming growth factor (TGF) α, and basic fibroblast contributes to cytoprotection by stimulating gastric mucus, increasing
growth factor (FGF), modulate the process of restitution. Larger defects mucosal blood flow, and maintaining epithelial cell barrier function.
that are not effectively repaired by restitution require cell prolifera- The central nervous system (CNS) and hormonal factors also play a role
tion. Epithelial cell regeneration is regulated by prostaglandins and in regulating mucosal defense through multiple pathways (Fig. 317-3).
growth factors such as EGF and TGF-α. In tandem with epithelial cell Since the discovery of Helicobacter pylori and its impact on gastric
renewal, formation of new vessels (angiogenesis) within the injured pathology, it has become clear that the stomach has an elaborate and
microvascular bed occurs. Both FGF and vascular endothelial growth complex inherent immunological system in place. Although a detailed
factor (VEGF) are important in regulating angiogenesis in the gastric description of the gastric immune system is beyond the scope of this
mucosa. In addition, the gastric peptide gastrin (see below) has been chapter several features are worth highlighting. The gastric immune
recently found to stimulate cell proliferation, migration, invasion and response to certain pathogens such as H. pylori (see below) involves
angiogenesis. It may also have the ability to regulate gastric stem cells. extensive interplay between innate (dendritic cell, epithelial cells, neu-
An elaborate microvascular system within the gastric submucosal trophils and macrophages) and adaptive (B and T cells) components.
layer is the key component of the subepithelial defense/repair system, Helper T cells (Th and Th Reg cells) have been extensively studied and
providing HCO3−, which neutralizes the acid generated by the parietal appear to play an important role in a broad array of gastric physiology
cell. Moreover, this microcirculatory bed provides an adequate supply of extending from gastric secretion to epithelial cell turnover via produc-
micronutrients and oxygen while removing toxic metabolic by-products. tion of a number of cytokines.
Several locally produced factors including nitric oxide (NO) (see below), The discovery of H. pylori has also led to the understanding that
hydrogen sulfide and prostacyclin contribute to the vascular protective the stomach, once thought to be devoid of microorganisms due to its
pathway through vasodilation of the microcirculation. highly adverse environment (acid and pepsin) can serve as host for
Prostaglandins play a central role in gastric epithelial defense/ bacterial communities consisting of hundreds of phylotypes, otherwise
repair (Fig. 317-4). The gastric mucosa contains abundant levels of known as its microbiota. The conceptual framework of the microbiome
prostaglandins that regulate the release of mucosal bicarbonate and has been receiving extensive attention in light of its importance in
mucus, inhibit parietal cell secretion, and are important in maintaining human health and disease. The overall relevance of the gastric microbi-
mucosal blood flow and epithelial cell restitution. Prostaglandins are ome and its impact on gastric pathology remains to be established but
derived from esterified arachidonic acid, which is formed from phos- it is likely that alteration of microorganism homeostasis will play a role
pholipids (cell membrane) by the action of phospholipase A2. A key in aspects of certain disorders like PUD, gastritis and gastric cancer.
enzyme that controls the rate-limiting step in prostaglandin synthesis
Physiology of Gastric Secretion HCl and pepsinogen are the
PART 10
is cyclooxygenase (COX), which is present in two isoforms (COX-1,

COX-2), each having distinct characteristics regarding structure, tissue two principal gastric secretory products capable of inducing mucosal
distribution, and expression. COX-1 is expressed in a host of tissues, injury. Gastric acid and pepsinogen play a physiologic role in protein
including the stomach, platelets, kidneys, and endothelial cells. This digestion; absorption of iron, calcium, magnesium, and vitamin B12; and
isoform is expressed in a constitutive manner and plays an important killing ingested bacteria. Acid secretion should be viewed as occurring
role in maintaining the integrity of renal function, platelet aggregation, under basal and stimulated conditions. Basal acid production occurs in
and gastrointestinal (GI) mucosal integrity. In contrast, the expression a circadian pattern, with highest levels occurring during the night and
of COX-2 is inducible by inflammatory stimuli, and it is expressed in lowest levels during the morning hours. Cholinergic input via the vagus
macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial nerve and histaminergic input from local gastric sources are the princi-
effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue pal contributors to basal acid secretion. Stimulated gastric acid secretion
inflammation are due to inhibition of COX-2; the toxicity of these drugs occurs primarily in three phases based on the site where the signal origi-
(e.g., GI mucosal ulceration and renal dysfunction) is related to inhibi- nates (cephalic, gastric, and intestinal). Sight, smell, and taste of food are
tion of the COX-1 isoform. The highly COX-2–selective NSAIDs have the components of the cephalic phase, which stimulates gastric secretion
the potential to provide the beneficial effect of decreasing tissue inflam- via the vagus nerve. The gastric phase is activated once food enters the
mation while minimizing toxicity in the GI tract. Selective COX-2 stomach. This component of secretion is driven by nutrients (amino
inhibitors have had adverse effects on the cardiovascular (CV) system, acids and amines) that directly (via peptone and amino acid receptors)
leading to increased risk of myocardial infarction. Therefore, the U.S. and indirectly (via stimulation of intramural gastrin releasing peptide
Food and Drug Administration (FDA) has removed two of these agents neurons) stimulate the G cell to release gastrin, which in turn activates
(valdecoxib and rofecoxib) from the market (see below). the parietal cell via direct and indirect mechanisms. Distention of the
stomach wall also leads to gastrin release and acid production. The last
phase of gastric acid secretion is initiated as food enters the intestine and
Membrane phospholipids is mediated by luminal distention and nutrient assimilation. A series of
pathways that inhibit gastric acid production are also set into motion
Phospholipase A2
during these phases. The GI hormone somatostatin is released from
endocrine cells found in the gastric mucosa (D cells) in response to HCl.
Arachidonic acid Somatostatin can inhibit acid production by both direct (parietal cell)
and indirect mechanisms (decreased histamine release from ECL cells,
Stomach Macrophages
Kidney COX-1 COX-2 Leukocytes ghrelin release from Gr cells and gastrin release from G cells). Addi-
Platelets housekeeping inflammation Fibroblasts tional neural (central and peripheral) and humoral (amylin, atrial natri-
Endothelium Endothelium uretic peptide [ANP], cholecystokinin, ghrelin, interleukin 11 [IL-11],
obestatin, secretin, and serotonin) factors play a role in counterbalanc-
ing acid secretion. Under physiologic circumstances, these phases occur
TXA2, PGI2, PGE2 PGI2, PGE2 simultaneously. Ghrelin, the appetite-regulating hormone expressed in
Gastrointestinal mucosal integrity Inflammation Gr cells in the stomach, and its related peptide motilin (released from
Platelet aggregation Mitogenesis the duodenum) may increase gastric acid secretion through stimulation
Renal function Bone formation
Other functions? of histamine release from ECL cells, but this remains to be confirmed.
The acid-secreting parietal cell is located in the oxyntic gland,
FIGURE 317-4 Schematic representation of the steps involved in synthesis of adjacent to other cellular elements (ECL cell, D cell) important in the
prostaglandin E2 (PGE2) and prostacyclin (PGI2). Characteristics and distribution of gastric secretory process (Fig. 317-5). This unique cell also secretes
the cyclooxygenase (COX) enzymes 1 and 2 are also shown. TXA2, thromboxane A2. intrinsic factor (IF) and IL-11. The parietal cell expresses receptors for

for pepsin activity. Pepsin activity is 2223
Vagus significantly diminished at a pH of 4 and
irreversibly inactivated and denatured at
a pH of ≥7. Many of the secretagogues
that stimulate acid secretion also stimu-
late pepsinogen release. The precise role
CGRP PACAP ACh VIP ACh ACh GRP ACh ACh
of pepsin in the pathogenesis of PUD
remains to be established.
+ – + – + + + – ■■PATHOPHYSIOLOGIC BASIS
– + + Parietal – D Cell OF PUD
EC Cell D Cell G Cell
Cell (SST)
(ANP)
+
(SST)
–
(Gastrin)
+
PUD encompasses both gastric and
H2 H3 duodenal ulcers (DUs). Ulcers are
+
+ + – defined as breaks in the mucosal surface
–
HP ECL Cell
– >5 mm in size, with depth to the sub-
(Chronic Antrum) (Histamine) mucosa. DUs and gastric ulcers (GUs)
share many common features in terms of
Acid
Antrum Fundus pathogenesis, diagnosis, and treatment,
HP (Acute)
but several factors distinguish them from
one another. H. pylori and NSAIDs are
FIGURE 317-5 Regulation of gastric acid secretion at the cellular level. ACh, acetylcholine; ANP, atrial natriuretic the most common risk factors for PUD,
peptide; CGRP, calcitonin gene-related peptide; EC, enterochromaffin; ECL, enterochromaffin-like; GRP, gastrin- with estimated odds ratios in the United
releasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive intestinal States of 3.7 and 3.3, respectively. Addi-
peptide. tional risk factors (odds ratio) include
chronic obstructive lung disease (2.34),
chronic renal insufficiency (2.29), current
several stimulants of acid secretion, including histamine (H2), gastrin tobacco use (1.99), former tobacco use (1.55), older age (1.67), three or
(cholecystokinin 2/gastrin receptor), and acetylcholine (muscarinic, M3). more doctor visits in a year (1.49), coronary heart disease (1.46), former

Binding of histamine to the H2 receptor leads to activation of adeny- alcohol use (1.29), African-American race (1.20), obesity (1.18), and dia-
late cyclase and the phosphoinositol pathways in turn resulting in an betes (1.13). The mechanisms by which some of these risk factors lead
increase in cyclic adenosine monophosphate (AMP) and intracellular to ulcer disease are highlighted below.
calcium respectively. Activation of the gastrin and muscarinic receptors
results in activation of the protein kinase C/phosphoinositide signaling
Epidemiology • DUODENAL ULCERS DUs are estimated to occur in
6–15% of the Western population. The incidence of DUs declined stead-
pathway. Each of these signaling pathways in turn regulates a series
ily from 1960 to 1980 and has remained stable since then. The death
of downstream kinase cascades that control the acid-secreting pump,
rates, need for surgery, and physician visits have decreased by >50%
H+,K+-ATPase. The discovery that different ligands and their corre-
over the past 30 years. The reason for the reduction in the frequency
sponding receptors lead to activation of different signaling pathways
of DUs is likely related to the decreasing frequency of H. pylori. Before
explains the potentiation of acid secretion that occurs when histamine
the discovery of H. pylori, the natural history of DUs was typified by
and gastrin or acetylcholine are combined. More importantly, this
frequent recurrences after initial therapy. Eradication of H. pylori has
observation explains why blocking one receptor type (H2) decreases
reduced these recurrence rates by >80 %.
acid secretion stimulated by agents that activate a different pathway
(gastrin, acetylcholine). Parietal cells also express receptors for ligands GASTRIC ULCERS GUs tend to occur later in life than duodenal lesions,
that inhibit acid production (glucagon-like peptide-1, prostaglandins, with a peak incidence reported in the sixth decade. More than one-half
somatostatin, and EGF). Histamine also stimulates gastric acid secre- of GUs occur in males and are less common than DUs, perhaps due to
tion indirectly by activating the histamine H3 receptor on D-cells, which the higher likelihood of GUs being silent and presenting only after a
inhibits somatostatin release. complication develops. Autopsy studies suggest a similar incidence of
The enzyme H+,K+-ATPase is responsible for generating the large DUs and GUs.
concentration of H+. It is a membrane-bound protein that consists of two Pathology • DUODENAL ULCERS DUs occur most often in the first
subunits, α and β. The active catalytic site is found within the α subunit; portion of the duodenum (>95%), with ~90% located within 3 cm of
the function of the β subunit is unclear. This enzyme uses the chemical the pylorus. They are usually ≤1 cm in diameter but can occasionally
energy of adenosine triphosphate (ATP) to transfer H+ ions from pari- reach 3–6 cm (giant ulcer). Ulcers are sharply demarcated, with depth
etal cell cytoplasm to the secretory canaliculi in exchange for K+. The at times reaching the muscularis propria. The base of the ulcer often
H+,K+-ATPase is located within the secretory canaliculus and in nonse- consists of a zone of eosinophilic necrosis with surrounding fibrosis.
cretory cytoplasmic tubulovesicles. The tubulovesicles are impermeable Malignant DUs are extremely rare.
to K+, which leads to an inactive pump in this location. The distribution
of pumps between the nonsecretory vesicles and the secretory canalic- GASTRIC ULCERS In contrast to DUs, GUs can represent a malignancy
ulus varies according to parietal cell activity (Fig. 317-2). Proton pumps and should be biopsied upon discovery. Benign GUs are most often
are recycled back to the inactive state in cytoplasmic vesicles once parie- found distal to the junction between the antrum and the acid secretory
tal cell activation ceases. Ezrin (an actin binding protein), actin, myosin, mucosa. Benign GUs are quite rare in the gastric fundus and are histo-
soluble N-ethylmaleimide-sensitive factor attachment protein receptors logically similar to DUs. Benign GUs associated with H. pylori are also
(SNAREs), small G proteins of the Rab family and secretory carrier associated with antral gastritis. In contrast, NSAID-related GUs are not
membrane proteins (SCAMPS) are postulated to participate in parie- accompanied by chronic active gastritis but may instead have evidence
of a chemical gastropathy, typified by foveolar hyperplasia, edema of
tal cell membrane translocation. In addition, acid secretion requires a
the lamina propria, and epithelial regeneration in the absence of H.
number of apical and basolateral parietal cell membrane chloride and
pylori. Extension of smooth-muscle fibers into the upper portions of the
potassium channels.
mucosa, where they are not typically found, may also occur.
The chief cell, found primarily in the gastric fundus, synthesizes and
secretes pepsinogen, the inactive precursor of the proteolytic enzyme Pathophysiology • DUODENAL ULCERS H. pylori and NSAID-
pepsin. The acid environment within the stomach leads to cleavage of induced injuries account for the majority of DUs. Many acid secretory
the inactive precursor to pepsin and provides the low pH (<2) required abnormalities have been described in DU patients. Of these, average

2224 basal and nocturnal gastric acid secretion appears to be increased in born later. About 10% of Americans <30 years of age are colonized with
DU patients as compared to controls; however, the level of overlap the bacteria. The rate of infection with H. pylori in industrialized coun-
between DU patients and control subjects is substantial. The reason for tries has decreased substantially in recent decades. The steady increase
this altered secretory process is unclear, but H. pylori infection may con- in the prevalence of H. pylori noted with increasing age is due primarily
tribute. Bicarbonate secretion is significantly decreased in the duodenal to a cohort effect, reflecting higher transmission during a period in
bulb of patients with an active DU as compared to control subjects. H. which the earlier cohorts were children. It has been calculated through
pylori infection may also play a role in this process (see below). mathematical models that improved sanitation during the latter half of
GASTRIC ULCERS As in DUs, the majority of GUs can be attributed to
the nineteenth century dramatically decreased transmission of H. pylori.
either H. pylori or NSAID-induced mucosal damage. Prepyloric GUs or Moreover, with the present rate of intervention, the organism will be
those in the body associated with a DU or a duodenal scar are similar in ultimately eliminated from the United States. Two factors that predis-
pathogenesis to DUs. Gastric acid output (basal and stimulated) tends pose to higher colonization rates include poor socioeconomic status
to be normal or decreased in GU patients. When GUs develop in the and less education. These factors, not race, are responsible for the rate
presence of minimal acid levels, impairment of mucosal defense factors of H. pylori infection in blacks and Hispanic Americans being double the
may be present. GUs have been classified based on their location: Type rate seen in whites of comparable age. Other risk factors for H. pylori
I occur in the gastric body and tend to be associated with low gastric infection are (1) birth or residence in a developing country, (2) domestic
acid production; type II occur in the antrum and gastric acid can vary crowding, (3) unsanitary living conditions, (4) unclean food or water,
from low to normal; type III occur within 3 cm of the pylorus and are and (5) exposure to gastric contents of an infected individual.
commonly accompanied by DUs and normal or high gastric acid pro- Transmission of H. pylori occurs from person to person, following an
duction; and type IV are found in the cardia and are associated with oral-oral or fecal-oral route. The risk of H. pylori infection is declining
low gastric acid production. in developing countries. The rate of infection in the United States has
fallen by >50% when compared to 30 years ago.
H. PYLORI AND ACID PEPTIC DISORDERS Gastric infection with the
Pathophysiology H. pylori infection is virtually always associated with a
bacterium H. pylori accounts for the majority of PUD (Chap. 158).
This organism also plays a role in the development of gastric mucosa- chronic active gastritis, but only 10–15% of infected individuals develop
associated lymphoid tissue (MALT) lymphoma and gastric adenocar- frank peptic ulceration. The basis for this difference is unknown, but is
cinoma. Although the entire genome of H. pylori has been sequenced, likely due to a combination of host and bacterial factors some of which
it is still not clear how this organism, which resides in the stomach, are outlined below. Initial studies suggested that >90% of all DUs were
causes ulceration in the duodenum. H. pylori eradication efforts may associated with H. pylori, but H. pylori is present in only 30–60% of indi-
lead to a decrease in gastric cancer in high-risk populations particularly viduals with GUs and 50–70% of patients with DUs. The pathophysi-
in individuals who have not developed chronic atrophic gastritis and ology of ulcers not associated with H. pylori or NSAID ingestion (or
PART 10
gastric metaplasia. the rare Zollinger-Ellison syndrome [ZES]) is becoming more relevant
as the incidence of H. pylori is dropping, particularly in the Western
The Bacterium The bacterium, initially named Campylobacter pyloridis, world (see below).
is a gram-negative microaerophilic rod found most commonly in The particular end result of H. pylori infection (gastritis, PUD, gastric
the deeper portions of the mucous gel coating the gastric mucosa or MALT lymphoma, gastric cancer) is determined by a complex interplay
between the mucous layer and the gastric epithelium. It may attach to between bacterial and host factors (Fig. 317-6).
gastric epithelium but under normal circumstances does not appear to Bacterial factors: H. pylori is able to facilitate gastric residence,
invade cells. It is strategically designed to live within the aggressive induce mucosal injury, and avoid host defense. Different strains of
environment of the stomach. It is S-shaped (~0.5–3 μm in size) and H. pylori produce different virulence factors including γ-glutamyl
contains multiple sheathed flagella. Initially, H. pylori resides in the transpeptidase (GGT), cytotoxin-associated gene A (cagA) product,
antrum but, over time, migrates toward the more proximal segments and virulence components vacuolating toxin (vacA), in addition to
of the stomach. The organism is capable of transforming into a coccoid pathogen-associated molecular patterns (PAMPs) such as flagella and
form, which represents a dormant state that may facilitate survival in lipopolysaccharide (LPS). A specific region of the bacterial genome,
adverse conditions. The genome of H. pylori (1.65 million base pairs) the pathogenicity island (cag-PAI), encodes the virulence factors Cag
encodes ~1500 proteins. Among this multitude of proteins there are fac- A and pic B. Vac A also contributes to pathogenicity, although it is not
tors that are essential determinants of H. pylori–mediated pathogenesis encoded within the pathogenicity island. These virulence factors, in
and colonization such as the outer membrane protein (Hop proteins), conjunction with additional bacterial constituents, can cause mucosal
urease, and the vacuolating cytotoxin (Vac A). Moreover, the majority damage, in part through their ability to target the host immune cells.
of H. pylori strains contain a genomic fragment that encodes the cag
pathogenicity island (cag-PAI). Several of the genes that make up cag-
PAI encode components of a type IV secretion island that translocates
Cag A into host cells. Once in the cell, Cag A activates a series of cellu-
lar events important in cell growth and cytokine production. H. pylori
also has extensive genetic diversity that in turn enhances its ability to
promote disease. The first step in infection by H. pylori is dependent
on the bacteria’s motility and its ability to produce urease. Urease
produces ammonia from urea, an essential step in alkalinizing the
surrounding pH. Additional bacterial factors include catalase, lipase, Bacterial factors Host factors
adhesins, platelet-activating factor, and pic B (induces cytokines). Mul- Structure Duration
tiple strains of H. pylori exist and are characterized by their ability to Adhesins Location
express several of these factors (Cag A, Vac A, etc.). It is possible that Porins Inflammatory response
Enzymes Genetics??
the different diseases related to H. pylori infection can be attributed to (urease, vac A, cag A, etc.)
different strains of the organism with distinct pathogenic features.
Epidemiology The prevalence of H. pylori varies throughout the world Chronic gastritis
and depends largely on the overall standard of living in the region. In Peptic ulcer disease
developing parts of the world, 80% of the population may be infected by Gastric MALT lymphoma
the age of 20, whereas the prevalence is 20–50% in industrialized coun- Gastric cancer
tries. In contrast, in the United States this organism is rare in childhood. FIGURE 317-6 Outline of the bacterial and host factors important in determining
The overall prevalence of H. pylori in the United States is ~30%, with H. pylori–induced gastrointestinal disease. MALT, mucosal-associated lymphoid
individuals born before 1950 having a higher rate of infection than those tissue.

For example, Vac A targets human CD4 T cells, inhibiting their pro- Parietal cell FUNDUS 2225
liferation and in addition can disrupt normal function of B cells, CD8 Vagus
T cells, macrophages, and mast cells. Multiple studies have demonstrated
that H. pylori strains that are cag-PAI positive are associated with a Canaliculus
higher risk of PUD, premalignant gastric lesions, and gastric cancer
Acetylcholine
than are strains that lack the cag-PAI. In addition, H. pylori may directly
inhibit parietal cell H+,K+-ATPase activity through a Cag A–dependent Histamine
mechanism, leading in part to the low acid production observed after +
+
acute infection with the organism. Urease, which allows the bacteria H, K ATPase ECL cell
to reside in the acidic stomach, generates NH3, which can damage epi- Tubulovesicles
+
thelial cells. The bacteria produce surface factors that are chemotactic
Histamine
for neutrophils and monocytes, which in turn contribute to epithelial +
– –
cell injury (see below). H. pylori makes proteases and phospholipases
ECL cell Somatostatin
that break down the glycoprotein lipid complex of the mucous gel, Somatostatin
thus reducing the efficacy of this first line of mucosal defense. H. pylori D cell
expresses adhesins (OMPs like BabA), which facilitate attachment of + Gastrin
the bacteria to gastric epithelial cells. Although LPS of gram-negative
bacteria often plays an important role in the infection, H. pylori LPS has ANTRUM
Blood vessel
low immunologic activity compared to that of other organisms. It may Gastrin
promote a smoldering chronic inflammation. G cell
Host factors: Studies in twins suggest that there may be genetic D cell
–
predisposition to acquire H. pylori. The inflammatory response to H. Somatostatin
pylori includes recruitment of neutrophils, lymphocytes (T and B),
macrophages, and plasma cells. The pathogen leads to local injury by FIGURE 317-7 Summary of potential mechanisms by which H. pylori may lead
binding to class II major histocompatibility complex (MHC) molecules to gastric secretory abnormalities. D, somatostatin cell; ECL, enterochromaffin-
like cell; G, G cell. (Adapted from J Calam et al: Gastroenterology 113:543, 1997.)
expressed on gastric epithelial cells, leading to cell death (apoptosis).
Moreover, bacterial strains that encode cag-PAI can introduce Cag
A into the host cells, leading to further cell injury and activation of pangastritis and normal or low gastric acid secretion. H. pylori infection

cellular pathways involved in cytokine production and repression of has also been associated with decreased duodenal mucosal bicarbonate
tumor-suppressor genes. Elevated concentrations of multiple cytok- production. Data supporting and contradicting each of these interest-
ines are found in the gastric epithelium of H. pylori–infected individ- ing theories have been demonstrated. Thus, the mechanism by which
uals, including interleukin (IL) 1α/β, IL-2, IL-6, IL-8, tumor necrosis H. pylori infection of the stomach leads to duodenal ulceration remains
factor (TNF) α, and interferon (IFN) γ. H. pylori infection also leads to to be established.
both a mucosal and a systemic humoral response, which does not lead In summary, the final effect of H. pylori on the GI tract is variable and
to eradication of the bacteria but further compounds epithelial cell determined by microbial and host factors. The type and distribution of
injury. Additional mechanisms by which H. pylori may cause epithe- gastritis correlate with the ultimate gastric and duodenal pathology
lial cell injury include (1) activated neutrophil-mediated production observed. Specifically, the presence of antral-predominant gastritis is
of reactive oxygen or nitrogen species and enhanced epithelial cell associated with DU formation; gastritis involving primarily the corpus
turnover and (2) apoptosis related to interaction with T cells (T helper predisposes to the development of GUs, gastric atrophy, and ultimately
1, or TH1, cells) and IFN-γ. Finally, the human stomach is colonized by gastric carcinoma (Fig. 317-8).
a host of commensal organisms that may affect the likelihood of H.
pylori–infection and subsequent mucosal injury. Moreover, coloniza- NSAID-INDUCED DISEASE • Epidemiology NSAIDs represent a group
tion of the stomach with H. pylori likely alters the composition of the of the most commonly used medications in the world and the United
gastric microbiota. The impact of the latter on gastric pathophysiology States. It is estimated that 7 billion dollars per year are spent on NSAIDs
remains unknown. H. pylori also appears to regulate NO formation via
different mechanisms that in turn may contribute to the organism’s
cytotoxic effects. Specifically, H. pylori derived factors, such as urease,
High level of acid production Duodenal ulcer
or the bacterium itself, stimulate NO synthase (NOS2) expression in
macrophages and in gastric epithelial cells leading to NO release and MALT
lymphoma
subsequent cytotoxic effect on surrounding cells. H. pylori also leads Antral-
to the formation of 8-nitroguanine (8-NO2-Gua), which in conjunction predominant
gastritis
with oncoprotein CagA, may contribute to the development of gastric
cancer. Chronic Nonatrophic Asymptomatic
Normal gastric H. pylori H. pylori
The reason for H. pylori–mediated duodenal ulceration remains mucosa infection
pangastritis
infection
unclear. Studies suggest that H. pylori associated with duodenal Corpus-
ulceration may be more virulent. In addition, certain specific bacterial predominant
atrophic Gastric ulcer
factors such as the DU-promoting gene A (dupA), may be associated Acute gastritis
H. pylori
with the development of DUs. Another potential contributing factor infection Intestinal metaplasia
is that gastric metaplasia in the duodenum of DU patients, which may
be due to high acid exposure (see below), permits H. pylori to bind to
it and produce local injury secondary to the host response. Another Dysplasia
hypothesis is that H. pylori antral infection could lead to increased acid
production, increased duodenal acid, and mucosal injury. Basal and Low level of acid production Gastric
cancer
stimulated (meal, gastrin-releasing peptide [GRP]) gastrin release are
increased in H. pylori–infected individuals, and somatostatin-secreting
Childhood Advanced age
D cells may be decreased. H. pylori infection might induce increased
acid secretion through both direct and indirect actions of H. pylori and FIGURE 317-8 Natural history of H. pylori infection. MALT, mucosal-associated
proinflammatory cytokines (IL-8, TNF, and IL-1) on G, D, and parietal lymphoid tissue. (Used with permission from S Suerbaum, P Michetti: N Engl J Med
cells (Fig. 317-7). GUs, in contrast, are associated with H. pylori–induced 347:1175, 2002.)

2226 world wide with more than 30 billion over-the-counter tablets and over lipophilic form when found within the acid environment of the stom-
100 million prescriptions sold yearly in the United States alone. In fact, ach. Under these conditions, NSAIDs migrate across lipid membranes
after the introduction of COX-2 inhibitors in the year 2000, the number of epithelial cells, leading to cell injury once trapped intracellularly in
of prescriptions written for NSAIDs was >111 million at a cost of $4.8 an ionized form. Topical NSAIDs can also alter the surface mucous
billion. Side effects and complications due to NSAIDs are considered layer, permitting back diffusion of H+ and pepsin, leading to further
the most common drug-related toxicities in the United States. The spec- epithelial cell damage. Moreover, enteric-coated or buffered prepara-
trum of NSAID-induced morbidity ranges from nausea and dyspepsia tions are also associated with risk of peptic ulceration. NSAIDs can also
(prevalence reported as high as 50–60%) to a serious GI complication lead to mucosal injury via production of additional pro-inflammatory
such as endoscopy-documented peptic ulceration (15–30% of individu- mediators like TNF and leukotrienes through simultaneous activation
als taking NSAIDs regularly) complicated by bleeding or perforation in of the lipoxygenase pathway.
as many as 1.5% of users per year. It is estimated that NSAID-induced The interplay between H. pylori and NSAIDs in the pathogenesis
GI bleeding accounts for 60,000–120,000 hospital admissions per year, of PUD is complex. Meta-analysis supports the conclusion that each
and deaths related to NSAID-induced toxicity may be as high as 16,000 of these aggressive factors is independent and synergistic risk factors
per year in the United States. Approximately 4–5% of patients develop for PUD and its complications such as GI bleeding. For example, erad-
symptomatic ulcers within 1 year. Unfortunately, dyspeptic symptoms ication of H. pylori reduces the likelihood of GI complications in high-
do not correlate with NSAID-induced pathology. Over 80% of patients risk individuals to levels observed in individuals with average risk of
with serious NSAID-related complications did not have preceding NSAID-induced complications.
dyspepsia. In view of the lack of warning signs, it is important to PATHOGENETIC FACTORS UNRELATED TO H. PYLORI AND NSAIDS IN ACID
identify patients who are at increased risk for morbidity and mortality PEPTIC DISEASE Cigarette smoking has been implicated in the patho-
related to NSAID usage. Even 75 mg/d of aspirin may lead to serious genesis of PUD. Not only have smokers been found to have ulcers more
GI ulceration; thus, no dose of NSAID is completely safe. In fact, the frequently than do nonsmokers, but smoking appears to decrease healing
incidence of mucosal injury (ulcers and erosions) in patients taking rates, impair response to therapy, and increase ulcer-related compli-
low-dose aspirin (75–325 mg) has been estimated to range from as low cations such as perforation. The mechanism responsible for increased
as 8 to as high as 60%. It appears that H. pylori infection increases the ulcer diathesis in smokers is unknown. Theories have included altered
risk of PUD-associated GI bleeding in chronic users of low-dose aspi- gastric emptying, decreased proximal duodenal bicarbonate production,
rin. Established risk factors include advanced age, history of ulcer, con- increased risk for H. pylori infection, and cigarette-induced generation of
comitant use of glucocorticoids, high-dose NSAIDs, multiple NSAIDs, noxious mucosal free radicals. Genetic predisposition may play a role in
concomitant use of anticoagulants, clopidogrel, and serious or multi- ulcer development. First-degree relatives of DU patients are three times as
system disease. Possible risk factors include concomitant infection with likely to develop an ulcer; however, the potential role of H. pylori infection
PART 10
H. pylori, cigarette smoking, and alcohol consumption. in contacts is a major consideration. Increased frequencies of blood group
Pathophysiology Prostaglandins play a critical role in maintaining gas- O and of the nonsecretor status have also been implicated as genetic
troduodenal mucosal integrity and repair. It therefore follows that risk factors for peptic diathesis. However, H. pylori preferentially binds
interruption of prostaglandin synthesis can impair mucosal defense and to group O antigens. Additional genetic factors have been postulated
repair, thus facilitating mucosal injury via a systemic mechanism. Ani- to predispose certain individuals to developing PUD and/or upper GI
mal studies have demonstrated that neutrophil adherence to the gastric bleeding. Specifically, genes encoding the NSAID-metabolizing enzymes
microcirculation plays an essential role in the initiation of NSAID- cytochrome P450 2C9 and 2C8 (CYP2C9 and CYP2C8) are potential sus-
induced mucosal injury. A summary of the pathogenetic pathways by ceptibility genes for NSAID-induced PUD, but unfortunately, the studies
which systemically administered NSAIDs may lead to mucosal injury have not been consistent in demonstrating this association. In a United
is shown in Fig. 317-9. Single nucleotide polymorphisms (SNPs) have Kingdom study, the CYP2C19*17 gain-of-function polymorphism was
been found in several genes, including those encoding certain subtypes associated with PUD in a Caucasian cohort, irrespective of ulcer etiology.
of cytochrome P450 (see below), interleukin-1β (IL-1β), angiotensinogen These findings need to be confirmed in broader studies. Psychological
(AGT), and an organic ion transporting polypeptide (SLCO1B1), but stress has been thought to contribute to PUD, but studies examining
these findings need confirmation in larger scale studies. the role of psychological factors in its pathogenesis have generated
Injury to the mucosa also occurs as a result of the topical encoun- conflicting results. Although PUD is associated with certain personality
ter with NSAIDs leading to increased epithelial surface permeability. traits (neuroticism), these same traits are also present in individuals with
Aspirin and many NSAIDs are weak acids that remain in a nonionized nonulcer dyspepsia (NUD) and other functional and organic disorders.
Diet has also been thought to play a role in peptic diseases. Certain
foods and beverages can cause dyspepsia, but no convincing studies
Endothelial effects Epithelial effects (due to indicate an association between ulcer formation and a specific diet. Spe-
• Stasis Ischemia prostaglandin depletion)
• ↑HCl secretion
cific chronic disorders have been shown to have a strong association with
• ↓Mucin secretion PUD: (1) advanced age, (2) chronic pulmonary disease, (3) chronic renal
• Direct toxicity failure, (4) cirrhosis, (5) nephrolithiasis, (6) α1-antitrypsin deficiency,
• ↓HCO3– secretion
“ion trapping”
• ↓Surface active and (7) systemic mastocytosis. Disorders with a possible association are
phospholipid (1) hyperparathyroidism, (2) coronary artery disease, (3) polycythemia
secretion vera, (4) chronic pancreatitis, (5) former alcohol use, (6) obesity, (7) African-
• ↓Epithelial cell
proliferation
American race, and (8) three or more doctor visits in a year.
Multiple factors play a role in the pathogenesis of PUD. The two
predominant causes are H. pylori infection and NSAID ingestion. PUD
not related to H. pylori or NSAIDs is increasing. Other less common
causes of PUD are shown in Table 317-1. These etiologic agents should
HEALING (spontaneous
ULCER Acid be considered as the incidence of H. pylori is decreasing. Independent
or therapeutic)
of the inciting or injurious agent, peptic ulcers develop as a result of an
imbalance between mucosal protection/repair and aggressive factors.
EROSIONS Gastric acid plays an important role in mucosal injury.
FIGURE 317-9 Mechanisms by which nonsteroidal anti-inflammatory drugs ■■CLINICAL FEATURES

may induce mucosal injury. (Adapted from J Scheiman et al: J Clin Outcomes
Management 3:23, 1996. Copyright 2003 Turner White Communications, Inc., www. History Abdominal pain is common to many GI disorders, includ-
turner-white.com. Used with permission.) ing DU and GU, but has a poor predictive value for the presence of

TABLE 317-1 Causes of Ulcers Not Caused by Helicobacter pylori and suggest dehydration secondary to vomiting or active GI blood loss. A 2227
NSAIDs severely tender, board-like abdomen suggests a perforation. Presence
Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease of a succussion splash indicates retained fluid in the stomach, suggest-
ing gastric outlet obstruction.
Infection
Cytomegalovirus PUD-Related Complications • GASTROINTESTINAL BLEEDING GI
Herpes simplex virus bleeding is the most common complication observed in PUD. Bleeding
Helicobacter heilmannii is estimated to occur in 19.4–57 per 100,000 individuals in a general
Drug/Toxin population or in ~15% of patients. Bleeding and complications of ulcer
Bisphosphonates
disease occur more often in individuals >60 years of age. The 30-day
mortality rate is as high as 2.5–10%. The higher incidence in the elderly
Chemotherapy
is likely due to the increased use of NSAIDs in this group. In addition,
Clopidogrel up to 80% of the mortality in PUD-related bleeding is due to nonbleed-
Crack cocaine ing causes such as multiorgan failure (24%), pulmonary complications
Glucocorticoids (when combined with NSAIDs) (24%), and malignancy (34%).
Mycophenolate mofetil Greater than 50% of patients with ulcer-related hemorrhage bleed
Potassium chloride without any preceding warning signs or symptoms.
Miscellaneous PERFORATION The second most common ulcer-related complication is
Basophilia in myeloproliferative disease perforation, being reported in as many as 6–7% of PUD patients with
Duodenal obstruction (e.g., annular pancreas) an estimated 30-day mortality of >20%. As in the case of bleeding,
Infiltrating disease the incidence of perforation in the elderly appears to be increasing
Ischemia secondary to increased use of NSAIDs. Perforation of DUs has become
Radiation therapy less common in light of the increased rates of H. pylori eradication with
Eosinophilic infiltration
NSAID induced GUs leading to perforation occurring more commonly.
Penetration is a form of perforation in which the ulcer bed tunnels into
Sarcoidosis
an adjacent organ. DUs tend to penetrate posteriorly into the pancreas,
Crohn’s disease
leading to pancreatitis, whereas GUs tend to penetrate into the left
Idiopathic hypersecretory state hepatic lobe. Gastrocolic fistulas associated with GUs have also been

Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory drugs. described.
GASTRIC OUTLET OBSTRUCTION Gastric outlet obstruction is the least
either DU or GU. Up to 87% of patients with NSAID-induced mucosal common ulcer-related complication, occurring in 1–2% of patients.
disease can present with a complication (bleeding, perforation, and A patient may have relative obstruction secondary to ulcer-related
obstruction) without antecedent symptoms. Despite this poor correla- inflammation and edema in the peripyloric region. This process often
tion, a careful history and physical examination are essential compo- resolves with ulcer healing. A fixed, mechanical obstruction secondary
nents of the approach to a patient suspected of having peptic ulcers. to scar formation in the peripyloric areas is also possible. The latter
Epigastric pain described as a burning or gnawing discomfort can requires endoscopic (balloon dilation) or surgical intervention. Signs
and symptoms relative to mechanical obstruction may develop insid-
be present in both DU and GU. The discomfort is also described as an
iously. New onset of early satiety, nausea, vomiting, increase of post-
ill-defined, aching sensation or as hunger pain. The typical pain pattern
prandial abdominal pain, and weight loss should make gastric outlet
in DU occurs 90 min to 3 h after a meal and is frequently relieved by
obstruction a possible diagnosis.
antacids or food. Pain that awakes the patient from sleep (between
midnight and 3 a.m.) is the most discriminating symptom, with two- Differential Diagnosis The list of GI and non-GI disorders that
thirds of DU patients describing this complaint. Unfortunately, this can mimic ulceration of the stomach or duodenum is quite extensive.
symptom is also present in one-third of patients with NUD (see below). The most commonly encountered diagnosis among patients seen for
Elderly patients are less likely to have abdominal pain as a manifes- upper abdominal discomfort is functional dyspepsia (FD) or essential
tation of PUD and may instead present with a complication such as dyspepsia which refers to a group of heterogeneous disorders typi-
ulcer bleeding or perforation. The pain pattern in GU patients may be fied by upper abdominal pain without the presence of an ulcer. The
different from that in DU patients, where discomfort may actually be symptoms can range from postprandial fullness and early satiety to
precipitated by food. Nausea and weight loss occur more commonly in epigastric burning pain. The dichotomy of this symptom complex
GU patients. Endoscopy detects ulcers in <30% of patients who have has led to the identification of two subcategories of FD including
dyspepsia. postprandial distress syndrome (PDS) and epigastric pain syndrome
The mechanism for development of abdominal pain in ulcer patients (EPS). Dyspepsia has been reported to occur in up to 30% of the U.S.
is unknown. Several possible explanations include acid-induced acti- population. Up to 80% of patients seeking medical care for dyspepsia
vation of chemical receptors in the duodenum, enhanced duodenal have a negative diagnostic evaluation. The etiology of FD is not estab-
sensitivity to bile acids and pepsin, or altered gastroduodenal motility. lished, but recent studies suggest that post-infectious states, certain
Variation in the intensity or distribution of the abdominal pain, foods and H. pylori infection may contribute to the pathogenesis of
as well as the onset of associated symptoms such as nausea and/or this common disorder.
vomiting, may be indicative of an ulcer complication. Dyspepsia that Several additional disease processes that may present with
becomes constant, is no longer relieved by food or antacids, or radi- “ulcer-like” symptoms include proximal GI tumors, gastroesoph-
ates to the back may indicate a penetrating ulcer (pancreas). Sudden ageal reflux, vascular disease, pancreaticobiliary disease (biliary
onset of severe, generalized abdominal pain may indicate perforation. colic, chronic pancreatitis), and gastroduodenal Crohn’s disease.
Pain worsening with meals, nausea, and vomiting of undigested food
suggest gastric outlet obstruction. Tarry stools or coffee-ground emesis Diagnostic Evaluation In view of the poor predictive value of
indicate bleeding. abdominal pain for the presence of a gastroduodenal ulcer and the
multiple disease processes that can mimic this disease, the clinician is
Physical Examination Epigastric tenderness is the most frequent often confronted with having to establish the presence of an ulcer. Doc-
finding in patients with GU or DU. Pain may be found to the right of umentation of an ulcer requires either a radiographic (barium study)
the midline in 20% of patients. Unfortunately, the predictive value of or an endoscopic procedure. However, a large percentage of patients
this finding is low. Physical examination is critically important for dis- with symptoms suggestive of an ulcer have NUD; testing for H. pylori
covering evidence of ulcer complication. Tachycardia and orthostasis and antibiotic therapy (see below) is appropriate for individuals who

2228
A B
FIGURE 317-10 Barium study demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.
are otherwise healthy and <45 years of age, before embarking on a Although the methods for diagnosing H. pylori are outlined in
diagnostic evaluation (Chap. 41). Chap. 158, a brief summary will be included here (Table 317-2). Several
Barium studies of the proximal GI tract are rarely used as a first test biopsy urease tests have been developed (PyloriTek, CLOtest, Hpfast,
for documenting an ulcer. The sensitivity of older single-contrast bar- Pronto Dry) that have a sensitivity and specificity of >90–95%. Several
ium meals for detecting a DU is as high as 80%, with a double-contrast noninvasive methods for detecting this organism have been developed.
study providing detection rates as high as 90%. Sensitivity for detection Three types of studies routinely used include serologic testing, the 13C- or
PART 10
is decreased in small ulcers (<0.5 cm), with presence of previous scar- 14

C-urea breath test, and the fecal H. pylori (Hp) antigen test (monoclonal
ring, or in postoperative patients. A DU appears as a well-demarcated antibody test). A urinary Hp antigen test appears promising.
crater, most often seen in the bulb (Fig. 317-10A). A GU may represent Occasionally, specialized testing such as serum gastrin and gastric
benign or malignant disease. Typically, a benign GU also appears as a acid analysis or sham feeding may be needed in individuals with com-
discrete crater with radiating mucosal folds originating from the ulcer
plicated or refractory PUD (see “Zollinger-Ellison Syndrome [ZES],”

margin (Fig. 317-10B). Ulcers >3 cm in size or those associated with a below). Screening for aspirin or NSAIDs (blood or urine) may also be
mass are more often malignant. Unfortunately, up to 8% of GUs that necessary in refractory H. pylori–negative PUD patients.
appear to be benign by radiographic appearance are malignant by
endoscopy or surgery. Radiographic studies that show a GU must be
followed by endoscopy and biopsy. TREATMENT
Endoscopy provides the most sensitive and specific approach for Peptic Ulcer Disease
examining the upper GI tract (Fig. 317-11). In addition to permitting
direct visualization of the mucosa, endoscopy facilitates photographic Before the discovery of H. pylori, the therapy of PUD was centered
documentation of a mucosal defect and tissue biopsy to rule out malig- on the old dictum by Schwartz of “no acid, no ulcer.” Although acid
nancy (GU) or H. pylori. Endoscopic examination is particularly helpful secretion is still important in the pathogenesis of PUD, eradication
in identifying lesions too small to detect by radiographic examination, of H. pylori and therapy/prevention of NSAID-induced disease is
for evaluation of atypical radiographic abnormalities, or to determine the mainstay of treatment. A summary of commonly used drugs for
if an ulcer is a source of blood loss. treatment of acid peptic disorders is shown in Table 317-3.
A B
FIGURE 317-11 Endoscopy demonstrating (A) a benign duodenal ulcer and (B) a benign gastric ulcer.

TABLE 317-2 Tests for Detection of Helicobacter pylori lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia 2229
with possible renal calcinosis and progression to renal insufficiency).
SENSITIVITY/
TEST SPECIFICITY, % COMMENTS Sodium bicarbonate may induce systemic alkalosis.
Invasive (Endoscopy/Biopsy Required) H2 Receptor Antagonists Four of these agents are presently avail-
Rapid urease 80–95/95–100 Simple, false negative with recent able (cimetidine, ranitidine, famotidine, and nizatidine), and their
use of PPIs, antibiotics, or bismuth structures share homology with histamine. Although each has
compounds different potency, all will significantly inhibit basal and stimu-
Histology 80–90/>95 Requires pathology processing lated acid secretion to comparable levels when used at therapeutic
and staining; provides histologic doses. Moreover, similar ulcer-healing rates are achieved with
information each drug when used at the correct dosage. Presently, this class
Culture —/— Time-consuming, expensive, of drug is often used for treatment of active ulcers (4–6 weeks)
dependent on experience; allows in combination with antibiotics directed at eradicating H. pylori
determination of antibiotic
susceptibility (see below).
Cimetidine was the first H2 receptor antagonist used for the treat-
Noninvasive
ment of acid peptic disorders.
Serology >80/>90 Inexpensive, convenient; not useful Cimetidine may have weak antiandrogenic side effects resulting
for early follow-up
in reversible gynecomastia and impotence, primarily in patients
Urea breath test >90/>90 Simple, rapid; useful for early follow- receiving high doses for prolonged periods of time (months to
up; false negatives with recent therapy
(see rapid urease test); exposure to
years). In view of cimetidine’s ability to inhibit cytochrome P450,
low-dose radiation with 14C test careful monitoring of drugs such as warfarin, phenytoin, and the-
Stool antigen >90/>90 Inexpensive, convenient ophylline is indicated with long-term usage. Other rare reversible
adverse effects reported with cimetidine include confusion and
Abbreviation: PPIs, proton pump inhibitors.
elevated levels of serum aminotransferases, creatinine, and serum
prolactin. Ranitidine, famotidine, and nizatidine are more potent H2
receptor antagonists than cimetidine. Each can be used once a day
ACID-NEUTRALIZING/INHIBITORY DRUGS
at bedtime for ulcer prevention, which was commonly done before
Antacids Before we understood the important role of histamine the discovery of H. pylori and the development of proton pump
in stimulating parietal cell activity, neutralization of secreted acid inhibitors (PPIs). Patients may develop tolerance to H2 blockers,

with antacids constituted the main form of therapy for peptic a rare event with PPIs (see below). Comparable nighttime dosing
ulcers. They are now rarely, if ever, used as the primary therapeu- regimens are cimetidine 800 mg, ranitidine 300 mg, famotidine 40
tic agent but instead are often used by patients for symptomatic mg, and nizatidine 300 mg.
relief of dyspepsia. The most commonly used agents are mixtures Additional rare, reversible systemic toxicities reported with H2
of aluminum hydroxide and magnesium hydroxide. Aluminum receptor antagonists include pancytopenia, neutropenia, anemia,
hydroxide can produce constipation and phosphate depletion; and thrombocytopenia, with a prevalence rate varying from 0.01
magnesium hydroxide may cause loose stools. Many of the com- to 0.2%. Cimetidine and ranitidine (to a lesser extent) can bind to
monly used antacids (e.g., Maalox, Mylanta) have a combination hepatic cytochrome P450; famotidine and nizatidine do not.
of both aluminum and magnesium hydroxide in order to avoid
these side effects. The magnesium-containing preparation should Proton Pump (H+,K+-ATPase) Inhibitors Omeprazole, esomepra-
not be used in chronic renal failure patients because of possible zole, lansoprazole, rabeprazole, and pantoprazole are substituted
hypermagnesemia, and aluminum may cause chronic neurotoxic- benzimidazole derivatives that covalently bind and irreversibly
ity in these patients. inhibit H+,K+-ATPase. Esomeprazole is the S-enantiomer of ome-
Calcium carbonate and sodium bicarbonate are potent antacids prazole, which is a racemic mixture of both S- and R-optical iso-
with varying levels of potential problems. The long-term use of mers. The R-isomer of lansoprazole, dexlansoprazole, is the most
calcium carbonate (converts to calcium chloride in the stomach) can recent PPI approved for clinical use. Its reported advantage is a
dual delayed-release system, aimed at improving treatment of
gastroesophageal reflux disease (GERD). These are the most potent
TABLE 317-3 Drugs Used in the Treatment of Peptic Ulcer Disease acid inhibitory agents available. Omeprazole and lansoprazole
DRUG TYPE/MECHANISM EXAMPLES DOSE are the PPIs that have been used for the longest time. Both are
Acid-Suppressing Drugs acid-labile and are administered as enteric-coated granules in a sus-
tained-release capsule that dissolves within the small intestine at a
Antacids Mylanta, Maalox, 100–140 meq/L 1 and
Tums, Gaviscon 3 h after meals and hs pH of 6. Lansoprazole is available in an orally disintegrating tablet
that can be taken with or without water, an advantage for individu-
H2 receptor antagonists Cimetidine 400 mg bid
als who have significant dysphagia. Absorption kinetics are similar
Ranitidine 300 mg hs
to the capsule. In addition, a lansoprazole-naproxen combination
Famotidine 40 mg hs
preparation that has been made available is targeted at decreasing
Nizatidine 300 mg hs NSAID-related GI injury (see below). Omeprazole is available as
Proton pump inhibitors Omeprazole 20 mg/d nonenteric-coated granules mixed with sodium bicarbonate in a
Lansoprazole 30 mg/d powder form that can be administered orally or via gastric tube. The
Rabeprazole 20 mg/d sodium bicarbonate has two purposes: to protect the omeprazole
Pantoprazole 40 mg/d from acid degradation and to promote rapid gastric alkalinization
Esomeprazole 20 mg/d and subsequent proton pump activation, which facilitates rapid
Dexlansoprazole 30 mg/d action of the PPI. Pantoprazole and rabeprazole are available as
enteric-coated tablets. Pantoprazole is also available as a parent-
Mucosal Protective Agents
eral formulation for intravenous use. These agents are lipophilic
Sucralfate Sucralfate 1 g qid compounds; upon entering the parietal cell, they are protonated
Prostaglandin analogue Misoprostol 200 μg qid and trapped within the acid environment of the tubulovesicular
Bismuth-containing Bismuth See anti-H. pylori and canalicular system. These agents potently inhibit all phases of
compounds subsalicylate (BSS) regimens (Table 317-4) gastric acid secretion. Onset of action is rapid, with a maximum
Abbreviation: hs, at bedtime (hora somni). acid inhibitory effect between 2 and 6 h after administration and

2230 duration of inhibition lasting up to 72–96 h. With repeated daily implicated in the development of iron, vitamin B12, and mag-
dosing, progressive acid inhibitory effects are observed, with basal nesium deficiency. A meta-analysis of nine observational studies
and secretagogue-stimulated acid production being inhibited by found a 40% increase in hypomagnesemia in PPI users as com-
>95% after 1 week of therapy. The half-life of PPIs is ~18 h; thus, it pared to non-users. One approach to consider in patients needing
can take between 2 and 5 days for gastric acid secretion to return to take PPI’s long term, is to check a complete blood count looking
to normal levels once these drugs have been discontinued. Because for evidence of anemia due to iron or B12 deficiency, vitamin B12
the pumps need to be activated for these agents to be effective, their level and a magnesium level after 1–2 years of PPI use but these
efficacy is maximized if they are administered before a meal (except recommendations are not evidence-based nor recommended by
for the immediate-release formulation of omeprazole) (e.g., in the expert opinion. PPIs may exert a negative effect on the antiplate-
morning before breakfast). Mild to moderate hypergastrinemia has let effect of clopidogrel. Although the evidence is mixed and
been observed in patients taking these drugs. Carcinoid tumors inconclusive, a small increase in mortality and readmission rate
developed in some animals given the drugs preclinically; however, for coronary events was seen in patients receiving a PPI while on
extensive experience has failed to demonstrate gastric carcinoid clopidogrel in earlier studies. Subsequently, three meta-analyses
tumor development in humans. Serum gastrin levels return to nor- reported an inverse correlation between clopidogrel and PPI use;
mal levels within 1–2 weeks after drug cessation. Rebound gastric therefore, the influence of this drug interaction on mortality is
acid hypersecretion has been described in H. pylori–negative indi- not clearly established. The mechanism involves the competi-
viduals after discontinuation of PPIs. It occurs even after relatively tion of the PPI and clopidogrel with the same cytochrome P450
short-term usage (2 months) and may last for up to 2 months (CYP2C19). Whether this is a class effect of PPIs is unclear; there
after the PPI has been discontinued. The mechanism involves gas- appears to be at least a theoretical advantage of pantoprazole
trin-induced hyperplasia and hypertrophy of histamine-secreting over the other PPIs, but this has not been confirmed. This drug
ECL cells. The clinical relevance of this observation is that individ- interaction is particularly relevant in light of the common use of
uals may have worsening symptoms of GERD or dyspepsia upon aspirin and clopidogrel for prevention of coronary events and the
stopping the PPI. Gradual tapering of the PPI and switching to an efficacy of PPIs in preventing GI bleeding in these patients. The
H2 receptor antagonist may prevent this from occurring. H. pylori– FDA has made several recommendations while awaiting further
induced inflammation and concomitant decrease in acid production evidence to clarify the impact of PPI therapy on clopidogrel use.
may explain why this does not occur in H. pylori–positive patients. Health care providers should continue to prescribe clopidogrel to
IF production is also inhibited, but vitamin B12-deficiency anemia is patients who require it and should reevaluate the need for starting
uncommon, probably because of the large stores of the vitamin. As or continuing treatment with a PPI. From a practical standpoint,
with any agent that leads to significant hypochlorhydria, PPIs may additional recommendations to consider include the following:
PART 10
interfere with absorption of drugs such as ketoconazole, ampicillin, Patients taking clopidogrel with aspirin, especially with other
iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the GI risk factors for bleeding, should receive GI protective ther-
earlier PPIs (omeprazole, lansoprazole). Rabeprazole, pantoprazole, apy. Although high-dose H2 blockers have been considered an
and esomeprazole do not appear to interact significantly with drugs option, these do not appear to be as effective as PPIs. If PPIs
metabolized by the cytochrome P450 system. The overall clinical are to be given, some have recommended that there be a 12-h
significance of this observation is not definitely established. Cau- separation between administration of the PPI and clopidogrel
tion should be taken when using theophylline, warfarin, diazepam, to minimize competition of the two agents with the involved
atazanavir, and phenytoin concomitantly with PPIs. cytochrome P450. One option is to give the PPI 30 min before
The list of potential side effects with long-term PPI use has stead- breakfast and the clopidogrel at bedtime. Insufficient data are
ily grown over the years. These agents are commonly used since available to firmly recommend one PPI over another. Additional
several formulations have become available as over the counter concerning side effects with long-term PPI use include increased
medications. Moreover, up to 70% of current prescriptions for cardiac risks independent of clopidogrel use, dementia, acute
long-term PPIs may be unwarranted. Interpretation of the multiple and chronic kidney injury. Again, the data are often retrospective
studies should take into consideration that the vast majority were and confounding variables were not consistently eliminated thus
retrospective observational studies in which confounding factors making it difficult to develop definitive association between PPIs
could not be accounted for entirely. and the toxicities outlined. A summary of the side effects with the
Long-term acid suppression, especially with PPIs, has been asso- corresponding relative risks is shown in Table 317-4. Ultimately,
ciated with a higher incidence of community-acquired pneumonia heightened awareness of inappropriate long-term use of PPIs is
as well as community and hospital acquired Clostridium difficile– paramount. Patients aged ≥65 years of age have a higher risk for
associated disease. A meta-analysis showed a 74% increased risk of some of the long-term side effects of PPIs highlighted above, in
Clostridium difficile infection and a 2.5-fold higher risk of reinfection part due to the higher prevalence of concomitant chronic diseases.
as compared to non-users. In light of these concerns the FDA pub- It is therefore essential to carefully select individuals, especially
lished a safety alert regarding the association between Clostridium among the elderly, who need long-term PPI therapy and discon-
difficile infection and PPI use. Although the risk of spontaneous bac- tinue it in those individuals who do not need it.
terial peritonitis in cirrhotics was thought to be increased, the data Development of novel acid inhibitory agents continues in an
here are less supportive. The impact of PPI-induced changes in the attempt to primarily address the need for better agents to treat
host microbiome is postulated to play a role in the increased risk of GERD. For example, modified H2 blockers with greater potency and
infection, but this theory needs to be confirmed. These observations duration as well as novel PPIs with longer half-life and potency are
require confirmation but should alert the practitioner to take caution under study. For example, tenatoprazole is a PPI containing an imi-
when recommending these agents for long-term use, especially in dazopyridine ring instead of a benzimidazole ring, which promotes
elderly patients at risk for developing pneumonia or Clostridium irreversible proton pump inhibition. This agent has a longer half-life
difficile infection. than the other PPIs and may be beneficial for inhibiting nocturnal
A population-based study revealed that long-term use of PPIs acid secretion, which has significant relevance in GERD. Additional
was associated with the development of hip fractures in older PPIs with longer half-life and combined with other agents are being
women. The absolute risk of fracture remained low despite an studied but the details are beyond the scope of this chapter. A second
observed increase associated with the dose and duration of acid new class of agents is the potassium-competitive acid pump antag-
suppression. The mechanism for this observation is not clear, and onists (P-CABs). These compounds inhibit gastric acid secretion via
this finding must be confirmed before making broad recommen- potassium competitive binding of the H+,K+-ATPase. Revaprazan
dations regarding the discontinuation of these agents in patients and venoprazan are the first two agents approved for use in Korea
who benefit from them. Long-term use of PPIs has also been and Japan, respectively.

TABLE 317-4 Evidence Supporting the Potential Adverse Effects of Extensive effort has been made in determining who of the many 2231
Proton Pump Inhibitor Drugs individuals with H. pylori infection should be treated. The common
ADVERSE EFFECT ADJUSTED OR (95% CI) conclusion arrived at by multiple consensus conferences around
Chronic kidney disease 1.50 (1.11–1.90)
the world is that H. pylori should be eradicated in patients with
documented PUD. This holds true independent of time of pre-
Acute kidney disease 2.52 (2.27–2.79)
sentation (first episode or not), severity of symptoms, presence of
Acute interstitial nephritis 3.00 (1.47–6.14)
confounding factors such as ingestion of NSAIDs, or whether the
Hypomagnesemia 1.43 (1.08–1.88) ulcer is in remission. Some have advocated treating patients with a
Clostridium difficile 1.74 (1.47–2.85) history of documented PUD who are found to be H. pylori–positive
Community-acquired pneumonia 1.34 (1.14–1.57) by stool antigen or breath testing. Between 60 and 90% of patients
Community-acquired pneumonia 1.05 (0.89–1.25) with gastric MALT lymphoma experience complete remission of
Bone fracture 1.33 (1.15–1.54) the tumor in response to H. pylori eradication. The Maastricht IV/
Abbreviation: OR, odds ratio.
Florence Consensus Report recommends a test-and-treat approach
Source: Adapted from AJ Schoenfeld, D Grady: Adverse effects associated with
for patients with uninvestigated dyspepsia if the local incidence of
proton pump inhibitors. JAMA Intern Med 176:172, 2016. H. pylori is >20%. The American College of Gastroenterology (ACG)
clinical guidelines (Developed for North America) recommend that
CYTOPROTECTIVE AGENTS individuals aged <60 with uninvestigated dyspepsia should be
tested and treated for H. pylori. In addition, recommendations
Sucralfate Sucralfate is a complex sucrose salt in which the hydroxyl from this consensus report and the ACG clinical guidelines include
groups have been substituted by aluminum hydroxide and sulfate. This testing and offering eradication of H. pylori in patients who will be
compound is insoluble in water and becomes a viscous paste within using NSAIDs (including low-dose aspirin) on a long-term basis,
the stomach and duodenum, binding primarily to sites of active ulcer- especially if there is a prior history of PUD. These individuals will
ation. Sucralfate may act by several mechanisms: serving as a phys- require continued PPI treatment as well as eradication treatment,
icochemical barrier, promoting a trophic action by binding growth because eradication of the organism alone does not eliminate the
factors such as EGF, enhancing prostaglandin synthesis, stimulating risk of gastroduodenal ulcers in patients already receiving long-term
mucus and bicarbonate secretion, and enhancing mucosal defense NSAIDs. Treating patients with NUD to prevent gastric cancer or
and repair. Toxicity from this drug is rare, with constipation being patients with GERD requiring long-term acid suppression remains
most common (2–3%). It should be avoided in patients with chronic controversial. Guidelines from the ACG suggest eradication

renal insufficiency to prevent aluminum-induced neurotoxicity. of H. pylori in patients who have undergone resection of early
Hypophosphatemia and gastric bezoar formation have also been gastric cancer. The Maastricht IV/Florence Consensus Report also
reported rarely. Standard dosing of sucralfate is 1 g qid. evaluated H. pylori treatment in gastric cancer prevention and rec-
Bismuth-Containing Preparations Sir William Osler considered ommends that eradication should be considered in the following sit-
bismuth-containing compounds the drug of choice for treating uations: first-degree relatives of family members with gastric cancer;
PUD. The resurgence in the use of these agents is due to their effect patients with previous gastric neoplasm treated by endoscopic or
against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth subtotal resection; individuals with a risk of gastritis (severe pangas-
subsalicylate (BSS, Pepto-Bismol) are the most widely used prepa- tritis or body-predominant gastritis) or severe atrophy; patients with
rations. The mechanism by which these agents induce ulcer healing gastric acid inhibition for >1 year; individuals with strong environ-
is unclear. Adverse effects with short-term use include black stools, mental risk factors for gastric cancer (heavy smoking; high exposure
constipation, and darkening of the tongue. Long-term use with high to dust, coal, quartz, or cement; and/or work in quarries); and H.
doses, especially with the avidly absorbed CBS, may lead to neuro- pylori–positive patients with a fear of gastric cancer. Finally the
toxicity. These compounds are commonly used as one of the agents ACG clinical guidelines recommend testing and offering H. pylori
in an anti-H. pylori regimen (see below). eradication to patients with unexplained iron deficiency anemia and
idiopathic thrombocytopenic purpura.
Prostaglandin Analogues In view of their central role in maintain- Multiple drugs have been evaluated in the therapy of H. pylori.
ing mucosal integrity and repair, stable prostaglandin analogues No single agent is effective in eradicating the organism. Combi-
were developed for the treatment of PUD. The mechanism by which nation therapy for 14 days provides the greatest efficacy, although
this rapidly absorbed drug provides its therapeutic effect is through regimens based on sequential administration of antibiotics also
enhancement of mucosal defense and repair. The most common appear promising (see below). A shorter administration course
toxicity noted with this drug is diarrhea (10–30% incidence). Other (7–10 days), although attractive, has not proved as successful as
major toxicities include uterine bleeding and contractions; miso- the 14-day regimens. The agents used with the greatest frequency
prostol is contraindicated in women who may be pregnant, and include amoxicillin, metronidazole, tetracycline, clarithromycin, and
women of childbearing age must be made clearly aware of this bismuth compounds.
potential drug toxicity. The standard therapeutic dose is 200 μg qid. Suggested treatment regimens for H. pylori are outlined in
Miscellaneous Drugs A number of drugs including anticholinergic Table 317-5 Choice of a particular regimen will be influenced by
agents and tricyclic antidepressants were used for treating acid several factors, including efficacy, patient tolerance, existing anti-
peptic disorders, but in light of their toxicity and the development biotic resistance, prior antibiotic use and cost of the drugs. The
of potent antisecretory agents, these are rarely, if ever, used today. aim for initial eradication rates should be 85–90%. Dual therapy
(PPI plus amoxicillin, PPI plus clarithromycin, ranitidine bismuth
THERAPY OF H. PYLORI citrate [Tritec] plus clarithromycin) is not recommended in view
The physician’s goal in treating PUD is to provide relief of symp- of studies demonstrating eradication rates of <80–85%. The com-
toms (pain or dyspepsia), promote ulcer healing, and ultimately bination of bismuth, metronidazole, and tetracycline was the first
prevent ulcer recurrence and complications. The greatest influence triple regimen found effective against H. pylori. The combination
of understanding the role of H. pylori in peptic disease has been the of two antibiotics plus either a PPI, H2 blocker, or bismuth com-
ability to prevent recurrence. Documented eradication of H. pylori in pound has comparable success rates. Addition of acid suppression
patients with PUD is associated with a dramatic decrease in ulcer assists in providing early symptom relief and enhances bacterial
recurrence to <10–20% as compared to 59% in GU patients and 67% eradication.
in DU patients when the organism is not eliminated. Eradication of Triple therapy, although effective, has several drawbacks, includ-
the organism may lead to diminished recurrent ulcer bleeding. The ing the potential for poor patient compliance and drug-induced side
effect of its eradication on ulcer perforation is unclear. effects. Compliance is being addressed by simplifying the regimens

2232 TABLE 317-5 Recommended First-Line Therapies for H. pylori Infection
REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL
Clarithromycin triple PPI (standard or double dose) BID 14 Yesa
Clarithromycin (500mg)
Amoxicillin (1 g) or Metronidazole (500 mg TID)
Bismuth quadruple PPI (standard dose) BID 10–14 Nob
Bismuth subcitrate (120–300 mg) or Subsalicylate (300 mg) QID
Tetracycline (500 mg) QID
Metronidazole (250–500 mg) QID (250)
TID to QID (500)
Concomitant PPI (standard dose) BID 10–14 No
Clarithromycin (500 mg)
Amoxicillin (1 g)
Nitroimidazole (500 mg)c
Sequential PPI (standard dose) BID 5–7 No
PPI, Clarithromycin (500 mg) + Nitroimidazole (500 mg)c BID 5–7
Hybrid PPI (standard dose) + Amox (1 g) BID 7 No
PPI, Amox, Clarithromycin (500mg), Nitroimidazole (500 mg)C BID 7
Levofloxacin triple PPI (standard or double dose) + Amox (1 g) BID 5–7 No
Levofloxacin (500 mg) QD
Amox (1 g) BID
Levofloxacin sequential PPI (standard or double dose) + Amox (1 g) BID 5–7 No
PPI, Amox, Levofloxacin (500 mg QD), Nitroimidazole BID 5–7
(500 mg)C
LOAD Levofloxacin (250 mg) QD 7–10 No
PPI (double dose) QD
Nitazoxanide (500 mg) BID
PART 10
Doxycycline (100 mg) QD

Several PPI, clarithromycin, and amoxicillin combinations have achieved FDA approval. PPI, clarithromycin and metronidazole is not an FDA-approved treatment regimen.
a
PPI, bismuth, tetracycline, and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen. C Metronidazole or tinidazole.
b
Abbreviations: BID, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; TID, three times daily; QD, once daily; QID, four times daily.
Source: Adapted from WD Chey et al: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 112:212, 2017.
so that patients can take the medications twice a day. Simpler (dual triple therapy is effective in eradicating the organism in >50% of
therapy) and shorter regimens (7 and 10 days) are not as effective as patients infected with a resistant strain. Clarithromycin resistance is
triple therapy for 14 days. Two anti-H. pylori regimens are available seen in 13–16% of individuals in the United States, with resistance
in prepackaged formulation: Prevpac (lansoprazole, clarithromycin, to amoxicillin being <1% and resistance to both metronidazole and
and amoxicillin) and Helidac (BSS, tetracycline, and metronidazole). clarithromycin in the 5% range. Resistance to tetracycline and rifab-
The contents of the Prevpac are to be taken twice per day for 14 days, utin (see below) is reported to be <2% in the United States. In light
whereas Helidac constituents are taken four times per day with an of the paucity of H. pylori antibiotic real time resistance data, asking
antisecretory agent (PPI or H2 blocker), also for at least 14 days. the patient about prior antibiotic exposure should be included in
Clarithromycin-based triple therapy should be avoided in settings the decision-making and used as a surrogate for potential antibiotic
where H. pylori resistance to this agent exceeds 15%. resistance especially when it comes to prior macrolide use. Clarith-
Side effects have been reported in up to 20–30% of patients on romycin use should be excluded in patients with prior macrolide
triple therapy. Bismuth may cause black stools, constipation, or usage. An approach to antibiotic selection for H. pylori therapy has
darkening of the tongue. The most feared complication with amox- been recommended in the ACG clinical guidelines (Fig. 317-12).
icillin is pseudomembranous colitis, but this occurs in <1–2% of Failure of H. pylori eradication with triple therapy in a compliant
patients. Amoxicillin can also lead to antibiotic-associated diarrhea, patient is usually due to infection with a resistant organism. A series
nausea, vomiting, skin rash, and allergic reaction. Concomitant use of salvage therapies for H. pylori are shown in Table 317-6. Quadru-
of probiotics may ameliorate some of the antibiotic side effects (see ple therapy (Table 317-4), where clarithromycin is substituted for
below). Tetracycline has been reported to cause rashes and, very metronidazole (or vice versa), should be the next step. The combi-
rarely, hepatotoxicity and anaphylaxis. nation of PPI, amoxicillin, and rifabutin for 10 days has also been
One important concern with treating patients who may not used successfully (86% cure rate) in patients infected with resistant
need therapy is the potential for development of antibiotic-resistant strains. Additional regimens considered for second-line therapy
strains. The incidence and type of antibiotic-resistant H. pylori strains include levofloxacin-based triple therapy (levofloxacin, amoxicillin,
vary worldwide. Strains resistant to metronidazole, clarithromycin, PPI) for 10 days and furazolidone-based triple therapy (furazoli-
amoxicillin, and tetracycline have been described, with the latter done, amoxicillin, PPI) for 14 days. Unfortunately, there is no uni-
two being uncommon. Antibiotic-resistant strains are the most versally accepted treatment regimen recommended for patients in
common cause for treatment failure in compliant patients. Unfortu- whom two courses of antibiotics have failed. If eradication is still not
nately, in vitro resistance does not predict outcome in patients. Cul- achieved in a compliant patient, then culture and sensitivity of the
ture and sensitivity testing of H. pylori is not performed routinely. organism should be considered. One challenge with this approach
Although resistance to metronidazole has been found in as many as is that culture and sensitivity testing is cumbersome and not widely
30% of isolates in North America and 80% in developing countries, available, thus H. pylori resistance data within specific communities

2233
Key Questions:
1. Is there a penicillin (PCN)
allergy?
2. Previous macrolide (MCL)
exposure for any reason?
PCN allergy: No PCN allergy: No PCN allergy: Yes PCN allergy: Yes
MCL exposure: No MCL exposure: Yes* MCL exposure: No MCL exposure: Yes*
Recommended Recommended Recommended Recommended

treatments: treatments: treatments: treatments:
Bismuth quadruple Bismuth quadruple Clarithromycin Bismuth quadruple
triple with
CONCOMITANT Levofloxacin triple
metronidazole
Clarithromycin triple Levofloxacin
Bismuth quadruple
With amoxicillin sequential
Other options: Other options:
Sequential Concomitant therapy?
HYBRID Sequential therapy?
Levofloxacin triple Hybrid therapy?

Levofloxacin LOAD?
sequential
LOAD?
*In regions where clarithromycin resistance is known

to be > 15% utilize recommendations for patients
with a history of macrolide exposure
For drugs, doses, and durations of specific first-line regimens, see Table 2.
FIGURE 317-12 Approach to selecting antibiotics for patients with H. pylori infection. (Adapted from WD Chey et al: ACG Clinical Guideline: Treatment of Helicobacter
pylori Infection. Am J Gastroenterol 112:212, 2017.)
TABLE 317-6 Salvage Therapies for H. pylori Infection

REGIMEN DRUGS (DOSES) DOSING FREQUENCY DURATION (DAYS) FDA APPROVAL
Bismuth quadruple PPI (standard dose) BID 14 Noa
Bismuth subcitrate (120–300 mg) or QID
subsalicylate (300 mg)
Tetracycline (500 mg) QID
Metronidazole (500 mg) TID or QID
Levofloxacin triple PPI (standard dose) BID 14 No
Levofloxacin (500 mg) QD
Amox (1 g) BID
Concomitant PPI (standard dose) BID 10–14 No
Clarithromycin (500 mg) BID
Amoxicillin (1 g) BID
Nitroimidazole (500 mg) BID or TID
Rifabutin triple PPI (standard dose) BID 10 No
Rifabutin (300 mg) QD
Amox (1 g) BID
High-dose dual PPI (standard to double dose) TID or QID 14 No
Amox (1 g TID or 750 mg QID) TID or QID
a
PPI, bismuth, tetracycline, and metronidazole prescribed separately is not an FDA-approved treatment regimen. However, Pylera, a combination
product containing bismuth subcitrate, tetracycline, and metronidazole combined with a PPI for 10 days is an FDA-approved treatment regimen.
Abbreviations: BID, twice daily; FDA, Food and Drug Administration; PPI, proton pump inhibitor; TID, three times daily; QD, once daily; QID, four
times daily.
Source: Adapted from WD Chey et al: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 112:212–238, 2017.

2234 are often not available. Non-culture-based approaches using molec- injurious agent should be stopped as the first step in the therapy of
ular markers to determine potential resistance through stool testing an active NSAID-induced ulcer. If that is possible, then treatment
are being developed but are not widely available. Additional factors with one of the acid inhibitory agents (H2 blockers, PPIs) is indi-
that may lower eradication rates include the patient’s country of ori- cated. Cessation of NSAIDs is not always possible because of the
gin (higher in Northeast Asia than other parts of Asia or Europe) and patient’s severe underlying disease. Only PPIs can heal GUs or DUs,
cigarette smoking. In addition, meta-analysis suggests that even the independent of whether NSAIDs are discontinued.
most effective regimens (quadruple therapy including PPI, bismuth, The widespread use of NSAIDs has created some concern due to
tetracycline, and metronidazole and triple therapy including PPI, the increasing likelihood of GI and CV side effects associated with
clarithromycin, and amoxicillin) may have suboptimal eradication these agents. The approach to primary prevention has included
rates (<80%), thus, demonstrating the need for the development of avoiding the agent, using the lowest possible dose of the agent
more efficacious treatments. for the shortest period of time possible, using NSAIDs that are
In view of the observation that 15–25% of patients treated with theoretically less injurious, using newer topical NSAID prepara-
first-line therapy may still remain infected with the organism, tions, and/or using concomitant medical therapy to prevent NSAID-
new approaches to treatment have been explored. One promising induced injury. Several nonselective NSAIDs that are associated with
approach is sequential therapy. Regimens examined consist of a lower likelihood of GI and CV toxicity include naproxen and ibu-
5 days of amoxicillin and a PPI, followed by an additional 5 days profen, although the beneficial effect may be eliminated if higher
of PPI plus tinidazole and clarithromycin or levofloxacin. One dosages of the agents are used. Primary prevention of NSAID-
promising regimen that has the benefit of being shorter in duration, induced ulceration can be accomplished by misoprostol (200 μg qid)
easier to take, and less expensive is 5 days of concomitant ther- or a PPI. High-dose H2 blockers (famotidine, 40 mg bid) have also
apy (PPI twice daily, amoxicillin 1 g twice daily, levofloxacin 500 shown some promise in preventing endoscopically documented
mg twice daily, and tinidazole 500 mg twice daily). Initial studies ulcers, although PPIs are superior. The highly selective COX-2 inhib-
have demonstrated eradication rates of >90% with good patient itors, celecoxib and rofecoxib, are 100 times more selective inhibitors
tolerance. Confirmation of these findings and applicability of this of COX-2 than standard NSAIDs, leading to gastric or duodenal
approach in the United States are needed, although some experts mucosal injury that is comparable to placebo; their utilization led
are recommending abandoning clarithromycin-based triple therapy to an increase in CV events and withdrawal from the market. Addi-
in the United States for the concomitant therapy or the alternative tional caution was engendered when the CLASS study demonstrated
sequential therapies highlighted above. that the advantage of celecoxib in preventing GI complications
Innovative non–antibiotic-mediated approaches have been was offset when low-dose aspirin was used simultaneously. There-
explored in an effort to improve eradication rates of H. pylori. Pre- fore, gastric protection therapy is required in individuals taking
PART 10
treatment of patients with N-acetylcysteine as a mucolytic agent to COX-2 inhibitors and aspirin prophylaxis. Finally, much of the work
destroy the H. pylori biofilm and therefore impair antibiotic resis- demonstrating the benefit of COX-2 inhibitors and PPIs on GI injury
tance has been examined, but more studies are needed to confirm the has been performed in individuals of average risk; it is unclear
applicability of this approach. In vitro studies suggest that certain if the same level of benefit will be achieved in high-risk patients.
probiotics like Lactobacillus or its metabolites can inhibit H. pylori. For example, concomitant use of warfarin and a COX-2 inhibitor
Administration of probiotics has been attempted in several clinical was associated with rates of GI bleeding similar to those observed
studies in an effort to maximize antibiotic-mediated eradication in patients taking nonselective NSAIDs. A combination of factors,
with varying results. Overall, it appears that the use of certain pro- including withdrawal of the majority of COX-2 inhibitors from the
biotics, such as Lactobacillus spp., Saccharomyces spp., Bifidobacterium market, the observation that low-dose aspirin appears to diminish
spp., and Bacillus clausii, did not alter eradication rates but impor- the beneficial effect of COX-2 selective inhibitors, and the growing
tantly decreased antibiotic-associated side effects including nausea, use of aspirin for prophylaxis of CV events, have significantly altered
dysgeusia, diarrhea, and abdominal discomfort/pain, resulting in the approach to gastric protective therapy during the use of NSAIDs.
enhanced tolerability of H. pylori therapies. Additional studies are A set of guidelines for the approach to the use of NSAIDs was pub-
needed to confirm the potential benefits of probiotics in this setting. lished by the ACG and is shown in Table 317-8. Individuals who are
Reinfection after successful eradication of H. pylori is rare in the not at risk for CV events do not use aspirin and are without risk for
United States (<1% per year). If recurrent infection occurs within the GI complications can receive nonselective NSAIDs without gastric
first 6 months after completing therapy, the most likely explanation protection. In those without CV risk factors but with a high potential
is recrudescence as opposed to reinfection. risk (prior GI bleeding or multiple GI risk factors) for NSAID-in-
THERAPY OF NSAID-RELATED GASTRIC OR DUODENAL INJURY duced GI toxicity, cautious use of a selective COX-2 inhibitor and
co-therapy with misoprostol or high-dose PPI are recommended.
Medical intervention for NSAID-related mucosal injury includes Individuals at moderate GI risk without cardiac risk factors can be
treatment of an active ulcer and primary prevention of future injury. treated with a COX-2 inhibitor alone or with a nonselective NSAID
Recommendations for the treatment and primary prevention of with misoprostol or a PPI. Individuals with CV risk factors, who
NSAID-related mucosal injury are listed in Table 317-7. Ideally, the
TABLE 317-8 Guide to NSAID Therapy

TABLE 317-7 Recommendations for Treatment of NSAID-Related NO/LOW NSAID GI RISK NSAID GI RISK
Mucosal Injury No CV risk Traditional NSAID Coxib or
CLINICAL SETTING RECOMMENDATION (no aspirin) Traditional NSAID + PPI or
Active ulcer misoprostol
NSAID discontinued H2 receptor antagonist or PPI Consider non-NSAID therapy
NSAID continued PPI CV risk Traditional NSAID + PPI A gastroprotective agent
(consider aspirin) or misoprostol if GI risk must be added if a traditional
Prophylactic therapy Misoprostol
warrants gastroprotection NSAID is prescribed
PPI Consider non-NSAID Consider non-NSAID therapy
Selective COX-2 inhibitor therapy
H. pylori infection Eradication if active ulcer present or there is a past Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti-
history of peptic ulcer disease inflammatory drug; PPI, proton pump inhibitor.
Abbreviations: COX-2, isoenzyme of cyclooxygenase; NSAID, nonsteroidal anti- Source: Adapted from AM Fendrick: Am J Manag Care 10:740, 2004. Reproduced
inflammatory drug; PPI, proton pump inhibitor. with permission of INTELLISPHERE, LLC via Copyright Clearance Center.

require low-dose aspirin and have low potential for NSAID-induced 2235
toxicity, should be considered for a non-NSAID agent or use of a New-Onset Dyspepsia
traditional NSAID such as naproxen (lower CV side effects) in com- >40 y/o
bination with gastric protection, if warranted. Finally, individuals Alarm Symptoms
with CV and GI risks who require aspirin must be considered for Exclude by history GERD, biliary
non-NSAID therapy, but if that is not an option, then gastric pro- pain, IBS, aerophagia,
tection with any type of NSAID must be considered. Any patient, medication-related
regardless of risk status, who is being considered for long-term tradi-
tional NSAID therapy, should also be considered for H. pylori testing –
and treatment if positive. Assuring the use of GI protective agents
with NSAIDs is difficult, even in high-risk patients. This is in part
due to under prescribing of the appropriate protective agent; other Noninvasive Hp testing
times the difficulty is related to patient compliance. The latter may
be due to patients forgetting to take multiple pills or preferring not + – +
to take the extra pill, especially if they have no GI symptoms. Sev-
eral NSAID gastroprotective-containing combination pills are now
commercially available, including double-dose famotidine with Anti-Hp Empiric trial or Refer to
ibuprofen, diclofenac with misoprostol, and naproxen with esome- therapy H2 blocker gastroenterologist
prazole. Although initial studies suggested improved compliance 4 weeks
and a cost advantage when taking these combination drugs, their after therapy
clinical benefit over the use of separate pills has not been established.
One additional concern with NSAID-induced GI complications is the Confirm eradication UBT
relatively low rate of primary care provider compliance with estab-
lished guidelines outlining preventative measures. An intervention Symptoms remain or recur
including professional education, informatics to facilitate review, and
financial incentives for practices to review patients’ charts to assess FIGURE 317-13 Overview of new-onset dyspepsia. GERD, gastroesophageal
appropriateness showed reduced rate of high-risk prescribing of antireflux disease; Hp, Helicobacter pylori; IBS, irritable bowel syndrome; UBT, urea
platelet medications and NSAIDs with a tendency towards improved breath test. (Adapted from BS Anand, DY Graham: Endoscopy 31:215, 1999.)

clinical outcomes. Efforts continue toward developing safer NSAIDs,
including topical NSAIDs, NSAID formulations that are rapidly
if these are negative for neoplasm, repeat endoscopy to document
absorbed (diclofenac potassium powder mixed with a buffering
healing at 8–12 weeks should be performed, with biopsy if the ulcer
agent, Prosorb and SoluMatrix technology), NO–releasing NSAIDs,
is still present. About 70% of GUs eventually found to be malignant
hydrogen sulfide–releasing NSAIDs, dual COX/5-LOX inhibitors,
undergo significant (usually incomplete) healing. Repeat endoscopy
NSAID prodrugs, or agents that can effectively sequester unbound
is warranted in patients with DU if symptoms persist despite medi-
NSAIDs without interfering with their efficacy.
cal therapy or a complication is suspected.
APPROACH AND THERAPY: SUMMARY The majority (>90%) of GUs and DUs heal with the conventional
Controversy continues regarding the best approach to the patient therapy outlined above. A GU that fails to heal after 12 weeks and a
who presents with dyspepsia (Chap. 41). The discovery of H. pylori DU that does not heal after 8 weeks of therapy should be considered
and its role in pathogenesis of ulcers has added a new variable to refractory. Once poor compliance and persistent H. pylori infection
the equation. Previously, if a patient <50 years of age presented with have been excluded, NSAID use, either inadvertent or surreptitious,
dyspepsia and without alarming signs or symptoms suggestive of must be excluded. In addition, cigarette smoking must be eliminated.
an ulcer complication or malignancy, an empirical therapeutic trial For a GU, malignancy must be meticulously excluded. Next, consid-
with acid suppression was commonly recommended. Although this eration should be given to a gastric acid hypersecretory state such
approach is practiced by some today, an approach presently gaining as ZES (see “Zollinger-Ellison Syndrome,” below) or the idiopathic
approval for the treatment of patients with dyspepsia is outlined in form, which can be excluded with gastric acid analysis. Although
Fig. 317-13. The referral to a gastroenterologist is for the potential a subset of patients have gastric acid hypersecretion of unclear
need of endoscopy and subsequent evaluation and treatment if the etiology as a contributing factor to refractory ulcers, ZES should
endoscopy is negative. be excluded with a fasting gastrin or secretin stimulation test (see
Once an ulcer (GU or DU) is documented, the main issue at stake below). More than 90% of refractory ulcers (either DUs or GUs) heal
after 8 weeks of treatment with higher doses of PPI (omeprazole,
is whether H. pylori or an NSAID is involved. With H. pylori present,
40 mg/d; lansoprazole 30–60 mg/d). This higher dose is also effec-
independent of the NSAID status, triple therapy is recommended for
tive in maintaining remission. Surgical intervention may be a consid-
14 days, followed by continued acid-suppressing drugs (H2 receptor
eration at this point; however, other rare causes of refractory ulcers
antagonist or PPIs) for a total of 4–6 weeks. H. pylori eradication
must be excluded before recommending surgery. Rare etiologies
should be documented 4 weeks after completing antibiotics. The
of refractory ulcers that may be diagnosed by gastric or duodenal
test of choice for documenting eradication is the laboratory-based
biopsies include ischemia, Crohn’s disease, amyloidosis, sarcoidosis,
validated monoclonal stool antigen test or a urea breath test (UBT).
lymphoma, eosinophilic gastroenteritis, smoking crack cocaine or
The patient must be off antisecretory agents when being tested for
infection (cytomegalovirus [CMV], tuberculosis, or syphilis).
eradication of H. pylori with UBT or stool antigen. Serologic testing
is not useful for the purpose of documenting eradication because SURGICAL THERAPY
antibody titers fall slowly and often do not become undetectable. Surgical intervention in PUD can be viewed as being either elective,
Some recommend that patients with complicated ulcer disease, or for treatment of medically refractory disease, or as urgent/emergent,
who are frail, should be treated with long-term acid suppression, for the treatment of an ulcer-related complication. The development
thus making documentation of H. pylori eradication a moot point. In of pharmacologic and endoscopic approaches for the treatment of
view of this discrepancy in practice, it would be best to discuss with peptic disease and its complications has led to a substantial decrease
the patient the different options available. in the number of operations needed for this disorder with a drop of
Several issues differentiate the approach to a GU versus a DU. >90% for elective ulcer surgery over the last four decades. Refractory
GUs, especially of the body and fundus, have the potential of being ulcers are an exceedingly rare occurrence. Surgery is more often
malignant. Multiple biopsies of a GU should be taken initially; even required for treatment of an ulcer-related complication.

2236 Hemorrhage is the most common ulcer-related complication,
occurring in ~15–25% of patients. Bleeding may occur in any age
group but is most often seen in older patients (sixth decade or
beyond). The majority of patients stop bleeding spontaneously, but
endoscopic therapy (Chap. 315) is necessary in some. Parenterally and
orally administered PPIs also decrease ulcer rebleeding in patients
who have undergone endoscopic therapy. Patients unresponsive or Antrum
refractory to endoscopic intervention will require angiographic inter- Fundus
vention or surgery (~5% of transfusion-requiring patients). Duodenum
Free peritoneal perforation occurs in ~2–3% of DU patients
with NSAID-induced GU perforations occurring more commonly.
Sudden onset of severe abdominal pain with peritoneal signs and
evidence of pneumoperitoneum on abdominal imaging is the clas-
sic presentation of a perforated viscous but this presentation occurs
in only two-thirds of patients. The latter is especially true in elderly
patients (>70 years old), obese individuals and in immunocompro-
mised patients. It is important to keep in mind that as in the case
of bleeding, up to 10% of these patients will not have antecedent
ulcer symptoms. Delay in diagnosis clearly leads to higher mortal-
ity thus early suspicion and intervention with nasogastric suction,
intravenous PPI, antibiotics and surgical consultation is essential.
Concomitant bleeding may occur in up to 10% of patients with
perforation, with mortality being increased substantially. Peptic
ulcer can also penetrate into adjacent organs, especially with a
posterior DU, which can penetrate into the pancreas, colon, liver,
or biliary tree.
Pyloric channel ulcers or DUs can lead to gastric outlet obstruc-
tion in ~2–3% of patients. This can result from chronic scarring or
from impaired motility due to inflammation and/or edema with
PART 10
pylorospasm. Patients may present with early satiety, nausea, vom- Billroth I Billroth II
iting of undigested food, and weight loss. Conservative manage-
FIGURE 317-14 Schematic representation of Billroth I and II procedures.
ment with nasogastric suction, intravenous hydration/nutrition,
and antisecretory agents is indicated for 7–10 days with the hope
that a functional obstruction will reverse. If a mechanical obstruction
selective vagotomy (≥10%), although the overall complication rates

persists, endoscopic intervention with balloon dilation may be effec- are the lowest of the three procedures.
tive. Surgery should be considered if all else fails. The procedure that provides the lowest rates of ulcer recurrence
Specific Operations for Duodenal Ulcers Surgical treatment was (1%) but has the highest complication rate is vagotomy (truncal or
originally designed to decrease gastric acid secretion. Operations selective) in combination with antrectomy. Antrectomy is aimed at
most commonly performed include (1) vagotomy and drainage eliminating an additional stimulant of gastric acid secretion, gastrin.
(by pyloroplasty, gastroduodenostomy, or gastrojejunostomy), Two principal types of reanastomoses are used after antrectomy:
(2) highly selective vagotomy (which does not require a drainage gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II)
procedure), and (3) vagotomy with antrectomy. The specific proce- (Fig. 317-14). Although Billroth I is often preferred over II, severe
dure performed is dictated by the underlying circumstances: elective duodenal inflammation or scarring may preclude its performance.
versus emergency, the degree and extent of duodenal ulceration, the Prospective, randomized studies confirm that partial gastrectomy
etiology of the ulcer (H. pylori, NSAIDs, malignancy), and the exper- followed by Roux-en-Y reconstruction leads to a significantly bet-
tise of the surgeon. Moreover, the trend has been toward a dramatic ter clinical, endoscopic, and histologic outcome than Billroth II
decrease in the need for surgery for treatment of refractory PUD, reconstruction.
and when needed, minimally invasive and anatomy-preserving Of these procedures, highly selective vagotomy may be the one
operations are preferred. of choice in the elective setting, except in situations where ulcer
Vagotomy is a component of each of these procedures and is recurrence rates are high (prepyloric ulcers and those refractory to
aimed at decreasing acid secretion through ablating cholinergic medical therapy). Selection of vagotomy and antrectomy may be
input to the stomach. Unfortunately, both truncal and selective vago- more appropriate in these circumstances.
tomy (preserves the celiac and hepatic branches) result in gastric These procedures have been traditionally performed by standard
atony despite successful reduction of both basal acid output (BAO; laparotomy. The advent of laparoscopic surgery has led several
decreased by 85%) and maximal acid output (MAO; decreased surgical teams to successfully perform highly selective vagotomy,
by 50%). Drainage through pyloroplasty or gastroduodenostomy truncal vagotomy/pyloroplasty, and truncal vagotomy/antrectomy
is required in an effort to compensate for the vagotomy-induced through this approach. An increase in the number of laparoscopic
gastric motility disorder. This procedure has an intermediate com- procedures for treatment of PUD has occurred. Laparoscopic repair
plication rate and a 10% ulcer recurrence rate. To minimize gastric of perforated peptic ulcers is safe, feasible for the experienced sur-
dysmotility, highly selective vagotomy (also known as parietal cell, geon and is associated with decreased postoperative pain, although
super-selective, or proximal vagotomy) was developed. Only the it does take longer than an open approach. Moreover, no difference
vagal fibers innervating the portion of the stomach that contains between the two approaches is noted in postoperative complications
parietal cells is transected, thus leaving fibers important for regu- or length of hospital stay.
lating gastric motility intact. Although this procedure leads to an Specific Operations for GUs The location and the presence of a
immediate decrease in both BAO and stimulated acid output, acid concomitant DU dictate the operative procedure performed for
secretion recovers over time. By the end of the first postoperative a GU. Antrectomy (including the ulcer) with a Billroth I anasto-
year, basal and stimulated acid output are ~30 and 50%, respectively, mosis is the treatment of choice for an antral ulcer. Vagotomy is
of preoperative levels. Ulcer recurrence rates are higher with highly performed only if a DU is present. Although ulcer excision with

vagotomy and drainage procedure has been proposed, the higher afferent loop that is partially obstructed. Cases refractory to dietary 2237
incidence of ulcer recurrence makes this a less desirable approach. measures may need surgical revision or conversion of the Billroth II
Ulcers located near the esophagogastric junction may require a anastomosis to a Roux-en-Y gastrojejunostomy.
more radical approach, a subtotal gastrectomy with a Roux-en-Y Dumping Syndrome Dumping syndrome consists of a series of
esophagogastrojejunostomy (Csendes’ procedure). A less aggres- vasomotor and GI signs and symptoms and occurs in patients who
sive approach, including antrectomy, intraoperative ulcer biopsy, have undergone vagotomy and drainage (especially Billroth pro-
and vagotomy (Kelling-Madlener procedure), may be indicated in cedures). Two phases of dumping, early and late, can occur. Early
fragile patients with a high GU. Ulcer recurrence approaches 30% dumping takes place 15–30 min after meals and consists of crampy
with this procedure. abdominal discomfort, nausea, diarrhea, belching, tachycardia,
Surgery-Related Complications Complications seen after surgery palpitations, diaphoresis, light-headedness, and, rarely, syncope.
for PUD are related primarily to the extent of the anatomic modi- These signs and symptoms arise from the rapid emptying of hyper-
fication performed. Minimal alteration (highly selective vagotomy) osmolar gastric contents into the small intestine, resulting in a fluid
is associated with higher rates of ulcer recurrence and less GI dis- shift into the gut lumen with plasma volume contraction and acute
turbance. More aggressive surgical procedures have a lower rate of intestinal distention. Release of vasoactive GI hormones (vasoactive
ulcer recurrence but a greater incidence of GI dysfunction. Overall, intestinal polypeptide, neurotensin, motilin) is also theorized to
morbidity and mortality related to these procedures are quite low. play a role in early dumping.
Morbidity associated with vagotomy and antrectomy or pyloro- The late phase of dumping typically occurs 90 min to 3 h after
plasty is ≤5%, with mortality ~1%. Highly selective vagotomy has meals. Vasomotor symptoms (light-headedness, diaphoresis, palpi-
lower morbidity and mortality rates of 1 and 0.3%, respectively. tations, tachycardia, and syncope) predominate during this phase.
In addition to the potential early consequences of any intraab- This component of dumping is thought to be secondary to hypogly-
dominal procedure (bleeding, infection, thromboembolism), gas- cemia from excessive insulin release.
troparesis, duodenal stump leak, and efferent loop obstruction can Dumping syndrome is most noticeable after meals rich in simple
be observed. carbohydrates (especially sucrose) and high osmolarity. Ingestion of
large amounts of fluids may also contribute. Up to 50% of postvago-
Recurrent Ulceration The risk of ulcer recurrence is directly related
tomy and drainage patients will experience dumping syndrome to
to the procedure performed. Ulcers that recur after partial gastric
some degree early on. Signs and symptoms often improve with time,
resection tend to develop at the anastomosis (stomal or marginal
but a severe protracted picture can occur in up to 1% of patients.
ulcer). Epigastric abdominal pain is the most frequent presenting
Dietary modification is the cornerstone of therapy for patients

complaint (>90%). Severity and duration of pain tend to be more
with dumping syndrome. Small, multiple (six) meals devoid of
progressive than observed with DUs before surgery.
simple carbohydrates coupled with elimination of liquids during
Ulcers may recur for several reasons, including incomplete vago-
tomy, inadequate drainage, retained antrum, and, less likely, persis- meals is important. Antidiarrheals and anticholinergic agents are
tent or recurrent H. pylori infection. ZES should have been excluded complementary to diet. Guar and pectin, which increase the viscos-
preoperatively. Surreptitious use of NSAIDs is an important reason ity of intraluminal contents, may be beneficial in more symptomatic
for recurrent ulcers after surgery, especially if the initial procedure individuals. Acarbose, an α-glucosidase inhibitor that delays diges-
was done for an NSAID-induced ulcer. Once H. pylori and NSAIDs tion of ingested carbohydrates, has also been shown to be beneficial
have been excluded as etiologic factors, the question of incomplete in the treatment of the late phases of dumping. The somatostatin
vagotomy or retained gastric antrum should be explored. For the lat- analogue octreotide has been successful in diet-refractory cases. This
ter, fasting plasma gastrin levels should be determined. If elevated, drug is administered subcutaneously (50 μg tid), titrated according to
retained antrum or ZES (see below) should be considered. Incom- clinical response. A long-acting depot formulation of octreotide can
plete vagotomy can be ruled out by gastric acid analysis coupled be administered once every 28 days and provides symptom relief
with sham feeding. In this test, gastric acid output is measured while comparable to the short-acting agent. In addition, patient weight gain
the patient sees, smells, and chews a meal (without swallowing). and quality of life appear to be superior with the long-acting form.
The cephalic phase of gastric secretion, which is mediated by the Postvagotomy Diarrhea Up to 10% of patients may seek medical
vagus, is being assessed with this study. An increase in gastric acid attention for the treatment of postvagotomy diarrhea. This compli-
output in response to sham feeding is evidence that the vagus nerve cation is most commonly observed after truncal vagotomy, which
is intact. A rise in serum pancreatic polypeptide >50% within 30 min is rarely performed today. Patients may complain of intermittent
of sham feeding is also suggestive of an intact vagus nerve. diarrhea that occurs typically 1–2 h after meals. Occasionally the
Medical therapy with H2 blockers will heal postoperative ulcer- symptoms may be severe and relentless. This is due to a motility
ation in 70–90% of patients. The efficacy of PPIs has not been fully disorder from interruption of the vagal fibers supplying the luminal
assessed in this group, but one may anticipate greater rates of ulcer gut. Other contributing factors may include decreased absorption of
healing compared to those obtained with H2 blockers. Repeat oper- nutrients (see below), increased excretion of bile acids, and release
ation (complete vagotomy, partial gastrectomy) may be required in of luminal factors that promote secretion. Diphenoxylate or lopera-
a small subgroup of patients who have not responded to aggressive mide is often useful in symptom control. The bile salt–binding agent
medical management. cholestyramine may be helpful in severe cases. Surgical reversal of
Afferent Loop Syndromes Although rarely seen today as a result a 10-cm segment of jejunum may yield a substantial improvement
of the decrease in the performance of Billroth II anastomosis, two in bowel frequency in a subset of patients.
types of afferent loop syndrome can occur in patients who have Bile Reflux Gastropathy A subset of post–partial gastrectomy
undergone this type of partial gastric resection. The more common patients who present with abdominal pain, early satiety, nausea,
of the two is bacterial overgrowth in the afferent limb secondary and vomiting will have mucosal erythema of the gastric remnant
to stasis. Patients may experience postprandial abdominal pain, as the only finding. Histologic examination of the gastric mucosa
bloating, and diarrhea with concomitant malabsorption of fats and reveals minimal inflammation but the presence of epithelial cell
vitamin B12. Cases refractory to antibiotics may require surgical injury. This clinical picture is categorized as bile or alkaline reflux
revision of the loop. The less common afferent loop syndrome can gastropathy/gastritis. Although reflux of bile is implicated as the
present with severe abdominal pain and bloating that occur 20–60 reason for this disorder, the mechanism is unknown. Prokinetic
min after meals. Pain is often followed by nausea and vomiting agents, cholestyramine, and sucralfate have been somewhat effec-
of bile-containing material. The pain and bloating may improve tive treatments. Severe refractory symptoms may require using
after emesis. The cause of this clinical picture is theorized to be either nuclear scanning with 99mTc-HIDA to document reflux or
incomplete drainage of bile and pancreatic secretions from an an alkaline challenge test, where 0.1 N NaOH is infused into the

2238 stomach in an effort to reproduce the patient’s symptoms. Surgical Epidemiology The true incidence of ZES is unknown but esti-
diversion of pancreaticobiliary secretions away from the gastric mates suggest that it varies from 0.1 to 1% of individuals presenting
remnant with a Roux-en-Y gastrojejunostomy consisting of a long with PUD with 0.1–3 individuals per year having this rare diagnosis.
(50–60 cm) Roux limb has been used in severe cases. Bilious vom- Females are slightly more commonly affected than males, and the
iting improves, but early satiety and bloating may persist in up to majority of patients are diagnosed between ages 30 and 50. Gastri-
50% of patients. nomas are classified into sporadic tumors (80%) and those associated
Maldigestion And Malabsorption Weight loss can be observed in up with multiple endocrine neoplasia (MEN) type 1 (see below). The
to 60% of patients after partial gastric resection. Patients can experi- widespread availability and use of PPIs has led to a decreased patient
ence a 10% loss of body weight, which stabilizes 3 months postop- referral for gastrinoma evaluation, delay in diagnosis, and an increase
eratively. A significant component of this weight reduction is due to in false-positive diagnoses of ZES. In fact, diagnosis may be delayed for
decreased oral intake. However, mild steatorrhea can also develop. ≥6 years after symptoms consistent with ZES are displayed.
Reasons for maldigestion/malabsorption include decreased gastric Pathophysiology Hypergastrinemia originating from an autono-
acid production, rapid gastric emptying, decreased food dispersion mous neoplasm is the driving force responsible for the clinical man-
in the stomach, reduced luminal bile concentration, reduced pan- ifestations in ZES. Gastrin stimulates acid secretion through gastrin
creatic secretory response to feeding, and rapid intestinal transit. receptors on parietal cells and by inducing histamine release from ECL
Decreased serum vitamin B12 levels can be observed after partial cells. Gastrin also has a trophic action on gastric epithelial cells. Long-
gastrectomy. This is usually not due to deficiency of intrinsic fac- standing hypergastrinemia leads to markedly increased gastric acid
tor (IF), since a minimal amount of parietal cells (source of IF) are secretion through both parietal cell stimulation and increased parietal
removed during antrectomy. Reduced vitamin B12 may be due to com- cell mass. The increased gastric acid output leads to peptic ulcer diath-
petition for the vitamin by bacterial overgrowth or inability to split the esis, erosive esophagitis, and diarrhea.
vitamin from its protein-bound source due to hypochlorhydria.
Iron-deficiency anemia may be a consequence of impaired Tumor Distribution Although early studies suggested that the
absorption of dietary iron in patients with a Billroth II gastrojejunos- vast majority of gastrinomas occurred within the pancreas, a significant
tomy. Absorption of iron salts is normal in these individuals; thus, a number of these lesions are extrapancreatic. Over 80% of these tumors
favorable response to oral iron supplementation can be anticipated. are found within the hypothetical gastrinoma triangle (confluence of
Folate deficiency with concomitant anemia can also develop in these the cystic and common bile ducts superiorly, junction of the second
patients. This deficiency may be secondary to decreased absorption and third portions of the duodenum inferiorly, and junction of the
or diminished oral intake. neck and body of the pancreas medially). Duodenal tumors constitute
Malabsorption of vitamin D and calcium resulting in osteoporosis the most common nonpancreatic lesion; between 50 and 75% of gastri-
PART 10
and osteomalacia is common after partial gastrectomy and gastroje- nomas are found here. Duodenal tumors are smaller, slower growing,
junostomy (Billroth II). Osteomalacia can occur as a late complica- and less likely to metastasize than pancreatic lesions. Less common
tion in up to 25% of post–partial gastrectomy patients. Bone fractures extrapancreatic sites include stomach, bones, ovaries, heart, liver, and
occur twice as commonly in men after gastric surgery as in a control lymph nodes. More than 60% of tumors are considered malignant,
population. It may take years before x-ray findings demonstrate with up to 30–50% of patients having multiple lesions or metastatic
diminished bone density. Elevated alkaline phosphatase, reduced disease at presentation. Histologically, gastrin-producing cells appear
serum calcium, bone pain, and pathologic fractures may be seen in well-differentiated, expressing markers typically found in endocrine
patients with osteomalacia. The high incidence of these abnormali- neoplasms (chromogranin, neuron-specific enolase).
ties in this subgroup of patients justifies treating them with vitamin
Clinical Manifestations Gastric acid hypersecretion is responsible
D and calcium supplementation indefinitely. Therapy is especially
for the signs and symptoms observed in patients with ZES. Peptic ulcer
important in females. Copper deficiency has also been reported in
is the most common clinical manifestation, occurring in >90% of gastri-
patients undergoing surgeries that bypass the duodenum, where
noma patients. Initial presentation and ulcer location (duodenal bulb)
copper is primarily absorbed. Patients may present with a rare syn-
may be indistinguishable from common PUD. Clinical situations that
drome that includes ataxia, myelopathy, and peripheral neuropathy.
should create suspicion of gastrinoma are ulcers in unusual locations
Gastric Adenocarcinoma The incidence of adenocarcinoma in (second part of the duodenum and beyond), ulcers refractory to stan-
the gastric stump is increased 15 years after resection. Some have dard medical therapy, ulcer recurrence after acid-reducing surgery,
reported a four- to fivefold increase in gastric cancer 20–25 years ulcers presenting with frank complications (bleeding, obstruction, and
after resection. The pathogenesis is unclear but may involve alka- perforation), or ulcers in the absence of H. pylori or NSAID ingestion.
line reflux, bacterial proliferation, or hypochlorhydria. The role Symptoms of esophageal origin are present in up to two-thirds of
of endoscopic screening is not clear, and most guidelines do not patients with ZES, with a spectrum ranging from mild esophagitis to
support its use. frank ulceration with stricture and Barrett’s mucosa.
Additional Complications Reflux esophagitis and a higher inci- Diarrhea, the next most common clinical manifestation, is found in
dence of gallstones and cholecystitis have been reported to patients up to 50% of patients. Although diarrhea often occurs concomitantly
undergoing subtotal gastrectomy. The latter is thought to be due to with acid peptic disease, it may also occur independent of an ulcer. Eti-
decreased gallbladder contractility associated with vagotomy and ology of the diarrhea is multifactorial, resulting from marked volume
bypass of the duodenum, leading to decreased postprandial release overload to the small bowel, pancreatic enzyme inactivation by acid,
of cholecystokinin. and damage of the intestinal epithelial surface by acid. The epithelial
damage can lead to a mild degree of maldigestion and malabsorption
of nutrients. The diarrhea may also have a secretory component due to
RELATED CONDITIONS the direct stimulatory effect of gastrin on enterocytes or the co-secretion
of additional hormones from the tumor such as vasoactive intestinal
■■ZOLLINGER–ELLISON SYNDROME peptide.
Severe peptic ulcer diathesis secondary to gastric acid hyperse- Gastrinomas can develop in the presence of MEN 1 syndrome
cretion due to unregulated gastrin release from a non-β cell often (Chaps. 80 and 381) in ~25% of patients. This autosomal dominant
well-differentiated neuroendocrine tumor (gastrinoma) defines the disorder involves primarily three organ sites: the parathyroid glands
components of ZES. Initially, ZES was typified by aggressive and (80–90%), pancreas (40–80%), and pituitary gland (30–60%). The syn-
refractory ulceration in which total gastrectomy provided the only drome is caused by inactivating mutations of the MEN1 tumor sup-
chance for enhancing survival. Today it can be cured by surgical resec- pressor gene found on the long arm of chromosome 11q13. The gene
tion in up to 40% of patients. encodes for Menin, which has an important role in DNA replication

and transcriptional regulation. A genetic diagnosis is obtained by subsequently lead to failure of the feedback inhibitory pathway, result- 2239
sequencing of the MEN1 gene, which can reveal mutations in 70–90% ing in net hypergastrinemia. Gastrin levels will thus be high in patients
of typical MEN 1 cases. A family may have an unknown mutation, using antisecretory agents for the treatment of acid peptic disorders
making a genetic diagnosis impossible, and therefore certain individu- and dyspepsia. H. pylori infection can also cause hypergastrinemia.
als will require a clinical diagnosis, which is determined by whether a Additional causes of elevated gastrin include retained gastric antrum;
patient has tumors in two of the three endocrine organs (parathyroid, G cell hyperplasia; gastric outlet obstruction; renal insufficiency;
pancreas/duodenum, or pituitary) or has a family history of MEN massive small-bowel obstruction; and conditions such as rheumatoid
1 and one of the endocrine organ tumors. In view of the stimulatory arthritis, vitiligo, diabetes mellitus, and pheochromocytoma. Although
effect of calcium on gastric secretion, the hyperparathyroidism and a fasting gastrin >10 times normal is highly suggestive of ZES, two-
hypercalcemia seen in MEN 1 patients may have a direct effect on ulcer thirds of patients will have fasting gastrin levels that overlap with
disease. Resolution of hypercalcemia by parathyroidectomy reduces levels found in the more common disorders outlined above, especially
gastrin and gastric acid output in gastrinoma patients. An additional if a PPI is being taken by the patient. The effect of the PPI on gastrin
distinguishing feature in ZES patients with MEN 1 is the higher inci- levels and acid secretion will linger several days after stopping the PPI;
dence of gastric carcinoid tumor development (as compared to patients therefore, it should be stopped for a minimum of 7 days before testing.
with sporadic gastrinomas). ZES presents and is diagnosed earlier in During this period, the patient should be placed on a histamine H2
MEN 1 patients, and they have a more indolent course as compared antagonist, such as famotidine, twice to three times per day. Although
to patients with sporadic gastrinoma. Gastrinomas tend to be smaller, this type of agent has a short-term effect on gastrin and acid secretion,
multiple, and located in the duodenal wall more often than is seen in it needs to be stopped 24 h before repeating fasting gastrin levels or
patients with sporadic ZES. Establishing the diagnosis of MEN 1 is performing some of the tests highlighted below. The patient may take
critical in order to provide genetic counseling to the patient and his or antacids for the final day, stopping them ~12 h before testing is per-
her family and also to determine the recommended surgical approach. formed. Heightened awareness of complications related to gastric acid
Therefore, gastrinoma patients should be screened for MEN I perform- hypersecretion during the period of PPI cessation is critical.
ing a detailed family history and obtaining several serum markers The next step at times needed for establishing a biochemical diag-
including calcium, parathyroid, prolactin and pancreatic polypeptide nosis of gastrinoma is to assess acid secretion. Nothing further needs
levels. to be done if decreased acid output in the absence of a PPI is observed.
A pH can be measured on gastric fluid obtained either during endos-
Diagnosis Biochemical measurements of gastrin and acid secretion
copy or through nasogastric aspiration; a pH <3 is suggestive of a
in patients suspected of ZES play an important role is establishing this
gastrinoma, but a pH >3 is not helpful in excluding the diagnosis.
rare diagnosis. Often, patients suspected of having ZES will be treated

In those situations where the pH is >3, formal gastric acid analysis
with a PPI in an effort to ameliorate symptoms and decrease the like-
should be performed if available. Normal BAO in nongastric surgery
lihood of possible acid-related complications. The presence of the PPI,
patients is typically <5 meq/h. A BAO >15 meq/h in the presence of
which will lower acid secretion and potentially elevate fasting gastrin
hypergastrinemia is considered pathognomonic of ZES, but up to 12%
levels in normal individuals, will make the diagnostic approach in
of patients with common PUD may have elevated BAO to a lesser
these individuals somewhat difficult. Significant morbidity related
degree that can overlap with levels seen in ZES patients. In an effort
to peptic diathesis has been described when stopping PPIs in gas-
to improve the sensitivity and specificity of gastric secretory studies, a
trinoma patients; therefore, a systematic approach in stopping these
BAO/ MAO ratio was established using pentagastrin infusion as a way
agents is warranted (see below). The first step in the evaluation of a
patient suspected of having ZES is to obtain a fasting gastrin level. A to maximally stimulate acid production, with a BAO/MAO ratio >0.6
list of clinical scenarios that should arouse suspicion regarding this being highly suggestive of ZES. Pentagastrin is no longer available in
diagnosis is shown in Table 317-9. Fasting gastrin levels obtained the United States, making measurement of MAO virtually impossible.
using a dependable assay are usually <150 pg/mL. A normal fasting An endoscopic method for measuring gastric acid output has been
gastrin, on two separate occasions, especially if the patient is on a PPI, developed but requires further validation.
virtually excludes this diagnosis. Virtually all gastrinoma patients will Gastrin provocative tests have been developed in an effort to dif-
have a gastrin level >150–200 pg/mL. Measurement of fasting gastrin ferentiate between the causes of hypergastrinemia and are especially
should be repeated to confirm the clinical suspicion. Some of the com- helpful in patients with indeterminate acid secretory studies. The tests
mercial biochemical assays used for measuring serum gastrin may be are the secretin stimulation test and the calcium infusion study. The
inaccurate. Variable specificity of the antibodies used have led to both most sensitive and specific gastrin provocative test for the diagnosis
false-positive and false-negative fasting gastrin levels, placing in jeop- of gastrinoma is the secretin study. An increase in gastrin of ≥120 pg
ardy the ability to make an accurate diagnosis of ZES. within 15 min of secretin injection has a sensitivity and specificity of
Multiple processes can lead to an elevated fasting gastrin level, the >90% for ZES. PPI-induced hypochlorhydria or achlorhydria may lead
most frequent of which are gastric hypochlorhydria and achlorhy- to a false-positive secretin test; thus, this agent must be stopped for
dria, with or without pernicious anemia. Gastric acid induces feed- 1 week before testing.
back inhibition of gastrin release. A decrease in acid production will The calcium infusion study is less sensitive and specific than the
secretin test, which, coupled with it being a more cumbersome study
with greater potential for adverse effects, relegates it to rare utilization
in the cases where the patient’s clinical characteristics are highly sug-
TABLE 317-9 When to Obtain a Fasting Serum Gastrin Level
gestive of ZES but the secretin stimulation is inconclusive.
Multiple ulcers
Ulcers in unusual locations; associated with severe esophagitis; resistant Tumor Localization Once the biochemical diagnosis of gastri-
to therapy with frequent recurrences; in the absence of nonsteroidal anti- noma has been confirmed, the tumor must be located. Multiple imag-
inflammatory drug ingestion or H. pylori infection ing studies have been used in an effort to enhance tumor localization
Ulcer patients awaiting surgery (Table 317-10). The broad range of sensitivity is due to the variable suc-
Extensive family history for peptic ulcer disease cess rates achieved by the different investigative groups. Endoscopic
Postoperative ulcer recurrence ultrasound (EUS) permits imaging of the pancreas with a high degree
Basal hyperchlorhydria of resolution (<5 mm). This modality is particularly helpful in exclud-
Unexplained diarrhea or steatorrhea ing small neoplasms within the pancreas and in assessing the presence
Hypercalcemia of surrounding lymph nodes and vascular involvement, but it is not
Family history of pancreatic islet, pituitary, or parathyroid tumor very sensitive for finding duodenal lesions. Several types of endocrine
tumors express cell-surface receptors for somatostatin, in particular
Prominent gastric or duodenal folds
the sub-type 2 (SSTR2). This permits the localization, staging, and

2240 TABLE 317-10 Sensitivity of Imaging Studies in Zollinger-Ellison The ultimate goal of surgery would be to provide a definitive
Syndrome cure. Improved understanding of tumor distribution has led to
SENSITIVITY, % immediate cure rates as high as 33% with 10-year disease-free inter-
vals as high as 95% in sporadic gastrinoma patients undergoing
PRIMARY METASTATIC
STUDY GASTRINOMA GASTRINOMA surgery. A positive outcome is highly dependent on the experience
Ultrasound 21–28 14
of the surgical team treating these rare tumors. Surgical therapy of
gastrinoma patients with MEN 1 remains controversial because of
CT scan 55–70 >85
the difficulty in rendering these patients disease-free with surgery.
Selective angiography 35–68 33–86
In contrast to the encouraging postoperative results observed in
Portal venous sampling 70–90 N/A patients with sporadic disease, only 6% of MEN 1 patients are dis-
SASI 55–78 41 ease-free 5 years after an operation. Moreover, in contrast to patients
MRI 55–70 >85 with sporadic ZES, the clinical course of MEN 1 patients is benign
OctreoScan 67–86 80–100 and rarely leads to disease-related mortality, recommending that
EUS 80–100 N/A early surgery be deferred. Some groups suggest surgery only if a
Abbreviations: CT, computed tomography; EUS, endoscopic ultrasonography; MRI,
clearly identifiable, nonmetastatic lesion is documented by struc-
magnetic resonance imaging; N/A, not applicable; OctreoScan, imaging with tural studies. Others advocate a more aggressive approach, where
111
In-pentreotide; SASI, selective arterial secretin injection. all patients free of hepatic metastasis are explored and all detected
tumors in the duodenum are resected; this is followed by enucle-
ation of lesions in the pancreatic head, with a distal pancreatectomy
prediction of therapeutic response to somatostatin analogues (see to follow. The outcome of the two approaches has not been clearly
below) bygastrinomas. The original functional scinitigraphic tool defined. Laparoscopic surgical interventions may provide attractive
developed measuring the uptake of the stable somatostatin analogue111 approaches in the future but currently seem to be of some limited
In-pentreotide (OctreoScan) has demonstrated sensitivity and speci- benefit in patients with gastrinoma because a significant percentage
ficity rates of >80%. More recently, PET-CT with 68Ga-DOTATATE has of the tumors may be extrapancreatic and difficult to localize with a
been developed and is superior than Octreoscan for assessing tumor laparoscopic approach. Finally, patients selected for surgery should
presence in patients with well-differentiated neuroendocrine tumors be individuals whose health status would lead them to tolerate a
such as gastrinomas, with sensitivity and specificity of >90%, making more aggressive operation and obtain the long-term benefits from
it the functional imaging study of choice when available. such aggressive surgery, which are often witnessed after 10 years.
Up to 50% of patients have metastatic disease at diagnosis. Success in Therapy of metastatic endocrine tumors in general remains sub-
PART 10
controlling gastric acid hypersecretion has shifted the emphasis of ther- optimal; gastrinomas are no exception. In light of the observation
apy toward providing a surgical cure. Detecting the primary tumor and that in many instances tumor growth is indolent and that many
excluding metastatic disease are critical in view of this paradigm shift. individuals with metastatic disease remain relatively stable for
Once a biochemical diagnosis has been confirmed, the patient should significant periods of time, many advocate not instituting systemic
first undergo an abdominal computed tomography (CT) scan, magnetic tumor-targeted therapy until evidence of tumor progression or
resonance imaging (MRI), or OctreoScan/PET-CT with 68Ga-DOTATATE refractory symptoms not controlled with PPIs are noted. Medi-
(depending on availability) to exclude metastatic disease. Once meta- cal approaches, including biological therapy (IFN-α, long-acting
static disease has been excluded, an experienced endocrine surgeon may somatostatin analogues, peptide receptor radionuclides), systemic
opt for exploratory laparotomy with intraoperative ultrasound or tran- chemotherapy (streptozotocin, 5-fluorouracil, and doxorubicin), and
sillumination. In other centers, careful examination of the peripancreatic hepatic artery embolization, may lead to significant toxicity without
area with EUS, accompanied by endoscopic exploration of the duode- a substantial improvement in overall survival. Use of temozolomide
num for primary tumors, will be performed before surgery. Selective with capecitabine has demonstrated radiographic regression and
arterial secretin injection may be a useful adjuvant for localizing tumors progression-free survival in patients with well-differentiated NETs
in a subset of patients. The extent of the diagnostic and surgical approach in the range of 70% and 18 months respectively. Systemic ther-
must be carefully balanced with the patient’s overall physiologic condi- apy with radiolabeled somatostatin analogues (Peptide Receptor
tion and the natural history of a slow-growing gastrinoma. Radiotherapy, PRRT) has been used in the therapy of metastatic
neuroendocrine tumors and appears to be very promising in terms
of radiographic, symptom, and progression-free survival, but addi-
TREATMENT tional studies are warranted. Several promising therapies are being
Zollinger-Ellison Syndrome explored, including radiofrequency ablation or cryoablation of liver
lesions and use of agents that block the vascular endothelial growth
Treatment of functional endocrine tumors is directed at ameliorating receptor pathway (sunitinib) or the mammalian target of rapamycin
the signs and symptoms related to hormone overproduction, cura- (Chap. 80).
tive resection of the neoplasm, and attempts to control tumor growth Surgical approaches, including debulking surgery and liver trans-
in metastatic disease. plantation for hepatic metastasis, have also produced limited benefit.
PPIs are the treatment of choice and have decreased the need The overall 5- and 10-year survival rates for gastrinoma patients
for total gastrectomy. Initial PPI doses tend to be higher than those are 62–75% and 47–53%, respectively. Individuals with the entire
used for treatment of GERD or PUD. The initial dose of omeprazole, tumor resected or those with a negative laparotomy have 5- and
lansoprazole, rabeprazole, or esomeprazole should be in the range 10-year survival rates >90%. Patients with incompletely resected
of 60 mg in divided doses in a 24-h period. Dosing can be adjusted tumors have 5- and 10-year survival rates of 43 and 25%,
to achieve a BAO <10 meq/h (at the drug trough) in surgery- respectively. Patients with hepatic metastasis have <20% sur-
naive patients and to <5 meq/h in individuals who have previously vival at 5 years. Favorable prognostic indicators include primary
undergone an acid-reducing operation. Although the somatostatin duodenal wall tumors, isolated lymph node tumor, the presence of
analogue has inhibitory effects on gastrin release from receptor- MEN 1, and undetectable tumor upon surgical exploration. Poor
bearing tumors and inhibits gastric acid secretion to some extent, outcome is seen in patients with shorter disease duration; higher
PPIs have the advantage of reducing parietal cell activity to a greater gastrin levels (>10,000 pg/mL); large pancreatic primary tumors
degree. Despite this, octreotide or lanreotide may be considered as (>3 cm); metastatic disease to lymph nodes, liver, and bone; and
adjunctive therapy to the PPI in patients with tumors that express Cushing’s syndrome. Rapid growth of hepatic metastases is also
somatostatin receptors and have peptic symptoms that are difficult predictive of poor outcome.
to control with high-dose PPI.

■■STRESS-RELATED MUCOSAL INJURY TABLE 317-11 Classification of Gastritis 2241
Patients suffering from shock, sepsis, massive burns, severe trauma, I. Acute gastritis
or head injury can develop acute erosive gastric mucosal changes or A. Acute H. pylori infection
frank ulceration with bleeding. Classified as stress-induced gastritis
B. Other acute infectious gastritides
or ulcers, injury is most commonly observed in the acid-producing
(fundus and body) portions of the stomach. The most common presen- 1. Bacterial (other than H. pylori)
tation is GI bleeding, which is usually minimal but can occasionally be 2. H. heilmannii
life-threatening. Respiratory failure requiring mechanical ventilation 3. Phlegmonous
and underlying coagulopathy are risk factors for bleeding, which tends 4. Mycobacterial
to occur 48–72 h after the acute injury or insult. 5. Syphilitic
Histologically, stress injury does not contain inflammation or H. 6. Viral
pylori; thus, “gastritis” is a misnomer. Although elevated gastric acid 7. Parasitic
secretion may be noted in patients with stress ulceration after head 8. Fungal
trauma (Cushing’s ulcer) and severe burns (Curling’s ulcer), mucosal II. Chronic atrophic gastritis
ischemia, breakdown of the normal protective barriers of the stomach,
A. Type A: Autoimmune, body-predominant
systemic release of cytokines, poor GI motility, and oxidative stress
B. Type B: H. pylori–related, antral-predominant
also play an important role in the pathogenesis. Acid must contribute
to injury in view of the significant drop in bleeding noted when acid C. Indeterminate
inhibitors are used as prophylaxis for stress gastritis. III. Uncommon forms of gastritis
Improvement in the general management of intensive care unit A. Lymphocytic
patients has led to a significant decrease in the incidence of GI bleeding B. Eosinophilic
due to stress ulceration. The estimated decrease in bleeding is from C. Crohn’s disease
20–30% to <5%. This improvement has led to some debate regarding D. Sarcoidosis
the need for prophylactic therapy. The high mortality associated with E. Isolated granulomatous gastritis
stress-induced clinically important GI bleeding (>40%) and the limited F. Russell body gastritis
benefit of medical (endoscopic, angiographic) and surgical therapy in a
patient with hemodynamically compromising bleeding associated with
stress ulcer/gastritis support the use of preventive measures in high-
this entity include streptococci, staphylococci, Escherichia coli, Proteus,

risk patients (mechanically ventilated, coagulopathy, multiorgan fail-
and Haemophilus species. Failure of supportive measures and antibiot-
ure, or severe burns). Metaanalysis comparing H2 blockers with PPIs
ics may result in gastrectomy.
for the prevention of stress-associated clinically important and overt GI
Other types of infectious gastritis may occur in immunocompro-
bleeding demonstrates superiority of the latter without increasing the
mised individuals such as AIDS patients. Examples include herpetic
risk of nosocomial infections, increasing mortality, or prolonging inten-
(herpes simplex) or CMV gastritis. The histologic finding of intranu-
sive care unit length of stay. Therefore, PPIs are the treatment of choice
clear inclusions would be observed in the latter.
for stress prophylaxis. Oral PPI is the best option if the patient can
tolerate enteral administration. Pantoprazole is available as an intrave- Chronic Gastritis Chronic gastritis is identified histologically
nous formulation for individuals in whom enteral administration is not by an inflammatory cell infiltrate consisting primarily of lymphocytes
possible. If bleeding occurs despite these measures, endoscopy, intraar- and plasma cells, with very scant neutrophil involvement. Distribution
terial vasopressin, and embolization are options. If all else fails, then of the inflammation may be patchy, initially involving superficial and
surgery should be considered. Although vagotomy and antrectomy glandular portions of the gastric mucosa. This picture may progress
may be used, the better approach would be a total gastrectomy, which to more severe glandular destruction, with atrophy and metaplasia.
has an exceedingly high mortality rate in this setting. Chronic gastritis has been classified according to histologic character-
istics. These include superficial atrophic changes and gastric atrophy.
■■GASTRITIS
The association of atrophic gastritis with the development of gastric
The term gastritis should be reserved for histologically documented
cancer has led to the development of endoscopic and serologic markers
inflammation of the gastric mucosa. Gastritis is not the mucosal
of severity. Some of these include gross inspection and classification
erythema seen during endoscopy and is not interchangeable with
of mucosal abnormalities during standard endoscopy, magnification
“dyspepsia.” The etiologic factors leading to gastritis are broad and
endoscopy, endoscopy with narrow band imaging and/or autofluores-
heterogeneous. Gastritis has been classified based on time course
cence imaging, and measurement of several serum biomarkers includ-
(acute vs chronic), histologic features, and anatomic distribution or
ing pepsinogen I and II levels, gastrin-17, and anti-H. pylori serologies.
proposed pathogenic mechanism (Table 317-11).
The clinical utility of these tools is currently being explored.
The correlation between the histologic findings of gastritis, the clin-
The early phase of chronic gastritis is superficial gastritis. The inflam-
ical picture of abdominal pain or dyspepsia, and endoscopic findings
matory changes are limited to the lamina propria of the surface mucosa,
noted on gross inspection of the gastric mucosa is poor. Therefore, there
with edema and cellular infiltrates separating intact gastric glands. The
is no typical clinical manifestation of gastritis.
next stage is atrophic gastritis. The inflammatory infiltrate extends
Acute Gastritis The most common causes of acute gastritis are deeper into the mucosa, with progressive distortion and destruction of
infectious. Acute infection with H. pylori induces gastritis. However, the glands. The final stage of chronic gastritis is gastric atrophy. Glandu-
H. pylori acute gastritis has not been extensively studied. It is reported lar structures are lost, and there is a paucity of inflammatory infiltrates.
as presenting with sudden onset of epigastric pain, nausea, and vom- Endoscopically, the mucosa may be substantially thin, permitting clear
iting, and limited mucosal histologic studies demonstrate a marked visualization of the underlying blood vessels.
infiltrate of neutrophils with edema and hyperemia. If not treated, this Gastric glands may undergo morphologic transformation in chronic
picture will evolve into one of chronic gastritis. Hypochlorhydria last- gastritis. Intestinal metaplasia denotes the conversion of gastric glands
ing for up to 1 year may follow acute H. pylori infection. to a small intestinal phenotype with small-bowel mucosal glands con-
Bacterial infection of the stomach or phlegmonous gastritis is a rare, taining goblet cells. The metaplastic changes may vary in distribution
potentially life-threatening disorder characterized by marked and dif- from patchy to fairly extensive gastric involvement. Intestinal metapla-
fuse acute inflammatory infiltrates of the entire gastric wall, at times sia is an important predisposing factor for gastric cancer (Chap. 76).
accompanied by necrosis. Elderly individuals, alcoholics, and AIDS Chronic gastritis is also classified according to the predominant site
patients may be affected. Potential iatrogenic causes include polypec- of involvement. Type A refers to the body-predominant form (autoim-
tomy and mucosal injection with India ink. Organisms associated with mune), and type B is the antral-predominant form (H. pylori–related).

2242 This classification is artificial in view of the difficulty in distinguishing
between these two entities. The term AB gastritis has been used to refer
to a mixed antral/body picture.
TYPE A GASTRITIS The less common of the two forms involves primar-
ily the fundus and body, with antral sparing. Traditionally, this form of
gastritis has been associated with pernicious anemia (Chap. 95) in the
presence of circulating antibodies against parietal cells and IF; thus, it is
also called autoimmune gastritis. H. pylori infection can lead to a similar
distribution of gastritis. The characteristics of an autoimmune picture
are not always present.
Antibodies to parietal cells have been detected in >90% of patients
with pernicious anemia and in up to 50% of patients with type A gas-
tritis. The parietal cell antibody is directed against H+,K+-ATPase. T
cells are also implicated in the injury pattern of this form of gastritis.
A subset of patients infected with H. pylori develop antibodies against
H+,K+-ATPase, potentially leading to the atrophic gastritis pattern
seen in some patients infected with this organism. The mechanism FIGURE 317-15 Chronic gastritis and H. pylori organisms. Steiner silver stain
is thought to involve molecular mimicry between H. pylori LPS and of superficial gastric mucosa showing abundant darkly stained microorganisms
H+,K+-ATPase. layered over the apical portion of the surface epithelium. Note that there is no
tissue invasion.
Parietal cell antibodies and atrophic gastritis are observed in family
members of patients with pernicious anemia. These antibodies are
observed in up to 20% of individuals aged >60 and in ~20% of patients is unknown, but it appears to be related to the chronic inflammation
with vitiligo and Addison’s disease. About one-half of patients with induced by the organism. Eradication of H. pylori as a general pre-
pernicious anemia have antibodies to thyroid antigens, and about 30% ventative measure for gastric cancer is being evaluated but is not yet
of patients with thyroid disease have circulating antiparietal cell anti- recommended.
bodies. Anti-IF antibodies are more specific than parietal cell antibodies Infection with H. pylori is also associated with development of a
for type A gastritis, being present in ~40% of patients with pernicious low-grade B cell lymphoma, gastric MALT lymphoma (Chap. 104). The
anemia. Another parameter consistent with this form of gastritis being chronic T cell stimulation caused by the infection leads to production
autoimmune in origin is the higher incidence of specific familial histo- of cytokines that promote the B cell tumor. The tumor should be ini-
PART 10
compatibility haplotypes such as HLA-B8 and HLA-DR3. tially staged with a CT scan of the abdomen and EUS. Tumor growth
The parietal cell–containing gastric gland is preferentially targeted remains dependent on the presence of H. pylori, and its eradication
in this form of gastritis, and achlorhydria results. Parietal cells are the is often associated with complete regression of the tumor. The tumor
source of IF, the lack of which will lead to vitamin B12 deficiency and its may take more than a year to regress after treating the infection. Such
sequelae (megaloblastic anemia, neurologic dysfunction). patients should be followed by EUS every 2–3 months. If the tumor is
Gastric acid plays an important role in feedback inhibition of gastrin stable or decreasing in size, no other therapy is necessary. If the tumor
release from G cells. Achlorhydria, coupled with relative sparing of the grows, it may have become a high-grade B cell lymphoma. When the
antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels tumor becomes a high-grade aggressive lymphoma histologically, it
can be markedly elevated (>500 pg/mL) in patients with pernicious loses responsiveness to H. pylori eradication.
anemia. ECL cell hyperplasia with frank development of gastric carci-
noid tumors may result from gastrin trophic effects. Hypergastrinemia
and achlorhydria may also be seen in nonpernicious anemia–associated
TREATMENT
type A gastritis. Chronic Gastritis
TYPE B GASTRITIS Type B, or antral-predominant, gastritis is the more Treatment in chronic gastritis is aimed at the sequelae and not the
common form of chronic gastritis. H. pylori infection is the cause of underlying inflammation. Patients with pernicious anemia will require
this entity. Although described as “antral-predominant,” this is likely parenteral vitamin B12 supplementation on a long-term basis. Eradi-
a misnomer in view of studies documenting the progression of the cation of H. pylori is often recommended even if PUD or a low-grade
inflammatory process toward the body and fundus of infected individ- MALT lymphoma is not present. Expert opinion suggests that patients
uals. The conversion to a pangastritis is time-dependent and estimated with atrophic gastritis complicated by intestinal metaplasia without
to require 15–20 years. This form of gastritis increases with age, being dysplasia should undergo surveillance endoscopy every 3 years.
present in up to 100% of persons aged >70. Histology improves after
H. pylori eradication. The number of H. pylori organisms decreases
dramatically with progression to gastric atrophy, and the degree of Miscellaneous Forms of Gastritis Lymphocytic gastritis is char-
inflammation correlates with the level of these organisms. Early on, acterized histologically by intense infiltration of the surface epithelium
with antral-predominant findings, the quantity of H. pylori is highest with lymphocytes. The infiltrative process is primarily in the body of
and a dense chronic inflammatory infiltrate of the lamina propria is the stomach and consists of mature T cells and plasmacytes. The etiol-
noted, accompanied by epithelial cell infiltration with polymorphonu- ogy of this form of chronic gastritis is unknown. It has been described
clear leukocytes (Fig. 317-15). in patients with celiac sprue, but whether there is a common factor
Multifocal atrophic gastritis, gastric atrophy with subsequent associating these two entities is unknown. No specific symptoms sug-
metaplasia, has been observed in chronic H. pylori–induced gastritis. gest lymphocytic gastritis. A subgroup of patients have thickened folds
This may ultimately lead to development of gastric adenocarcinoma noted on endoscopy. These folds are often capped by small nodules
(Fig. 317-8; Chap. 76). H. pylori infection is now considered an inde- that contain a central depression or erosion; this form of the disease is
pendent risk factor for gastric cancer. Worldwide epidemiologic called varioliform gastritis. H. pylori probably plays no significant role in
studies have documented a higher incidence of H. pylori infection in lymphocytic gastritis. Therapy with glucocorticoids or sodium cromo-
patients with adenocarcinoma of the stomach as compared to control glycate has obtained unclear results.
subjects. Seropositivity for H. pylori is associated with a three- to Marked eosinophilic infiltration involving any layer of the stomach
sixfold increased risk of gastric cancer. This risk may be as high as (mucosa, muscularis propria, and serosa) is characteristic of eosinophilic
ninefold after adjusting for the inaccuracy of serologic testing in the gastritis. Affected individuals will often have circulating eosinophilia
elderly. The mechanism by which H. pylori infection leads to cancer with clinical manifestation of systemic allergy. Involvement may range

from isolated gastric disease to diffuse eosinophilic gastroenteritis. and H. pylori serology, and pH testing of gastric aspirate during endos- 2243
Antral involvement predominates, with prominent edematous folds copy should be included as part of the initial evaluation of patients
being observed on endoscopy. These prominent antral folds can lead to with large gastric folds.
outlet obstruction. Patients can present with epigastric discomfort, nau-
sea, and vomiting. Treatment with glucocorticoids has been successful. TREATMENT
Several systemic disorders may be associated with granulomatous
gastritis. Gastric involvement has been observed in Crohn’s disease. Ménétrier’s Disease
Involvement may range from granulomatous infiltrates noted only
on gastric biopsies to frank ulceration and stricture formation. Gastric Medical therapy with anticholinergic agents, prostaglandins, PPIs,
Crohn’s disease usually occurs in the presence of small-intestinal dis- prednisone, somatostatin analogues (octreotide) and H2 receptor
ease. Several rare infectious processes can lead to granulomatous gas- antagonists yields varying results. Ulcers should be treated with a
tritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis. standard approach. The discovery that MD is associated with over-
Other unusual causes of this form of gastritis include sarcoidosis, idio- stimulation of the EGFR pathway has led to the successful use of the
EGF inhibitory antibody, cetuximab, in these patients. Specifically,
pathic granulomatous gastritis, and eosinophilic granulomas involving
four of seven patients who completed a 1-month trial with this agent
the stomach. Establishing the specific etiologic agent in this form of
demonstrated near complete histologic remission and improvement
gastritis can be difficult, at times requiring repeat endoscopy with
in symptoms. Cetuximab is now considered the first-line treatment for
biopsy and cytology. Occasionally, a surgically obtained full-thickness
MD, leaving total gastrectomy for severe disease with persistent and
biopsy of the stomach may be required to exclude malignancy.
substantial protein loss despite therapy with this agent.
Russell body gastritis (RBG) is a mucosal lesion of unknown etiology
that has a pseudotumoral endoscopic appearance. Histologically, it is
defined by the presence of numerous plasma cells containing Russell ■■FURTHER READING
bodies (RBs) that express kappa and lambda light chains. Only 10 cases Basuroy R et al: Neuroendocrine tumors. Gastroenterol Clin N Am
have been reported, and 7 of these have been associated with H. pylori 45:487, 2016.
infection. The lesion can be confused with a neoplastic process, but it Chan JA, Kulke MH: Medical management of pancreatic neuroen-
is benign in nature, and the natural history of the lesion is not known. docrine tumors: Current and future therapy. Surg Oncol Clin N Am
There have been cases of resolution of the lesion when H. pylori was 25:423, 2016.
eradicated. Chey WD et al: ACG Clinical Guideline: Treatment of Helicobacter pylori
Infection. Am J Gastroenterol 112:212, 2017.

■■MÉNÉTRIER’S DISEASE Clancy TE: Surgical management of pancreatic neuroendocrine
Ménétrier’s disease (MD) is a very rare gastropathy characterized tumors. Hematol Oncol Clin N Am 30:103, 2016.
by large, tortuous mucosal folds. MD has an average age of onset Davis JL, Ripley RT: Postgastrectomy syndromes and nutritional con-
of 40–60 years with a male predominance. The differential diagnosis siderations following gastric surgery. Surg Clin N Am 97:277, 2017.
of large gastric folds includes ZES, malignancy (lymphoma, infiltrating Dreischulte T: Safer prescribing—A trial of education, informatics,
carcinoma), infectious etiologies (CMV, histoplasmosis, syphilis, tuber- and financial incentives. N Engl J Med 374:1053, 2016.
culosis), gastritis polyposa profunda, and infiltrative disorders such Epelboym I, Mazeh H: Zollinger-Ellison Syndrome: Classical consider-
as sarcoidosis. MD is most commonly confused with large or multiple ations and current controversies. Oncologist 19:44, 2014.
gastric polyps (prolonged PPI use) or familial polyposis syndromes. Graham DY: Helicobacter pylori update: Gastric cancer, reliable therapy,
The mucosal folds in MD are often most prominent in the body and and possible benefits. Gastroenterology 148:719, 2015.
fundus, sparing the antrum. Histologically, massive foveolar hyperpla- Hunt RH et al: The stomach in health and disease. Gut 64:1650, 2015.
sia (hyperplasia of surface and glandular mucous cells) and a marked Kim HU: Diagnostic and treatment approaches for refractory peptic
reduction in oxyntic glands and parietal cells and chief cells are noted. ulcers. Clin Endosc 48:285, 2015.
This hyperplasia produces the prominent folds observed. The pits of the Laine L: Upper gastrointestinal bleeding due to a peptic ulcer. N Engl
gastric glands elongate and may become extremely dilated and tortuous. J Med 374:2367, 2016.
Although the lamina propria may contain a mild chronic inflammatory McCarberg BH, Cryer B: Evolving therapeutic strategies to improve
infiltrate including eosinophils and plasma cells, MD is not considered a nonsteroidal anti-inflammatory drug safety. Am J Ther 22:167, 2015.
form of gastritis. The etiology of this unusual clinical picture in children Melcarne L et al: Management of NSAID-associated peptic ulcer dis-
is often CMV, but the etiology in adults is unknown. Overexpression of ease. Expert Rev Gastroenterol Hepatol 6:723, 2016.
the growth factor TGF-α has been demonstrated in patients with MD. Patel KA, Howden CW: Update on the diagnosis and management
The overexpression of TGF-α in turn results in overstimulation of the of Helicobacter pylori infection in adults. J Clin Gastroenterol 49:461,
epidermal growth factor receptor (EGFR) pathway and increased pro- 2015.
liferation of mucus cells, resulting in the observed foveolar hyperplasia. Pelletier JP et al: Efficacy and safety of oral and analgesics in the
The clinical presentation in adults is usually insidious and progres- management of osteoarthritis: Evidence from real-life setting trials
sive. Epigastric pain, nausea, vomiting, anorexia, peripheral edema, and surveys. Semin Arthritis Rheum 45:S22, 2016.
and weight loss are signs and symptoms in patients with MD. Occult Scarpignato C et al: Effective and safe proton pump inhibitor therapy
GI bleeding may occur, but overt bleeding is unusual and, when in acid-related disease—A position paper addressing benefits and
present, is due to superficial mucosal erosions. In fact, bleeding is potential harms of acid suppression. BMC Med 14:179, 2016.
more often seen in one of the common mimics of MD, gastric polypo- Schoenfeld AJ, Grady D: Adverse effects associate with proton pump
sis. Twenty to 100% of patients (depending on time of presentation) inhibitors. JAMA Int Med 176:172, 2016.
develop a protein-losing gastropathy due to hypersecretion of gastric Schubert ML: Gastric acid secretion. Curr Opin Gastroenterol 32:452,
mucus accompanied by hypoalbuminemia and edema. Gastric acid 2016.
secretion is usually reduced or absent because of the decreased parietal Singh S et al: Diagnosis and management of gastrointestinal neuroen-
cells. Large gastric folds are readily detectable by either radiographic docrine tumors: An evidence-based Canadian consensus. Cancer
(barium meal) or endoscopic methods. Endoscopy with deep mucosal Treat Rev 47:32, 2016.
biopsy, preferably full thickness with a snare technique, is required Sugano K et al: Kyoto global consensus report on Helicobacter pylori
to establish the diagnosis and exclude other entities that may present gastritis. Gut 64:1353, 2015.
similarly. A nondiagnostic biopsy may lead to a surgically obtained Talley NJ: Functional dyspepsia: New insights into pathogenesis and
full-thickness biopsy to exclude malignancy. Although MD is consid- therapy. Korean J Intern Med 31:444, 2016.
ered premalignant by some, the risk of neoplastic progression is not Vinik AI, Chaya C: Clinical presentation and diagnosis of neuroendo-
defined. Complete blood count, serum gastrin, serum albumin, CMV crine tumors. Hematol Oncol Clin N Am 30:21, 2016.

2244 two studies—determination of stool electrolytes and observation of the
318 Disorders of Absorption

Henry J. Binder
effect of a fast on stool output—can help make this distinction.
The demonstration of the effect of prolonged (>24 h) fasting on stool
output can suggest that a dietary nutrient is responsible for the individ-
ual’s diarrhea. Secretory diarrhea associated with enterotoxin-induced
traveler’s diarrhea would not be affected by prolonged fasting, as
enterotoxin-induced stimulation of intestinal fluid and electrolyte
Disorders of absorption constitute a broad spectrum of conditions with
secretion is not altered by eating. In contrast, diarrhea secondary to
multiple etiologies and varied clinical manifestations. Almost all of
lactose malabsorption in primary lactase deficiency would undoubt-
these clinical problems are associated with diminished intestinal absorp- edly cease during a prolonged fast. Thus, a substantial decrease in
tion of one or more dietary nutrients and are often referred to as the stool output by a fasting patient during quantitative stool collection
malabsorption syndrome. This term is not ideal as it represents a patho- lasting at least 24 h is presumptive evidence that the diarrhea is related
physiologic state, does not provide an etiologic explanation for the to malabsorption of one or more dietary nutrients. The persistence
underlying problem, and should not be considered an adequate final of stool output during fasting indicates that the diarrhea is likely
diagnosis. The only clinical conditions in which absorption is increased secretory and that its cause is not a dietary nutrient. Either a luminal
are hemochromatosis and Wilson’s disease, in which absorption of iron (e.g., E. coli enterotoxin) or a circulating (e.g., vasoactive intestinal
and copper, respectively, is elevated. peptide) secretagogue could be responsible for unaltered persistence
Most malabsorption syndromes are associated with steatorrhea, an of a patient’s diarrhea during a prolonged fast. The observed effects
increase in stool fat excretion to >7% of dietary fat intake. Some malab- of fasting can be compared and correlated with stool electrolyte and
sorption disorders are not associated with steatorrhea: primary lactase osmolality determinations.
deficiency, a congenital absence of the small-intestinal brush border Measurement of stool electrolytes and osmolality requires compari-
disaccharidase enzyme lactase, is associated with lactose “malabsorp- son of Na+ and K+ concentrations in liquid stool with the osmolality of
tion,” and pernicious anemia is associated with a marked decrease in the stool in order to determine the presence or absence of a so-called
intestinal absorption of cobalamin (vitamin B12) due to an absence of stool osmotic gap. The following formula is used:
gastric parietal-cell intrinsic factor, which is required for cobalamin
absorption. 2 × (stool [Na+] + stool [K+]) ≤ stool osmolality
Disorders of absorption must be included in the differential diagno-
The cation concentrations are doubled to estimate stool anion
sis of diarrhea (Chap. 42). First, diarrhea is frequently associated with
concentrations. The presence of a significant osmotic gap suggests
and/or is a consequence of the diminished absorption of one or more
the presence in stool water of a substance (or substances) other than
dietary nutrients. The diarrhea may be secondary either to the intesti-
PART 10
Na/K/anions, which is presumably responsible for the patient’s diar-

nal process that is responsible for the steatorrhea or to steatorrhea per
rhea. Originally, stool osmolality was measured, but it is almost invari-
se. Thus, celiac disease (see below) is associated with both extensive
ably greater than the required 290–300 mosmol/kg H2O, reflecting
morphologic changes in the small-intestinal mucosa and reduced
bacterial degradation of nonabsorbed carbohydrate either immediately
absorption of several dietary nutrients; in contrast, the diarrhea of
before defecation or in the stool jar while specimen awaits chemical
steatorrhea is the result of the effect of nonabsorbed dietary fatty acids

analysis, even when the stool is refrigerated. As a result, the stool
on intestinal (usually colonic) ion transport. For example, oleic and ric-
osmolality should be assumed to be 300 mosmol/kg H2O. A low stool
inoleic acids (a bacterially hydroxylated fatty acid that is also the active
osmolality (<290 mosmol/kg H2O) reflects the addition of either dilute
ingredient in castor oil, a widely used laxative) induce active colonic
urine or water, indicating either collection of urine and stool together or
Cl ion secretion, most likely secondary to increasing intracellular Ca.
so-called factitious diarrhea, a form of Münchausen’s syndrome. When
In addition, diarrhea per se may result in mild steatorrhea (<11 g of fat
the calculated difference in the formula above is >50, an osmotic gap
excretion while on a 100-g fat diet). Second, most patients will indicate
exists; its presence suggests that the diarrhea is due to a nonabsorbed
that they have diarrhea, not that they have fat malabsorption. Third,
dietary nutrient—for example a fatty acid and/or a carbohydrate.
many intestinal disorders that have diarrhea as a prominent symptom
When this difference is <25, it is presumed that a dietary nutrient is not
(e.g., ulcerative colitis, traveler’s diarrhea secondary to an enterotoxin responsible for the diarrhea. Since elements of both osmotic diarrhea
produced by Escherichia coli) do not necessarily have diminished (i.e., due to malabsorption of a dietary nutrient) and secretory diarrhea
absorption of any dietary nutrient. may be present, this distinction at times is less clear-cut at the bedside
Diarrhea as a symptom (i.e., when the term is used by patients to than when used as a teaching example. Ideally, the presence of an
describe their bowel movement pattern) may reflect a decrease in osmotic gap will be associated with a marked decrease in stool output
stool consistency, an increase in stool volume, an increase in number during a prolonged fast, while an osmotic gap will likely be absent in
of bowel movements, or any combination of these three changes. In an individual whose stool output is not reduced substantially during
contrast, diarrhea as a sign is a quantitative increase in stool water a period of fasting.
or weight of >200–225 mL or g per 24 h when a Western-type diet is
consumed. Individuals consuming a diet with higher-fiber content may
normally have a stool weight of up to 400 g/24 h. Thus, the clinician
NUTRIENT DIGESTION AND ABSORPTION
The lengths of the small intestine and the colon are ~300 and ~80 cm,
must clarify what an individual patient means by diarrhea. Some 10%
respectively. However, the effective functional surface area is ~600-
of patients referred to gastroenterologists for further evaluation of
fold greater than that of a hollow tube as a result of folds, villi (in the
unexplained diarrhea do not have an increase in stool water when this
small intestine), and microvilli. The functional surface area of the small
variable is determined quantitatively. Such patients may have small,
intestine is somewhat greater than that of a doubles tennis court. In
frequent, somewhat loose bowel movements with stool urgency that
addition to nutrient digestion and absorption, the intestinal epithelia
is indicative of proctitis, but do not have an increase in stool weight
have several other functions:
or volume. In addition, an occasional patient will describe their fecal
incontinence as diarrhea due to social embarrassment. 1. Barrier and immune defense. The intestine is exposed to a large num-
It is also critical to establish whether a patient’s diarrhea is second- ber of potential antigens and enteric and invasive microorganisms,
ary to diminished absorption of one or more dietary nutrients rather and it is extremely effective at preventing the entry of almost all of
than being due to small- and/or large-intestinal fluid and electrolyte these agents. The intestinal mucosa also synthesizes and secretes
secretion. The former has often been termed osmotic diarrhea, while secretory IgA.
the latter has been referred to as secretory diarrhea. Unfortunately, both 2. Fluid and electrolyte absorption and secretion. The intestine absorbs
secretory and osmotic elements can be present simultaneously in the ~7–8 L of fluid daily, a volume comprising dietary fluid intake
same disorder; thus, this distinction is not always precise. Nonetheless, (1–2 L/d) and salivary, gastric, pancreatic, biliary, and intestinal

fluid (6–7 L/d). Several stimuli, especially bacteria and bacterial NORMAL 2245
enterotoxins, induce fluid and electrolyte secretion that may lead to
diarrhea (Chap. 128). Cholesterol
3. Synthesis and secretion of several proteins. The intestinal mucosa is a
major site for the production of proteins, including apolipoproteins.
4. Production of several bioactive amines and peptides. The intestine is one
Bile acids
of the largest endocrine organs in the body and produces several 0.5 g synthesized
amines (e.g., 5-hydroxytryptophan) and peptides that serve as para- per day [Bile acids]
crine and hormonal mediators of intestinal function. >4 mM
The small and large intestines are distinct anatomically (villi are Bile acid
pool size Jejunum
present in the small intestine but are absent in the colon) and func-
4.0 g
tionally (nutrient digestion and absorption take place in the small Ileum
intestine but not in the colon). No precise anatomic characteristics sep- Na
arate duodenum, jejunum, and ileum, although certain nutrients are
absorbed exclusively in specific areas of the small intestine. However,
villous cells in the small intestine (surface epithelial cells in the colon) 0.5 g COLON
and crypt cells have distinct anatomic and functional characteristics. Bile acids
Intestinal epithelial cells are continuously renewed; new proliferating excreted per day
epithelial cells at the base of the crypt migrate over 48–72 h to the tip of FIGURE 318-1 Schematic representation of the enterohepatic circulation of bile
the villus (or surface of the colon), where they exist as well-developed acids. Bile-acid synthesis is cholesterol catabolism and occurs in the liver. Bile
epithelial cells with digestive and absorptive function. This high rate acids are secreted in bile and are stored in the gallbladder between meals and
of cell turnover explains the relatively rapid resolution of diarrhea and at night. Food in the duodenum induces the release of cholecystokinin, a potent
other digestive-tract side effects during chemotherapy as new cells not stimulus for gallbladder contraction resulting in bile-acid entry into the duodenum.
Bile acids are primarily absorbed via an Na-dependent transport process that
exposed to these toxic agents are produced. Equally important is the is located only in the ileum. A relatively small quantity of bile acids (~500 mg)
paradigm of separation of villous/surface cell and crypt cell functions. is not absorbed in a 24-h period and is lost in stool. Fecal bile-acid losses are
Digestive hydrolytic enzymes are present primarily in the brush border matched by bile-acid synthesis. The bile-acid pool (the total amount of bile acids
of villous epithelial cells. Absorptive and secretory functions are also in the body) is ~4 g and is circulated twice during each meal or six to eight times
separate: villous/surface cells are primarily, but not exclusively, the site in a 24-h period.
CHAPTER 318 Disorders of Absorption

for absorptive function, while secretory function is located in crypts of
both the small and large intestines. ~500 mg of bile acids daily; the bile acids are conjugated to either
Nutrients, minerals, and vitamins are absorbed by one or more taurine or glycine (to form tauroconjugated and glycoconjugated bile
active-transport mechanisms. These mechanisms are energy dependent acids, respectively) and are secreted into the duodenum in bile. The
and are mediated by membrane transport proteins. These processes primary functions of bile acids are to (1) promote bile flow, (2) solubi-
will result in the net movement of a substance against or in the absence lize cholesterol and phospholipid in the gallbladder by mixed micelle
of an electrochemical concentration gradient. Intestinal absorption of formation, and (3) enhance dietary lipid digestion and absorption by
amino acids and monosaccharides (e.g., glucose) is also a specialized forming mixed micelles in the proximal small intestine.
form of active transport—secondary active transport. The movement of Bile acids are primarily absorbed by an active, Na+-dependent pro-
actively transported nutrients against a concentration gradient is Na+ cess that takes place exclusively in the ileum; to a lesser extent, they are
dependent and is due to a Na+ gradient across the apical membrane. absorbed by non-carrier-mediated transport processes in the jejunum,
The Na+ gradient is maintained by Na+,K+-adenosine triphosphatase ileum, and colon. Conjugated bile acids that enter the colon are decon-
(ATPase), the so-called Na+ pump located on the basolateral mem- jugated by colonic bacterial enzymes. The unconjugated bile acids are
brane, which extrudes Na+ and maintains low intracellular [Na] as
rapidly absorbed by nonionic diffusion. Colonic bacterial enzymes also
well as the Na+ gradient across the apical membrane. As a result, active
dehydroxylate bile acids to secondary bile acids.
glucose absorption and glucose-stimulated Na+ absorption require
Bile acids absorbed from the intestine return to the liver via the
both the apical membrane transport protein SGLT1 and the basolateral
portal vein and are then re-secreted (Fig. 318-1). Bile-acid synthesis is
Na+,K+-ATPase. In addition to requiring Na+ for its absorption, glucose
largely autoregulated by 7α-hydroxylase, the initial enzyme in choles-
stimulates Na+ and fluid absorption; this effect is the physiologic basis
terol degradation. A decrease in the quantity of bile acids returning to
of oral rehydration therapy for the treatment of diarrhea (Chap. 42).
the liver from the intestine is associated with an increase in bile-acid
The mechanisms of intestinal fluid and electrolyte absorption and
synthesis/cholesterol catabolism (mediated by fibroblast growth factor
secretion are discussed in Chap. 42.
[FGF19]), which helps keep the bile-acid pool size relatively constant.
Although the intestinal epithelial cells are crucial mediators of
However, the capacity to increase bile-acid synthesis is limited to ~2- to
absorption and of ion and water flow, the several cell types in the
2.5-fold (see below). The bile-acid pool size is ~4 g. The pool is circu-
lamina propria (e.g., mast cells, macrophages, myofibroblasts) and
lated via the enterohepatic circulation about twice during each meal, or
the enteric nervous system interact with the epithelium to regulate
six to eight times during a 24-h period. A relatively small quantity of
mucosal cell function. Intestinal function results from the integrated
bile acids is not absorbed and is excreted in stool daily; this fecal loss is
responses and interactions of intestinal epithelial cells and intestinal
matched by hepatic bile-acid synthesis.
muscle.
Defects in any of the steps in enterohepatic circulation of bile acids
■■ENTEROHEPATIC CIRCULATION OF BILE ACIDS can result in a decrease in the duodenal concentration of conjugated
Bile acids are not present in the diet but are synthesized in the liver by bile acids and consequently in the development of steatorrhea. Thus,
a series of enzymatic steps that also represent cholesterol catabolism. steatorrhea can be caused by abnormalities in bile-acid synthesis and
Indeed, interruption of the enterohepatic circulation of bile acids can excretion, their physical state in the intestinal lumen, and reabsorption
reduce serum cholesterol levels by 10% before a new steady state is (Table 318-1).
established. Bile acids are either primary or secondary. Primary bile Synthesis Decreased bile-acid synthesis and steatorrhea have been
acids are synthesized in the liver from cholesterol, and secondary bile demonstrated in chronic liver disease, but steatorrhea often is not a
acids are synthesized from primary bile acids in the intestine by colonic major component of illness in these patients.
bacterial enzymes. The two primary bile acids in humans are cholic
acid and chenodeoxycholic acid; the two most abundant secondary bile Secretion Although bile-acid secretion may be reduced or absent
acids are deoxycholic acid and lithocholic acid. The liver synthesizes in biliary obstruction, steatorrhea is rarely a significant medical

2246 TABLE 318-1 Defects in Enterohepatic Circulation of Bile Acids TABLE 318-2 Comparison of Bile Acid and Fatty Acid Diarrhea
PATHOPHYSIOLOGIC BILE-ACID DIARRHEA FATTY ACID DIARRHEA
PROCESS DEFECT DISEASE EXAMPLE Extent of ileal disease Limited Extensive
Synthesis Decreased hepatic Cirrhosis Ileal bile-acid absorption Reduced Reduced
function
Fecal bile-acid excretion Increased Increased
Biliary secretion Altered canalicular Primary biliary cirrhosis
Fecal bile-acid loss Yes No
function
compensated by hepatic
Maintenance of Bacterial overgrowth Jejunal diverticulosis synthesis
conjugated bile acids
Bile-acid pool size Normal Reduced
Reabsorption Abnormal ileal function Crohn’s disease
Intraduodenal (bile acid) Normal Reduced
Steatorrhea None or mild >20 g
Response to Yes No
problem in these patients. In contrast, primary biliary cirrhosis rep- cholestyramine
resents a defect in canalicular excretion of organic anions, including Response to low-fat diet No Yes
bile acids, and not infrequently is associated with steatorrhea and
its consequences (e.g., chronic bone disease). Thus, the osteopenia/
osteomalacia and other chronic bone abnormalities often present in the result is impaired micelle formation and steatorrhea. This second
patients with primary biliary cirrhosis and other cholestatic syndromes situation is often called fatty acid diarrhea. Cholestyramine may not be
are secondary to steatorrhea that then leads to calcium and vitamin D effective (and may even exacerbate the diarrhea by further depleting
malabsorption as well as to the effects of cholestasis (e.g., bile acids and the intraduodenal bile-acid concentration); however, a low-fat diet
inflammatory cytokines). to reduce fatty acid entry into the colon can be effective. Two clinical
Maintenance of Conjugated Bile Acids In bacterial over- features—the length of the ileal section removed and the degree of
growth syndromes associated with diarrhea, steatorrhea, and macro- steatorrhea—can predict whether an individual patient will respond
cytic anemia, a colonic type of bacterial flora is increased in the small to cholestyramine. Unfortunately, these predictors are imperfect, and
intestine. Steatorrhea is primarily a result of the decrease in conjugated a therapeutic trial of cholestyramine is often necessary to establish
bile acids secondary to their deconjugation by colonic-type bacteria. whether an individual patient will benefit from cholestyramine.
Two complementary explanations account for the resulting impairment Table 318-2 contrasts the characteristics of bile-acid diarrhea (small ileal
of micelle formation: (1) Unconjugated bile acids are rapidly absorbed dysfunction) and fatty acid diarrhea (large ileal dysfunction).
PART 10
in the jejunum by nonionic diffusion, and the result is a reduced con- Bile-acid diarrhea can also occur in the absence of ileal inflammation
centration of duodenal bile acids; and (2) the critical micellar concentra- and/or resection and is characterized by an abnormal 75SeHCAT reten-
tion (CMC) of unconjugated bile acids is higher than that of conjugated tion study and reduced ileal release of FGF19, a negative regulator of
bile acids; therefore, unconjugated bile acids are less effective than bile-acid synthesis, with a consequent increase in bile-acid synthesis
conjugated bile acids in micelle formation. and secretion that exceeds ileal bile-acid absorption. The diarrhea in
these patients also responds to cholestyramine.

Reabsorption Ileal dysfunction caused by either Crohn’s disease
or surgical resection results in a decrease in bile-acid reabsorption in the ■■LIPIDS
ileum and an increase in the delivery of bile acids to the large intestine. The Steatorrhea is caused by one or more defects in the digestion and absorp-
resulting clinical consequences—diarrhea with or without steatorrhea— tion of dietary fat. The average intake of dietary fat in the United States
are determined by the degree of ileal dysfunction and the response of the is ~120–150 g/d, and fat absorption is linear to dietary fat intake. The
enterohepatic circulation to bile-acid losses (Table 318-2). Patients with total load of fat presented to the small intestine is considerably greater,
limited ileal disease or resection often have diarrhea but not steatorrhea. as substantial amounts of lipid are secreted in bile each day (see “Entero-
The diarrhea, a result of stimulation of active Cl secretion by bile acids hepatic Circulation of Bile Acids,” above). Three types of fatty acids
in the colon, has been called bile-acid diarrhea or choleretic enteropathy compose fats: long-chain fatty acids (LCFAs), medium-chain fatty acids
and responds promptly to cholestyramine, an anion-binding resin. (MCFAs), and short-chain fatty acids (SCFAs) (Table 318-3). Dietary
Steatorrhea does not develop because hepatic synthesis of bile acids fat is exclusively composed of long-chain triglycerides (LCTs)—that
increases to compensate for the rate of fecal bile-acid losses, resulting is, glycerol that is bound via ester linkages to three LCFAs. While the
in maintenance of both the bile-acid pool size and the intraduodenal majority of dietary LCFAs have carbon chain lengths of 16 or 18, all
concentrations of bile acids. In contrast, patients with greater degrees fatty acids of carbon chain length >12 are metabolized in the same
of ileal disease and/or resection often have diarrhea and steatorrhea manner; saturated and unsaturated fatty acids are handled identically.
that do not respond to cholestyramine. In this situation, ileal disease Assimilation of dietary lipid requires three integrated processes:
is also associated with increased volumes of bile acids entering the (1) an intraluminal, or digestive, phase; (2) a mucosal, or absorptive,
colon; however, hepatic synthesis can no longer increase sufficiently phase; and (3) a delivery, or postabsorptive, phase. An abnormality at
to maintain the bile-acid pool size. As a consequence, the intraduode- any site involved in these processes can cause steatorrhea (Table 318-4).
nal concentration of bile acids is reduced to less than the CMC, and Therefore, it is essential that any patient with steatorrhea be evaluated
TABLE 318-3 Comparison of Different Types of Fatty Acids

LONG-CHAIN MEDIUM-CHAIN SHORT-CHAIN
Carbon chain length >12 8–12 <8
Present in diet In large amounts In small amounts No
Origin In diet as triglycerides Only in small amounts in diet as Bacterial degradation in colon of
triglycerides nonabsorbed carbohydrate to fatty
acids
Primary site of absorption Small intestine Small intestine Colon
Requires pancreatic lipolysis Yes No No
Requires micelle formation Yes No No
Present in stool Minimal No Substantial

TABLE 318-4 Defects in Lipid Digestion and Absorption in lowering of intraduodenal pH and inactivation of endogenous pancre- 2247
Steatorrhea atic lipase or of therapeutically administered lipase.
PATHOPHYSIOLOGIC Overlying the microvillus membrane of the small intestine is the
PHASE, PROCESS DEFECT DISEASE EXAMPLE so-called unstirred water layer, a relatively stagnant aqueous phase
Digestive that must be traversed by the products of lipolysis that are primarily
water insoluble. Water-soluble mixed micelles provide a mechanism
Lipolysis formation Decreased lipase Chronic pancreatitis
secretion
by which the water-insoluble products of lipolysis can reach the
luminal plasma membrane of villous epithelial cells—the site for lipid
Micelle formation Decreased intraduodenal See Table 318-1
bile acids absorption. Mixed micelles are molecular aggregates composed of fatty
acids, monoglycerides, phospholipids, cholesterol, and conjugated
Absorptive
bile acids. These mixed micelles are formed when the concentration
Mucosal uptake and Mucosal dysfunction Celiac disease of conjugated bile acids is greater than its CMC, which differs among
re-esterification
the several bile acids present in the small-intestinal lumen. Conjugated
Postabsorptive bile acids, synthesized in the liver and excreted into the duodenum in
Chylomicron formation Absent β-lipoproteins Abetalipoproteinemia bile, are regulated by the enterohepatic circulation (see above). Steat-
Delivery from intestine Abnormal lymphatics Intestinal orrhea can result from impaired movement of fatty acids across the
lymphangiectasia unstirred aqueous fluid layer in two situations: (1) an increase in the
relative thickness of the unstirred water layer that occurs in bacterial
overgrowth syndromes (see below) secondary to functional stasis
to identify the specific physiologic defect in overall lipid digestion/ (e.g., scleroderma); and (2) a decrease in the duodenal concentration of
absorption, as therapy will be determined by the specific etiology. conjugated bile acids below the CMC, resulting in impaired micelle
The digestive phase has two components: lipolysis and micelle for- formation. Thus, steatorrhea can be caused by one or more defects in
mation. Although dietary lipid is in the form of LCTs, the intestinal the enterohepatic circulation of bile acids.
mucosa does not absorb triglycerides; they must first be hydrolyzed Uptake and re-esterification constitute the absorptive phase of lipid
(Fig. 318-2). The initial step in lipid digestion is the formation of emul- digestion/absorption. Although passive diffusion has been thought to
sions of finely dispersed lipid, which is accomplished by mastication be responsible, a carrier-mediated process may mediate fatty acid and
and gastric contractions. Lipolysis, the hydrolysis of triglycerides to monoglyceride uptake. Regardless of the uptake process, fatty acids
free fatty acids, monoglycerides, and glycerol by lipase, is initiated in and monoglycerides are re-esterified by a series of enzymatic steps in

the stomach by lingual and gastric lipases that have a pH optimum of the endoplasmic reticulum to form triglycerides, in which lipid exits
4.5–6.0. About 20–30% of total lipolysis occurs in the stomach. Lipolysis from the intestinal epithelial cell. Impaired lipid absorption as a result
is completed in the duodenum and jejunum by pancreatic lipase, which of mucosal inflammation (e.g., celiac disease) and/or intestinal resec-
is inactivated by a pH <7.0. Pancreatic lipolysis is greatly enhanced by tion can also lead to steatorrhea.
the presence of a second pancreatic enzyme, colipase, which facilitates The re-esterified triglycerides require the formation of chylomicrons
the movement of lipase to the triglyceride. to permit their exit from the small-intestinal epithelial cell and their
Impaired lipolysis can lead to steatorrhea and can occur in the pres- delivery to the liver via the lymphatics. Chylomicrons are composed of
ence of pancreatic insufficiency due to chronic pancreatitis in adults β-lipoprotein and contain triglycerides, cholesterol, cholesterol esters,
or cystic fibrosis in children and adolescents. Normal lipolysis can and phospholipids and enter the lymphatics, not the portal vein. Defects
be maintained by ~5% of maximal pancreatic lipase secretion; thus, in the postabsorptive phase of lipid digestion/absorption can also result in
steatorrhea is a late manifestation of these disorders. A reduction in steatorrhea, but these disorders are uncommon. Abetalipoproteinemia,
intraduodenal pH can also result in altered lipolysis, as pancreatic or acanthocytosis, is a rare disorder of impaired synthesis of β-lipopro-
lipase is inactivated at pH <7. Thus, ~15% of patients who have gastri- tein associated with abnormal erythrocytes (acanthocytes), neurologic
noma (Chap. 317), with substantial increases in gastric acid secretion problems, and steatorrhea (Chap. 400). Lipolysis, micelle formation,
from ectopic production of gastrin (usually from an islet cell adenoma), and lipid uptake are all normal in patients with abetalipoproteinemia,
have diarrhea, and some have steatorrhea believed to be secondary but the re-esterified triglyceride cannot exit the epithelial cell because
to acid inactivation of pancreatic lipase. Similarly, patients who have of the failure to produce chylomicrons. Small-intestinal biopsy samples
chronic pancreatitis (with reduced lipase secretion) often have a obtained from these rare patients in the postprandial state reveal lip-
decrease in pancreatic bicarbonate secretion, which will also result in a id-laden small-intestinal epithelial cells that become perfectly normal
in appearance after a 72- to 96-h fast. Similarly,
abnormalities of intestinal lymphatics (e.g., intes-
Pancreas Liver Jejunal Mucosa Lymphatics
tinal lymphangiectasia) may also be associated
Lipolysis Micellar Absorption Delivery with steatorrhea as well as protein loss (see
Solubilization below). Steatorrhea can result from defects at any
with Bile Acid
of the several steps in lipid digestion/absorption.
(1) Esterification The mechanism of lipid digestion/absorption
Fatty acids
Fatty acids outlined above is limited to dietary lipid, which
Triglycerides
Triglycerides
To tissues is almost exclusively in the form of LCTs (Table

for utilization
of fat 318-3). Medium-chain triglycerides (MCTs), com-
β-Monoglyceride Cholesterol posed of fatty acids with carbon chain lengths of
β-Monoglyceride Phospholipid
β–Lipoprotein 8–12, are present in large amounts in coconut oil
and are used as a nutritional supplement. MCTs
(2) Chylomicron
formation can be digested and absorbed by a pathway dif-
ferent from that involved in LCT digestion and
absorption; at one time, MCTs held promise as
an important treatment for steatorrhea of almost
FIGURE 318-2 Schematic representation of lipid digestion and absorption. Dietary lipid is in the form of all etiologies. Unfortunately, they have been less
long-chain triglycerides. The overall process can be divided into (1) a digestive phase that includes both
lipolysis and micelle formation requiring pancreatic lipase and conjugated bile acids, respectively, in the
therapeutically effective than expected because,
duodenum; (2) an absorptive phase for mucosal uptake and re-esterification; and (3) a postabsorptive for reasons that are not completely understood,
phase that includes chylomicron formation and exit from the intestinal epithelial cell via lymphatics. their use often is not associated with an increase
(Courtesy of John M. Dietschy, MD; with permission.) in body weight.

2248 In contrast to LCTs, MCTs do not require pancreatic lipolysis as they TABLE 318-5 Primary Lactase Deficiency in Adult Ethnic Groups
can be absorbed intact by the intestinal epithelial cell. Further, micelle PREVALENCE OF LACTASE
formation is not necessary for the absorption of MCTs (or MCFAs, if ETHNIC GROUP DEFICIENCY, %
hydrolyzed by pancreatic lipase). MCTs are absorbed more efficiently Northern European 5–15
than LCTs for the following reasons: (1) The rate of absorption is
Mediterranean 60–85
greater for MCTs than for LCFAs; (2) after absorption, MCFAs are not
African black 85–100
re-esterified; (3) after absorption, MCTs are hydrolyzed to MCFAs;
African American 45–80
(4) MCTs do not require chylomicron formation to exit intestinal epithe-
lial cells; and (5) the route of MCT exit is via the portal vein and not via American white 10–25
lymphatics. Thus, the absorption of MCTs is greater than that of LCTs Native American 50–95
in pancreatic insufficiency, conditions with reduced intraduodenal Mexican American 40–75
bile-acid concentrations, small-intestinal mucosal disease, abetalipo- Asian 90–100
proteinemia, and intestinal lymphangiectasia. Source: From FJ Simoons: Am J Dig Dis 23:963, 1978.
SCFAs are not dietary lipids but are synthesized by colonic bacterial
enzymes from nonabsorbed carbohydrate and are the anions present
at the highest concentration in stool (80–130 mM). The SCFAs in stool primary lactase deficiency in several ethnic groups. Lactase persistence
are primarily acetate, propionate, and butyrate, whose carbon chain in adults is an abnormality due to a defect in the regulation of its matu-
lengths are 2, 3, and 4, respectively. Butyrate is the primary nutrient ration. In contrast, secondary lactase deficiency occurs in association with
for colonic epithelial cells, and its deficiency can be associated with small-intestinal mucosal disease, with abnormalities in both structure
one or more colitides. SCFAs conserve calories and carbohydrate: and function of other brush border enzymes and transport processes.
carbohydrates that are not completely absorbed in the small intestine Secondary lactase deficiency is often seen in celiac disease.
will not be absorbed in the large intestine because of the absence of As lactose digestion is rate-limiting compared to glucose/galactose
both disaccharidases and SGLT1, the transport protein that mediates absorption, lactase deficiency is associated with significant lactose
monosaccharide absorption. In contrast, SCFAs are rapidly absorbed malabsorption. Some individuals with lactose malabsorption develop
and stimulate colonic NaCl and fluid absorption. Most antibiotic- symptoms such as diarrhea, abdominal pain, cramps, and/or flatus.
associated diarrhea not caused by Clostridium difficile is due to antibiotic Most individuals with primary lactase deficiency do not have symp-
suppression of the colonic microbiota, with a resulting decrease in toms. Since lactose intolerance may be associated with symptoms sug-
SCFA production. As C. difficile accounts for only ~15–20% of all anti- gestive of irritable bowel syndrome, persistence of such symptoms in
biotic-associated diarrhea, a relative decrease in colonic production of an individual who exhibits lactose intolerance while on a strict lactose-
PART 10
SCFA is likely the cause of most antibiotic-associated diarrhea. free diet suggests that the person’s symptoms were related to irritable
The clinical manifestations of steatorrhea are a consequence both of bowel syndrome.
the underlying disorder responsible for its development and of steat- The development of symptoms of lactose intolerance is related to
orrhea per se. Depending on the degree of steatorrhea and the level of several factors:
dietary intake, significant fat malabsorption may lead to weight loss.
1. Amount of lactose in the diet.

Steatorrhea per se can be responsible for diarrhea; if the primary cause
2. Rate of gastric emptying. Symptoms are more likely when gastric emp-
of the steatorrhea has not been identified, a low-fat diet can often ame-
tying is rapid than when it is slower. Therefore, skim milk is more
liorate the diarrhea by decreasing fecal fat excretion. Steatorrhea is com-
likely to be associated with symptoms of lactose intolerance than
monly associated with fat-soluble vitamin deficiency, which requires
whole milk, as the rate of gastric emptying after skim milk intake
replacement with water-soluble preparations of these vitamins.
is more rapid. Similarly, diarrhea following subtotal gastrectomy is
Disorders of absorption may also be associated with malabsorption
often a result of lactose intolerance, as gastric emptying is acceler-
of other dietary nutrients—most often carbohydrates—with or without ated in patients with a gastrojejunostomy.
a decrease in dietary lipid digestion and absorption. Therefore, knowl- 3. Small-intestinal transit time. Although the small and large intestines
edge of the mechanisms of digestion and absorption of carbohydrates, both contribute to the development of symptoms, many symptoms
proteins, and other minerals and vitamins is useful in the evaluation of of lactase deficiency are related to the interaction of colonic bacteria
patients with altered intestinal nutrient absorption. and nonabsorbed lactose. More rapid small-intestinal transit makes
■■CARBOHYDRATES symptoms more likely.
Carbohydrates in the diet are present in the form of starch, disaccha- 4. Colonic compensation by production of SCFAs from nonabsorbed lactose.
rides (sucrose and lactose), and glucose. Carbohydrates are absorbed Reduced levels of colonic microflora, which can follow antibiotic
only in the small intestine and only in the form of monosaccharides. use, are associated with increased symptoms after lactose ingestion,
Therefore, before their absorption, starch and disaccharides must first especially in a lactase-deficient individual.
be digested by pancreatic amylase and intestinal brush border disac- Glucose-galactose or monosaccharide malabsorption may also be
charidases to monosaccharides. Monosaccharide absorption occurs associated with diarrhea and is due to a congenital absence of SGLT1.
by a Na-dependent process mediated by the brush border transport Diarrhea develops when individuals with this disorder ingest car-
protein SGLT1. bohydrates that contain actively transported monosaccharides (e.g.,
Lactose malabsorption is the only clinically important disorder of glucose, galactose) but not when they ingest monosaccharides that are
carbohydrate absorption. Lactose, the disaccharide present in milk, not actively transported (e.g., fructose). Fructose is absorbed by the
requires digestion by brush border lactase to its two constituent brush border transport protein GLUT 5, a facilitated diffusion process
monosaccharides, glucose and galactose. Lactase is present in almost that is not Na-dependent and is distinct from SGLT1. In contrast, some
all species in the postnatal period but then disappears throughout the individuals develop diarrhea as a result of the consumption of large
animal kingdom, except in humans. Lactase activity persists in many quantities of sorbitol, a sugar used in diabetic candy; sorbitol is only
individuals throughout life. Two different types of lactase deficiency minimally absorbed because of the absence of an intestinal absorptive
exist—primary and secondary. In primary lactase deficiency, a genetically transport mechanism for this sugar.
determined decrease or absence of lactase is noted, while all other
aspects of both intestinal absorption and brush border enzymes are ■■PROTEINS
normal. In a number of nonwhite groups, primary lactase deficiency is Protein is present in food almost exclusively as polypeptides and
common in adulthood. In fact, Northern European and North Amer- requires extensive hydrolysis to di- and tripeptides and amino acids
ican whites are the only groups to maintain small-intestinal lactase before absorption. Proteolysis occurs in both the stomach and the small
activity throughout adult life. Table 318-5 presents the incidence of intestine; it is mediated by pepsin, which is secreted as pepsinogen

by gastric chief cells, and by trypsinogen and other peptidases from 2249
timed, quantitative stool-fat determination. From a practical stand-
pancreatic acinar cells. The proenzymes pepsinogen and trypsinogen
point, stool collections are invariably difficult and often incomplete,
must be activated to pepsin (by pepsin at a pH <5) and trypsin (by
as nobody wants to handle stool. A qualitative test—Sudan III
the intestinal brush border enzyme enterokinase and subsequently by
staining—has long been available to document an increase in stool
trypsin), respectively. Proteins are absorbed by separate transport sys-
fat. This test is rapid and inexpensive but, as a qualitative test, does
tems for di- and tripeptides and for different types of amino acids—for
not establish the degree of fat malabsorption and is best used as a
example neutral and dibasic. Alterations in either protein or amino
preliminary screening study. Many of the blood, breath, and isoto-
acid digestion and absorption are rarely observed clinically, even in the
pic tests that have been developed (1) do not directly measure fat
presence of extensive small-intestinal mucosal inflammation. However,
absorption; (2) exhibit excellent sensitivity when steatorrhea is obvi-
three rare genetic disorders involve protein digestion/absorption:
ous and severe but poor sensitivity when steatorrhea is mild (e.g.,
(1) Enterokinase deficiency is due to an absence of the brush border
assays for stool chymotrypsin and elastase, which can potentially
enzyme that converts the proenzyme trypsinogen to trypsin and is
distinguish pancreatic from nonpancreatic etiologies of steatorrhea);
associated with diarrhea, growth retardation, and hypoproteinemia;
or (3) have not survived the transition from the research laboratory
(2) Hartnup’s syndrome, a defect in neutral amino acid transport, is
to commercial application.
characterized by a pellagra-like rash and neuropsychiatric symptoms;
Nevertheless, routine laboratory studies (i.e., complete blood
and (3) cystinuria, a defect in dibasic amino acid transport, is associated
count, prothrombin time, serum protein determination, alkaline
with renal calculi and chronic pancreatitis.
phosphatase) may suggest dietary nutrient depletion, especially defi-
ciencies of iron, folate, cobalamin, and vitamins D and K. Additional
APPROACH TO THE PATIENT studies include measurement of serum carotene, cholesterol, albumin,
Malabsorption iron, folate, and cobalamin levels. The serum carotene level can also
be reduced if the patient’s dietary intake of leafy vegetables is poor.
The clues provided by the history, symptoms, and initial preliminary If steatorrhea and/or altered absorption of other nutrients are
observations will serve to limit extensive, ill-focused, and expensive suspected, history, clinical observations, and laboratory testing can
laboratory and imaging studies. For example, a clinician evaluating help detect deficiency of a nutrient, especially of a fat-soluble
a patient who has symptoms suggestive of malabsorption and has vitamin (A, D, E, or K). Thus, evidence of metabolic bone disease
recently undergone extensive small-intestinal resection for mesen- with elevated alkaline phosphatase concentrations and/or reduced
teric ischemia should direct the initial assessment almost exclusively serum calcium levels suggests vitamin D malabsorption. A defi-
to defining whether a short-bowel syndrome might explain the ciency of vitamin K is suggested by an elevated prothrombin time in

entire clinical picture. Similarly, the development of a pattern of an individual without liver disease who is not taking anticoagulants.
bowel movements suggestive of steatorrhea in a patient with long- Macrocytic anemia leads to an evaluation for possible cobalamin
standing alcohol abuse and chronic pancreatitis should prompt an or folic acid malabsorption. Iron-deficiency anemia in the absence
assessment of pancreatic exocrine function. of occult bleeding from the gastrointestinal tract in either a male
The classic picture of malabsorption is rarely seen today in most patient or a nonmenstruating female patient requires an evaluation
parts of the United States. As a consequence, diseases with malab- for iron malabsorption and the exclusion of celiac disease, as iron is
sorption must be suspected in individuals who have less severe absorbed exclusively in the proximal small intestine.
symptoms and signs and subtle evidence of the altered absorption At times, however, a timed (72-h) quantitative stool collection,
of only a single nutrient rather than obvious evidence of the malab- preferably while the patient is on a defined diet, must be undertaken
sorption of multiple nutrients. in order to determine stool fat content and establish the diagnosis
Although diarrhea can be caused by changes in fluid and elec- of steatorrhea. The presence of steatorrhea then requires further
trolyte movement in either the small or the large intestine, dietary assessment to identify the pathophysiologic process(es) responsible
nutrients are absorbed almost exclusively in the small intestine. for the defect in dietary lipid digestion/absorption (Table 318-4).
Therefore, the demonstration of diminished absorption of a dietary Other studies include the d-xylose test, duodenal mucosal biopsy,
nutrient provides unequivocal evidence for small-intestinal disease, small-intestinal radiologic examination, and tests of pancreatic exo-
although colonic dysfunction may also be present (e.g., Crohn’s crine function.
disease may involve both the small and large intestines). Dietary
nutrient absorption may be segmental or diffuse along the small URINARY d-XYLOSE TEST
intestine and is site specific. Thus, for example, calcium, iron, and The urinary d-xylose test for carbohydrate absorption provides an
folic acid are exclusively absorbed by active-transport processes in assessment of proximal small-intestinal mucosal function. d-Xylose,
the proximal small intestine, especially the duodenum; in contrast, a pentose, is absorbed almost exclusively in the proximal small
the active-transport mechanisms for both cobalamin and bile acids intestine. The d-xylose test is usually performed by administering
are operative only in the ileum. Therefore, in an individual who years 25 g of d-xylose and collecting urine for 5 h. An abnormal test (excre-
previously has had an intestinal resection, the details of which are tion of <4.5 g) primarily reflects duodenal/jejunal mucosal disease.
not presently available, a presentation with evidence of calcium, folic The d-xylose test can also be abnormal in patients with blind loop
acid, and/or iron malabsorption but without cobalamin deficiency syndrome (as a consequence primarily of an abnormal intestinal
makes it likely that the duodenum and proximal jejunum, but not mucosa) and, as a false-positive study, in patients with large collec-
the ileum, were resected. tions of fluid in a third space (i.e., ascites, pleural fluid). The ease of
Some nutrients—for example glucose, amino acids, and lipids— obtaining a mucosal biopsy of the small intestine by endoscopy and
are absorbed throughout the small intestine, although their rate the false-negative rate of the d-xylose test have led to its diminished
of absorption is greater in the proximal than in the distal seg- use. When small-intestinal mucosal disease is suspected, a small-
ments. However, after segmental resection of the small intestine, intestinal mucosal biopsy should be performed.
the remaining segments undergo both morphologic and functional
RADIOLOGIC EXAMINATION
“adaptation” to enhance absorption. Such adaptation is secondary
to the presence of luminal nutrients and hormonal stimuli and may Radiologic examination of the small intestine using barium contrast
not be complete in humans for several months after resection. Adap- (small-bowel series or study) can provide important information in
tation is critical for the survival of individuals who have undergone the evaluation of the patient with presumed or suspected malab-
massive resection of the small intestine and/or colon. sorption. This study is most often performed in conjunction with
Establishing the presence of steatorrhea and identifying its spe- an examination of the esophagus, stomach, and duodenal bulb.
cific cause are often quite difficult. The “gold standard” remains a Because insufficient barium is given to the patient to permit an

2250
adequate examination of the small-intestinal mucosa, especially in material from the proximal small-intestinal mucosa. The primary
the ileum, many gastrointestinal radiologists alter the procedure by indications for a small-intestinal biopsy are evaluation of a patient
performing either a small-bowel series in which a large amount of (1) either with documented or suspected steatorrhea or with chronic
barium is given by mouth, without concurrent examination of the diarrhea, and (2) with diffuse or focal abnormalities of the small
esophagus and stomach, or an enteroclysis study in which a large intestine defined on a small-intestinal series. Lesions seen on small-
amount of barium is introduced into the duodenum via a fluoro- bowel biopsy can be classified into three categories (Table 318-6):
scopically placed tube. In addition, many of the diagnostic features
1. Diffuse, specific lesions. Relatively few diseases associated with
initially described by radiologists to denote the presence of small-
altered nutrient absorption have specific histopathologic abnor-
intestinal disease (e.g., flocculation, segmentation) are rarely seen
malities on small-intestinal mucosal biopsy, and these diseases
with current barium suspensions. Nonetheless, in skilled hands, bar-
are uncommon. Whipple’s disease is characterized by the presence
ium contrast examination of the small intestine can yield important
information. For example, with extensive mucosal disease, intestinal of periodic acid–Schiff (PAS)–positive macrophages in the lamina
dilation can be seen as a dilution of barium from increased intestinal propria; the bacilli that are also present may require electron
fluid secretion (Fig. 318-3). A normal barium contrast study does not microscopic examination for identification (Fig. 318-4). Abetali-
exclude the possibility of small-intestinal disease. However, a small- poproteinemia is characterized by a normal mucosal appearance
bowel series remains useful in the search for anatomic abnormali- except for the presence of mucosal absorptive cells that contain
ties, such as strictures and fistulas (as in Crohn’s disease) or blind lipid postprandially and disappear after a prolonged period
loop syndrome (e.g., multiple jejunal diverticula) and to define the of either fat-free intake or fasting. Immune globulin deficiency is
extent of a previous surgical resection. Other imaging studies that associated with a variety of histopathologic findings on small-
assess the integrity of small-intestinal morphology are CT enterogra- intestinal mucosal biopsy. The characteristic feature is the
phy and magnetic resonance enterography. Capsule endoscopy and absence of or substantial reduction in the number of plasma cells
double-balloon enteroscopy are other useful aids in the diagnostic in the lamina propria; the mucosal architecture may be either
assessment of small-intestinal pathology and most often are used to perfectly normal or flat (i.e., villous atrophy). As patients with
identify a small-intestinal bleeding site. immune globulin deficiency are often infected with Giardia lam-
blia, Giardia trophozoites may also be seen in the biopsy.
BIOPSY OF SMALL-INTESTINAL MUCOSA 2. Patchy, specific lesions. Several diseases feature an abnormal
A small-intestinal mucosal biopsy is essential in the evaluation of a small-intestinal mucosa with a patchy distribution. As a result,
patient with documented steatorrhea or chronic diarrhea (i.e., that biopsy samples obtained randomly or in the absence of endo-
lasting >3 weeks) (Chap. 42). The ready availability of endoscopic scopically visualized abnormalities may not reveal diagnostic
PART 10
equipment to examine the stomach and duodenum has led to its features. Intestinal lymphoma can at times be diagnosed on
almost uniform use as the preferred method of obtaining histologic mucosal biopsy by the identification of malignant lymphoma
FIGURE 318-3 Barium contrast small-intestinal radiologic examinations. A. Normal individual. B. Celiac disease. C. Jejunal diverticulosis. D. Crohn’s disease.
(Courtesy of Morton Burrell, MD, Yale University; with permission.)

TABLE 318-6 Diseases That Can Be Diagnosed by Small-Intestinal 2251
patients with diarrhea; the etiologic agents include Cryptosporidium,
Mucosal Biopsies
Isospora belli, microsporidia, Cyclospora, Toxoplasma, cytomegalovi-
LESIONS PATHOLOGIC FINDINGS rus, adenovirus, Mycobacterium avium-intracellulare, and G. lamblia.
Diffuse, Specific In immunocompromised patients, when Candida, Aspergillus, Cryp-
Whipple’s disease Lamina propria includes macrophages tococcus, or Histoplasma organisms are seen on duodenal biopsy, their
containing material positive on periodic acid– presence generally reflects systemic infection. Apart from Whipple’s
Schiff staining disease and infections in the immunocompromised host, small-
Agammaglobulinemia No plasma cells; either normal or absent villi bowel biopsy is seldom used as the primary mode of diagnosis of
(“flat mucosa”) infection. Even giardiasis is more easily diagnosed by stool antigen
Abetalipoproteinemia Normal villi; epithelial cells vacuolated with studies and/or duodenal aspiration than by duodenal biopsy.
fat postprandially Patients with steatorrhea require assessment of pancreatic exocrine
Patchy, Specific function, which is often abnormal in chronic pancreatitis. The secre-
Intestinal lymphoma Malignant cells in lamina propria and tin test that collects pancreatic secretions by duodenal intubation
submucosa following intravenous administration of secretin is the only test that
Intestinal lymphangiectasia Dilated lymphatics; clubbed villi directly measures pancreatic exocrine function but is available only
Eosinophilic gastroenteritis Eosinophil infiltration of lamina propria and at a few specialized centers. Endoscopic approaches (endoscopic ret-
mucosa rograde cholangiopancreatography, endoscopic ultrasound) provide
Amyloidosis Amyloid deposits an excellent assessment of pancreatic duct anatomy but do not assess
Crohn’s disease Noncaseating granulomas exocrine function (Chap. 340).
Infection by one or more Specific organisms Table 318-7 summarizes the results of the d-xylose test, the
microorganisms (see text) Schilling test, and small-intestinal mucosal biopsy in patients with
Mastocytosis Mast cell infiltration of lamina propria steatorrhea of various etiologies.
Diffuse, Nonspecific
Celiac disease Short or absent villi; mononuclear infiltrate;
epithelial cell damage; hypertrophy of crypts SPECIFIC DISEASE ENTITIES
Tropical sprue Similar to celiac disease
■■CELIAC DISEASE
Bacterial overgrowth Patchy damage to villi; lymphocyte infiltration
Celiac disease is a common cause of malabsorption of one or

Folate deficiency Short villi; decreased mitosis in crypts; more nutrients. Although celiac disease was originally consid-
megalocytosis
ered largely a disease of white individuals, especially persons
Vitamin B12 deficiency Similar to folate deficiency
of European descent, recent observations have established that it is a
Radiation enteritis Similar to folate deficiency common disease with protean manifestations, a worldwide distribu-
Zollinger-Ellison syndrome Mucosal ulceration and erosion from acid tion, and an estimated incidence in the United States that is as high as
Protein-calorie malnutrition Villous atrophy; secondary bacterial 1 in 113 people. Its incidence has increased over the past 50 years.
overgrowth Celiac disease has had several other names, including nontropical
Drug-induced enteritis Variable histology sprue, celiac sprue, adult celiac disease, and gluten-sensitive enteropa-
thy. The etiology of celiac disease is not known, but environmental,
immunologic, and genetic factors are important. Celiac disease is con-
cells in the lamina propria and submucosa (Chap. 104). Dilated sidered an “iceberg” disease. A small number of individuals have
lymphatics in the submucosa and sometimes in the lamina pro- classic symptoms and manifestations related to nutrient malabsorption
pria indicate lymphangiectasia associated with hypoproteinemia along with a varied natural history; the onset of symptoms can occur at
secondary to protein loss into the intestine. Eosinophilic gas- all points from the first year of life through the eighth decade. A much
troenteritis comprises a heterogeneous group of disorders with a larger number of individuals have “atypical celiac disease,” with man-
spectrum of presentations and symptoms, with an eosinophilic ifestations that are not obviously related to intestinal malabsorption
infiltrate of the lamina propria, and with or without peripheral (e.g., anemia, osteopenia, infertility, and neurologic symptoms). Finally,
eosinophilia. The patchy nature of the infiltrate and its presence an even larger number of persons have “silent celiac disease”; they are
in the submucosa often lead to an absence of histopathologic essentially asymptomatic despite abnormal small-intestinal histopa-
findings on mucosal biopsy. As the involvement of the duode- thology and serologies (see below).
num in Crohn’s disease is also submucosal and not necessarily The hallmark of celiac disease is an abnormal small-intestinal biopsy
continuous, mucosal biopsies are not the most direct approach (Fig. 318-4) and the response of the condition (including symptoms
to the diagnosis of duodenal Crohn’s disease (Chap. 319). Amy- and histologic changes on small-intestinal biopsy) to the elimination
loid deposition can be identified by Congo Red staining in some of gluten from the diet. The histologic changes have a proximal-to-
patients with amyloidosis involving the duodenum (Chap. 108). distal intestinal distribution of severity, which probably reflects the
3. Diffuse, nonspecific lesions. Celiac disease presents with a char- exposure of the intestinal mucosa to varied amounts of dietary gluten.
acteristic mucosal appearance on duodenal/proximal jejunal The symptoms do not necessarily correlate with histologic changes,
mucosal biopsy that is not diagnostic of the disease. The diag- especially as many newly diagnosed patients with celiac disease
nosis of celiac disease is established by clinical, histologic, and may be asymptomatic or only minimally symptomatic (often with no
immunologic responses to a gluten-free diet. Tropical sprue (see gastrointestinal symptoms).
below) is associated with histologic findings similar to those of The symptoms of celiac disease may appear with the introduction
celiac disease after a tropical or subtropical exposure but does of cereals into an infant’s diet, although spontaneous remissions often
not respond to gluten restriction; most often symptoms improve occur during the second decade of life that may be either permanent
with antibiotics and folate administration. or followed by the reappearance of symptoms over several years.
Several microorganisms can be identified in small-intestinal Alternatively, the symptoms of celiac disease may first become evident
biopsy samples, establishing a correct diagnosis. At times, the biopsy at almost any age throughout adulthood. In many patients, frequent
is performed specifically to diagnose infection (e.g., Whipple’s dis- spontaneous remissions and exacerbations occur. The symptoms range
ease or giardiasis). In most other instances, the infection is detected from significant malabsorption of multiple nutrients, with diarrhea,
incidentally during the workup for diarrhea or other abdominal steatorrhea, weight loss, and the consequences of nutrient depletion
(i.e., anemia and metabolic bone disease), to the total absence of gas-
symptoms. Many of these infections occur in immunocompromised
trointestinal symptoms despite evidence of the depletion of a single

2252
PART 10
FIGURE 318-4 Small-intestinal mucosal biopsies. A. Normal individual. B. Untreated celiac disease. C. Treated celiac disease. D. Intestinal lymphangiectasia.
E. Whipple’s disease. F. Lymphoma. G. Giardiasis. (Courtesy of Marie Robert, MD, Yale University; with permission.)
nutrient (e.g., iron or folate deficiency, osteomalacia, edema from pro- and rye. In addition to the role of gluten restriction in treatment, the
tein loss). Asymptomatic relatives of patients with celiac disease have instillation of gluten into the normal-appearing rectum and the distal
been identified as having this disease either by small-intestinal biopsy ileum of patients with celiac disease results in morphologic changes
or by serologic studies (e.g., antiendomysial antibodies, tissue transglu- within hours.
taminase [tTG], deamidated gliadin peptide). The availability of these An immunologic component in the pathogenesis of celiac disease
“celiac serologies” has led to a substantial increase in the frequency of is critical and involves both adaptive and innate immune responses.
diagnosis of celiac disease, and the diagnosis is now being made pri- Serum antibodies—IgA antigliadin, antiendomysial, and anti-tTG
marily in patients without “classic” symptoms but with atypical and antibodies—are present, but it is not known whether such antibod-
subclinical presentations. ies are primary or secondary to the tissue damage. The presence of
Etiology The etiology of celiac disease is not known, but environ- antiendomysial antibody is 90–95% sensitive and 90–95% specific;
mental, immunologic, and genetic factors all appear to contribute to the the antigen recognized by antiendomysial antibody is tTG, which
disease. One environmental factor is the clear association of the disease deaminates gliadin, which is presented to HLA-DQ2 or HLA-DQ8 (see
with gliadin, a component of gluten that is present in wheat, barley, below). Antibody studies are frequently used to identify patients with
TABLE 318-7 Results of Diagnostic Studies in Steatorrhea of Various Etiologies

d-XYLOSE TEST SCHILLING TEST DUODENAL MUCOSAL BIOPSY
Chronic pancreatitis Normal 50% abnormal; if abnormal, normal Normal
with pancreatic enzyme treatment
Bacterial overgrowth syndromes Normal or only modestly abnormal Often abnormal; if abnormal, normal Usually normal
after antibiotic treatment
Ileal disease Normal Abnormal Normal
Celiac disease Decreased Normal Abnormal: probably “flat”
Intestinal lymphangiectasia Normal Normal Abnormal: “dilated lymphatics”

celiac disease; patients with these antibodies should undergo duodenal refractory sprue) that includes some patients who (1) respond to restric- 2253
biopsy. This autoantibody has not been linked to a pathogenetic mech- tion of other dietary protein (e.g., soy); (2) respond to glucocorticoid
anism (or mechanisms) responsible for celiac disease. Nonetheless, this treatment; (3) are “temporary” (i.e., whose clinical and morphologic
antibody is useful in establishing the true prevalence of celiac disease findings disappear after several months or years); or (4) fail to respond
in the general population. A 4-week course of treatment with predniso- to all measures and have a fatal outcome, with or without documented
lone induces a remission in a patient with celiac disease who continues complications of celiac disease, such as the development of intestinal
to eat gluten and converts the “flat” abnormal duodenal biopsy to a T cell lymphoma or autoimmune enteropathy.
more normal-appearing one. In addition, gliadin peptides interact with Therapeutic approaches that do not include a gluten-free diet are
gliadin-specific T cells that mediate tissue injury and induce the release being developed and include the use of peptidases to inactivate toxic
of one or more cytokines (e.g., interferon γ) that cause tissue injury. gliadin peptides and of small molecules to block toxic peptide uptake
Genetic factor(s) are also involved in celiac disease. The incidence across intestinal tight junctions.
of symptomatic celiac disease varies widely in different popula-
tion groups (high among whites, low among blacks and Asians) Mechanism of Diarrhea The diarrhea in celiac disease has
and is 10% among first-degree relatives of celiac disease patients. How- several pathogenetic mechanisms. Diarrhea may be secondary to
ever, serologic studies provide clear evidence that celiac disease is (1) steatorrhea, which is primarily a result of changes in jejunal mucosal
present worldwide. Furthermore, all patients with celiac disease function; (2) secondary lactase deficiency, a consequence of changes in
express the HLA-DQ2 or HLA-DQ8 allele, although only a minority of jejunal brush border enzymatic function; (3) bile-acid malabsorption
people expressing DQ2/DQ8 have celiac disease. Absence of DQ2/ resulting in bile-acid–induced fluid secretion in the colon (in cases with
DQ8 excludes the diagnosis of celiac disease. more extensive disease involving the ileum); and (4) endogenous fluid
secretion resulting from crypt hyperplasia. Celiac disease patients with
Diagnosis A small-intestinal biopsy is required to establish a diag- more severe involvement may improve temporarily with dietary lactose
nosis of celiac disease (Fig. 318-4). A biopsy should be performed when and fat restriction while awaiting the full effects of total gluten restric-
patients have symptoms and laboratory findings suggestive of nutrient tion, which constitutes primary therapy.
malabsorption and/or deficiency as well as a positive tTG antibody
test. Since the presentation of celiac disease is often subtle, without Associated Diseases Celiac disease is associated with derma-
overt evidence of malabsorption or nutrient deficiency, a relatively titis herpetiformis (DH), but this association has not been explained.
low threshold for biopsy performance is important. It is more prudent Patients with DH have characteristic papulovesicular lesions that
to perform a biopsy than another test of intestinal absorption that can respond to dapsone. Almost all patients with DH have histologic
never completely exclude or establish this diagnosis. changes in the small intestine consistent with celiac disease, although

The diagnosis of celiac disease requires the detection of charac- usually much milder and less diffuse in distribution. Most patients
teristic histologic changes on small-intestinal biopsy together with a with DH have mild or no gastrointestinal symptoms. In contrast, rela-
prompt clinical and histologic response after the institution of a gluten- tively few patients with celiac disease have DH.
free diet. If IgA antiendomysial or tTG antibodies have been detected Celiac disease is also associated with diabetes mellitus type 1, IgA
in serologic studies, they too should disappear after a gluten-free diet deficiency, Down’s syndrome, and Turner’s syndrome. The clinical
is started. With the increase in the number of patients diagnosed with importance of the association with diabetes is that, although severe
celiac disease (mostly by serologic studies), the spectrum of histologic watery diarrhea without evidence of malabsorption is most often
changes seen on duodenal biopsy has increased and includes findings diagnosed as “diabetic diarrhea” (Chap. 396), assay of antiendomysial
that are not as severe as the classic changes shown in Fig. 318-4. The antibodies and/or a small-intestinal biopsy must be considered to
classic changes seen on duodenal/jejunal biopsy are restricted to the exclude celiac disease.
mucosa and include (1) an increase in the number of intraepithelial
lymphocytes; (2) absence or a reduced height of villi, which causes a
Complications The most important complication of celiac disease
is the development of cancer. The incidences of both gastrointestinal
flat appearance with increased crypt cell proliferation resulting in crypt
and nongastrointestinal neoplasms as well as intestinal lymphoma
hyperplasia and loss of villous structure, with consequent villous, but
are elevated among patients with celiac disease. For unexplained
not mucosal, atrophy; (3) a cuboidal appearance and nuclei that are
reasons, the frequency of lymphoma in patients with celiac disease is
no longer oriented basally in surface epithelial cells; and (4) increased
higher in Ireland and the United Kingdom than in the United States.
numbers of lymphocytes and plasma cells in the lamina propria
The possibility of lymphoma must be considered whenever a patient
(Fig. 318-4B). Although these features are characteristic of celiac dis-
with celiac disease who has previously done well on a gluten-free diet
ease, they are not diagnostic because a similar appearance can develop
eosinophilic enteritis, and milk-protein intolerance in children and is no longer responsive to gluten restriction or a patient who presents
occasionally in lymphoma, bacterial overgrowth, Crohn’s disease, and with clinical and histologic features consistent with celiac disease
gastrinoma with acid hypersecretion. However, a characteristic histo- does not respond to a gluten-free diet. Other complications of celiac
logic appearance that reverts toward normal after the initiation of a disease include the development of intestinal ulceration independent
gluten-free diet establishes the diagnosis of celiac disease (Fig. 318-4C). of lymphoma and so-called refractory sprue (see above) and collage-
Readministration of gluten, with or without an additional small-intes- nous sprue. In collagenous sprue, a layer of collagen-like material is
tinal biopsy, is not necessary. present beneath the basement membrane; patients with collagenous
A number of patients exhibit nonceliac gluten sensitivity; that is, they sprue generally do not respond to a gluten-free diet and often have
have gastrointestinal symptoms that respond to gluten restriction but a poor prognosis.
do not have celiac disease. The basis for such gluten sensitivity is not
known. ■■TROPICAL SPRUE
Tropical sprue is a poorly understood syndrome that affects
Failure to Respond to Gluten Restriction The most common both expatriates and natives in certain but not all tropical
cause of persistent symptoms in a patient who fulfills all the criteria areas and is manifested by chronic diarrhea, steatorrhea,
for the diagnosis of celiac disease is continued intake of gluten. Gluten is weight loss, and nutritional deficiencies, including those of both folate
ubiquitous, and a significant effort must be made to exclude all gluten and cobalamin. This disease affects 5–10% of the population in some
from the diet. Use of rice flour in place of wheat flour is very helpful, tropical areas.
and several support groups provide important aid to patients with Chronic diarrhea in a tropical environment is most often caused by
celiac disease and to their families. More than 90% of patients who infectious agents, including G. lamblia, Yersinia enterocolitica, C. difficile,
have the characteristic findings of celiac disease respond to complete Cryptosporidium parvum, and Cyclospora cayetanensis. Tropical sprue
dietary gluten restriction. The remainder constitute a heterogeneous should not be entertained as a possible diagnosis until the presence of
group (whose condition is often called refractory celiac disease or cysts and trophozoites has been excluded in three stool samples. Chronic

2254 infections of the gastrointestinal tract and diarrhea in patients with or
TREATMENT
without AIDS are discussed in Chaps. 128, 129, and 197.
The small-intestinal mucosa of individuals living in tropical areas is Tropical Sprue
not identical to that of individuals who reside in temperate climates. In
residents of tropical areas, biopsies reveal a mild alteration of villous Broad-spectrum antibiotics and folic acid are most often curative,
architecture with a modest increase in mononuclear cells in the lamina especially if the patient leaves the tropical area and does not return.
propria, which on occasion can be as severe as that seen in celiac dis- Tetracycline should be used for up to 6 months and may be associ-
ease. These changes are observed both in native residents and in expa- ated with improvement within 1–2 weeks. Folic acid alone induces
triates living in tropical regions and are usually associated with mild hematologic remission as well as improvement in appetite, weight
decreases in absorptive function, but they revert to “normal” when an gain, and some morphologic changes in small-intestinal biopsy.
individual moves or returns to a temperate area. Some have suggested Because of marked folate deficiency, folic acid is most often given
that the changes seen in tropical enteropathy and in tropical sprue rep- together with antibiotics.
resent different ends of the spectrum of a single entity, but convincing
evidence to support this concept is lacking. ■■SHORT-BOWEL SYNDROME
In the past few years the term “environmental enteropathy” has Short-bowel syndrome is a descriptive term for the myriad clinical prob-
been introduced as the diagnosis of many patients (especially infants lems that follow resection of various lengths of the small intestine or, on
and children) who had previously been diagnosed as tropical sprue. rare occasions, are congenital (e.g., microvillous inclusion disease). The
Such patients have physical and/or mental shunting. However, exact factors that determine both the type and degree of symptoms include
delineation of this newly designated entity is lacking. (1) the specific segment (jejunum vs ileum) resected, (2) the length of
the resected segment, (3) the integrity of the ileocecal valve, (4) whether
Etiology Because tropical sprue responds to antibiotics, the consen- any large intestine has also been removed, (5) residual disease in the
sus is that it may be caused by one or more infectious agents. Nonethe- remaining small and/or large intestine (e.g., Crohn’s disease, mesen-
less, the etiology and pathogenesis of tropical sprue are uncertain. First, teric artery disease), and (6) the degree of adaptation in the remaining
its occurrence is not evenly distributed in all tropical areas; rather, it is intestine. Short-bowel syndrome can occur in persons of any age, from
found in specific locations, including southern India, the Philippines, neonates to the elderly.
and several Caribbean islands (e.g., Puerto Rico, Haiti), but is rarely Three different situations in adults mandate intestinal resection:
observed in Africa, Jamaica, or Southeast Asia. Second, an occasional (1) mesenteric vascular disease, including atherosclerosis, thrombotic
individual does not develop symptoms of tropical sprue until long phenomena, and vasculitides; (2) primary mucosal and submucosal
after having left an endemic area. For this reason, celiac disease (often disease (e.g., Crohn’s disease); and (3) operations without preexisting
referred to as celiac sprue) was originally called nontropical sprue to
PART 10
small-intestinal disease (e.g., after trauma).

distinguish it from tropical sprue. Third, multiple microorganisms After resection of the small intestine, the residual intestine under-
have been identified in jejunal aspirates, with relatively little consis- goes adaptation of both structure and function that may last for up
tency among studies. Klebsiella pneumoniae, Enterobacter cloacae, and to 6–12 months. Continued intake of dietary nutrients and calories is
E. coli have been implicated in some studies of tropical sprue, while required to stimulate adaptation via direct contact with the intestinal
other studies have favored a role for a toxin produced by one or more mucosa, the release of one or more intestinal hormones, and pancreatic
of these bacteria. Fourth, the incidence of tropical sprue appears to and biliary secretions. Thus, enteral nutrition with calorie administra-
have decreased substantially during the past two or three decades, tion must be maintained, especially in the early postoperative period,
perhaps in relation to improved sanitation in many tropical countries even if an extensive intestinal resection requiring parenteral nutrition
during this time. Some have speculated that the reduced occurrence is (PN) has been performed. The subsequent ability of such patients to
attributable to the wider use of antibiotics in acute diarrhea, especially absorb nutrients will not be known for several months, until adaptation
in travelers to tropical areas from temperate countries. Fifth, the role is complete.
of folic acid deficiency in the pathogenesis of tropical sprue requires Multiple factors besides the absence of intestinal mucosa (required
clarification. Folic acid is absorbed exclusively in the duodenum and for lipid, fluid, and electrolyte absorption) contribute to diarrhea and
proximal jejunum, and most patients with tropical sprue have evidence steatorrhea in these patients. Removal of the ileum, and especially the
of folate malabsorption and depletion. Although folate deficiency can ileocecal valve, is often associated with more severe diarrhea than jeju-
cause changes in small-intestinal mucosa that are corrected by folate nal resection. Without part or all of the ileum, diarrhea can be caused
replacement, several earlier studies reporting that tropical sprue could by an increase in bile acids entering the colon; these acids stimulate
be cured by folic acid did not provide an explanation for the “insult” colonic fluid and electrolyte secretion. Absence of the ileocecal valve
that was initially responsible for folate malabsorption. is also associated with a decrease in intestinal transit time and bacte-
The clinical pattern of tropical sprue varies in different areas of the rial overgrowth from the colon. The presence of the colon (or a major
world (e.g., India vs Puerto Rico). Not infrequently, individuals in portion) is associated with substantially less diarrhea and a lower
southern India initially report the occurrence of acute enteritis before likelihood of intestinal failure (an inability to maintain nutrition without
the development of steatorrhea and malabsorption. In contrast, in parenteral support) as a result of fermentation of nonabsorbed carbo-
Puerto Rico, a more insidious onset of symptoms and a more dramatic hydrates to SCFAs. The latter are absorbed in the colon and stimulate
response to antibiotics are seen than in some other locations. Tropical Na and water absorption, improving overall fluid balance. Lactose
sprue in different areas of the world may not be the same disease, and intolerance as a result of the removal of lactase-containing mucosa as
similar clinical entities may have different etiologies. well as gastric hypersecretion may also contribute to the diarrhea.
Diagnosis The diagnosis of tropical sprue is best based on an In addition to diarrhea and/or steatorrhea, a range of nonintestinal
abnormal small-intestinal mucosal biopsy in an individual with symptoms is observed in some patients. The frequency of renal calcium
chronic diarrhea and evidence of malabsorption who is either residing oxalate calculi increases significantly in patients with a small-intestinal
or has recently lived in a tropical country. The small-intestinal biopsy in resection and an intact colon; this greater frequency is due to an
tropical sprue does not reveal pathognomonic features but resembles, increase in oxalate absorption by the large intestine, with subsequent
and can often be indistinguishable from, that seen in celiac disease enteric hyperoxaluria. Two possible mechanisms for the increase in
(Fig. 318-4). The biopsy sample in tropical sprue has less villous archi- oxalate absorption in the colon have been suggested: (1) increased
tectural alteration and more mononuclear cell infiltrate in the lamina bile acids and fatty acids that augment colonic mucosal permeability,
propria. In contrast to those of celiac disease, the histologic features of resulting in enhanced oxalate absorption; and (2) increased fatty acids
tropical sprue manifest with a similar degree of severity throughout the that bind calcium, resulting in an enhanced amount of soluble oxalate
small intestine, and a gluten-free diet does not result in either clinical or that is then absorbed. Since oxalate is high in relatively few foods
histologic improvement in tropical sprue. (e.g., spinach, rhubarb, tea), dietary restrictions alone do not constitute

adequate treatment. Cholestyramine (an anion-binding resin) and unconjugated bile acids. Unconjugated bile acids are absorbed more 2255
calcium have proved useful in reducing hyperoxaluria. Similarly, an rapidly than conjugated bile acids; as a result, the intraduodenal
increase in cholesterol gallstones is related to a decrease in the bile-acid concentration of bile acids is reduced. In addition, the CMC of uncon-
pool size, which results in the generation of cholesterol supersatura- jugated bile acids is higher than that of conjugated bile acids, and the
tion in gallbladder bile. Gastric hypersecretion of acid occurs in many result is a decrease in micelle formation. Diarrhea is due, at least in part,
patients after large resections of the small intestine. The etiology is to steatorrhea, when it is present. However, some patients manifest
unclear but may be related to either reduced hormonal inhibition of diarrhea without steatorrhea, and it is assumed that the colonic-type
acid secretion or increased gastrin levels due to reduced small-intestinal bacteria in these patients are producing one or more bacterial entero-
catabolism of circulating gastrin. The resulting gastric acid secretion toxins that are responsible for fluid secretion and diarrhea.
may be an important factor contributing to diarrhea and steatorrhea.
A reduced pH in the duodenum can inactivate pancreatic lipase and/ Etiology The etiology of these different disorders is bacterial
or precipitate duodenal bile acids, thereby increasing steatorrhea, and proliferation in the small-intestinal lumen secondary to anatomic or
an increase in gastric secretion can create a volume overload relative to functional stasis or to a communication between the relatively sterile
the reduced small-intestinal absorptive capacity. Inhibition of gastric small intestine and the colon, with its high levels of aerobic and anaer-
acid secretion with proton pump inhibitors can help reduce diarrhea obic bacteria. Several examples of anatomic stasis have been identified:
and steatorrhea. (1) one or more diverticula (both duodenal and jejunal) (Fig. 318-3C);
(2) fistulas and strictures related to Crohn’s disease (Fig. 318-3D); (3)
a proximal duodenal afferent loop following subtotal gastrectomy
TREATMENT and gastrojejunostomy; (4) a bypass of the intestine (e.g., a jejunoileal
Short-Bowel Syndrome bypass for obesity); and (5) dilation at the site of a previous intestinal
anastomosis. These anatomic derangements are often associated with
Treatment of short-bowel syndrome depends on the severity of the presence of a segment (or segments) of intestine out of continuity
symptoms and on whether the individual is able to maintain caloric of propagated peristalsis, with consequent stasis and bacterial prolif-
and electrolyte balance with oral intake alone. Initial treatment eration. Bacterial overgrowth syndromes can also occur in the absence
includes judicious use of opiates (including codeine) to reduce stool of an anatomic blind loop when functional stasis is present. Impaired
output and establish an effective diet. If the colon is in situ, the peristalsis and bacterial overgrowth in the absence of a blind loop occur
initial diet should be low in fat and high in carbohydrate in order in scleroderma, where motility abnormalities exist in both the esopha-
to minimize diarrhea from fatty acid stimulation of colonic fluid gus and the small intestine (Chap. 353). Functional stasis and bacterial

secretion. MCTs (see Table 318-3), a low-lactose diet, and various overgrowth can also develop in association with diabetes mellitus and
soluble fiber–containing diets should also be tried. In the absence of in the small intestine when a direct connection exists between the small
an ileocecal valve, possible bacterial overgrowth must be considered and large intestines, including an ileocolonic resection, or occasionally
and treated. If gastric acid hypersecretion is contributing to diarrhea after an enterocolic anastomosis that permits entry of bacteria into the
and steatorrhea, a proton pump inhibitor may be helpful. Usually small intestine as a result of bypassing the ileocecal valve.
none of these therapeutic approaches provides an instant solution,
but each can contribute to the reduction of disabling diarrhea.
Diagnosis The diagnosis may be suspected from the combination
of a low serum cobalamin level and an elevated serum folate level, as
The patient’s vitamin and mineral status must also be monitored;
enteric bacteria frequently produce folate compounds that are absorbed
replacement therapy should be initiated if indicated. Fat-soluble
in the duodenum. Ideally, the bacterial overgrowth syndromes are
vitamins, folate, cobalamin, calcium, iron, magnesium, and zinc
diagnosed by the demonstration of increased levels of aerobic and/or
are the most critical factors to monitor on a regular basis. If these
anaerobic colonic-type bacteria in a jejunal aspirate obtained by intuba-
approaches are not successful, home PN is an established therapy
tion. However, this specialized test is rarely available. Breath hydrogen
that can be maintained for many years. Small-intestinal transplanta-
testing with administration of lactulose (a nondigestible disaccharide)
tion is becoming established as a possible approach for individuals
has also been used to detect bacterial overgrowth. Often, the diagnosis
with extensive intestinal resection who cannot be maintained with-
is suspected clinically and confirmed by the response to treatment.
out PN—that is, those with intestinal failure. A recombinant ana-
logue of glucagon-like peptide 2 (GLP-2; teduglutide) is approved
for use in patients with PN-dependent short-bowel syndrome on the TREATMENT
basis of its ability to increase intestinal growth, improve absorption,
and reduce requirement for PN.
Bacterial Overgrowth Syndromes
Primary treatment should be directed, if at all possible, to the
■■BACTERIAL OVERGROWTH SYNDROMES surgical correction of an anatomic blind loop. In the absence of
Bacterial overgrowth syndromes comprise a group of disorders with diar- functional stasis, it is important to define the anatomic relationships
rhea, steatorrhea, and macrocytic anemia whose common feature is the responsible for stasis and bacterial overgrowth. For example, bac-
proliferation of colonic-type bacteria within the small intestine. This terial overgrowth secondary to strictures, one or more diverticula,
bacterial proliferation is due to stasis caused by impaired peristalsis or a proximal afferent loop can potentially be cured by surgical
(functional stasis), changes in intestinal anatomy (anatomic stasis), or correction of the anatomic state. In contrast, the functional stasis of
direct communication between the small and large intestine. These scleroderma or certain anatomic stasis states (e.g., multiple jejunal
conditions have also been referred to as stagnant bowel syndrome or blind diverticula) cannot be corrected surgically, and these conditions
loop syndrome. should be treated with broad-spectrum antibiotics. Tetracycline
used to be the initial drug of choice; because of increasing resis-
Pathogenesis The manifestations of bacterial overgrowth syn- tance, however, other antibiotics, such as metronidazole, amox-
dromes are a direct consequence of the presence of increased amounts icillin/clavulanic acid, rifaximin and cephalosporins, have been
of a colonic-type bacterial flora, such as E. coli or Bacteroides, in the employed. The antibiotic should be given for ~3 weeks or until
small intestine. Macrocytic anemia is due to cobalamin—not folate— symptoms remit. Although the natural history of these conditions
deficiency. Most bacteria require cobalamin for growth, and increased is chronic, antibiotics should not be given continuously. Symptoms
concentrations of bacteria use up the relatively small amounts of usually remit within 2–3 weeks of initial antibiotic therapy. Treat-
dietary cobalamin. Steatorrhea is due to impaired micelle formation ment need not be repeated until symptoms recur. For frequent
as a consequence of a reduced intraduodenal concentration of conju- recurrences, several treatment strategies exist, but the use of antibi-
gated bile acids and the presence of unconjugated bile acids. Certain otics for 1 week per month, whether or not symptoms are present,
bacteria, including Bacteroides, deconjugate conjugated bile acids to is often most effective.

2256 Unfortunately, therapy for bacterial overgrowth syndromes is by excess protein loss into the gastrointestinal tract. Normally, ~10%
largely empirical, with an absence of clinical trials on which to of total protein catabolism occurs via the gastrointestinal tract. Evi-
base rational decisions regarding antibiotic choice, treatment dura- dence of increased protein loss into the gastrointestinal tract is found
tion, and/or the best approach to therapy for recurrences. Bacterial in >65 different diseases, which can be classified into three groups:
overgrowth may also occur as a component of another chronic (1) mucosal ulceration, such that the protein loss primarily represents
disease, such as Crohn’s disease, radiation enteritis, or short-bowel exudation across damaged mucosa (e.g., ulcerative colitis, gastroin-
syndrome. Treatment of the bacterial overgrowth in these settings testinal carcinomas, and peptic ulcer); (2) nonulcerated mucosa, but
will not cure the underlying problem but may be very important in with evidence of mucosal damage so that the protein loss represents
ameliorating a subset of clinical problems that are related to bacterial loss across epithelia with altered permeability (e.g., celiac disease and
overgrowth. Ménétrier’s disease in the small intestine and stomach, respectively);
and (3) lymphatic dysfunction, representing either primary lymphatic
■■WHIPPLE’S DISEASE disease or lymphatic disease secondary to partial lymphatic obstruc-
Whipple’s disease is a chronic multisystemic disease associated with tion that may occur as a result of enlarged lymph nodes or cardiac
diarrhea, steatorrhea, weight loss, arthralgia, and central nervous disease.
system (CNS) and cardiac problems; it is caused by the bacterium Tro- Diagnosis The diagnosis of protein-losing enteropathy is sug-
pheryma whipplei. Until the identification of T. whipplei by polymerase gested by peripheral edema and low serum albumin and globulin
chain reaction, the hallmark of Whipple’s disease had been the presence levels in the absence of renal and hepatic disease. An individual with
of PAS-positive macrophages in the small intestine (Fig. 318-4E) and protein-losing enteropathy only rarely has selective loss of only albu-
other organs with evidence of disease. min or only globulins. Therefore, marked reduction of serum albumin
Etiology T. whipplei, a small (50–500 nm) gram-positive bacillus with normal serum globulins should not initiate an evaluation for
in the group Actinobacteria, has low virulence but high infectivity. protein-losing enteropathy but should suggest renal and/or hepatic
Symptoms of Whipple’s disease are relatively minimal compared to the disease. Likewise, reduced serum globulins with normal serum albu-
bacterial burden in multiple tissues. min levels are more likely a result of reduced globulin synthesis rather
than enhanced globulin loss into the intestine. An increase in protein
Clinical Presentation The onset of Whipple’s disease is insid- loss into the gastrointestinal tract has been documented by the admin-
ious and is characterized by diarrhea, steatorrhea, abdominal pain, istration of one of several radiolabeled proteins and its quantitation in
weight loss, migratory large-joint arthropathy, and fever as well as oph- stool during a 24- or 48-h period. Unfortunately, none of these radi-
thalmologic and CNS symptoms. Dementia is a relatively late symp- olabeled proteins is available for routine clinical use. α1-Antitrypsin, a
tom and an extremely poor prognostic sign, especially in patients who protein that accounts for ~4% of total serum proteins and is resistant to
PART 10
experience relapse after the induction of a remission with antibiotics. proteolysis, can be used to detect enhanced rates of serum protein loss
For unexplained reasons, the disease occurs primarily in middle-aged into the intestinal tract but cannot be used to assess gastric protein loss
white men. The steatorrhea in these patients is generally believed to because of its degradation in an acid milieu. α1-Antitrypsin clearance
be secondary to both small-intestinal mucosal injury and lymphatic is measured by determining stool volume as well as both stool and
obstruction due to the increased number of PAS-positive macrophages
plasma α1-antitrypsin concentrations. In addition to the loss of protein

in the lamina propria of the small intestine. via abnormal and distended lymphatics, peripheral lymphocytes may
Diagnosis The diagnosis of Whipple’s disease is suggested by a be lost via lymphatics, with consequent relative lymphopenia. Thus,
multisystemic disease in a patient with diarrhea and steatorrhea. Tissue lymphopenia in a patient with hypoproteinemia indicates increased
biopsy of the small intestine and/or other organs that may be involved loss of protein into the gastrointestinal tract.
(e.g., liver, lymph nodes, heart, eyes, CNS, or synovial membranes), Patients with increased protein loss into the gastrointestinal tract
given the patient’s symptoms, is the primary approach. The presence from lymphatic obstruction often have steatorrhea and diarrhea. The
of PAS-positive macrophages containing the characteristic small bacilli steatorrhea is a result of altered lymphatic flow as lipid-containing chy-
is suggestive of this diagnosis. However, T. whipplei–containing mac- lomicrons exit from intestinal epithelial cells via intestinal lymphatics
rophages can be confused with PAS-positive macrophages containing (Table 318-4; Fig. 318-4). In the absence of mechanical or anatomic lym-
M. avium complex, which may be a cause of diarrhea in AIDS. The phatic obstruction, intrinsic intestinal lymphatic dysfunction—with or
presence of the T. whipplei bacillus outside of macrophages is a more without lymphatic dysfunction in the peripheral extremities—has been
important indicator of active disease than is their presence within the designated intestinal lymphangiectasia. Similarly, ~50% of individuals
macrophages. T. whipplei has now been successfully grown in culture. with intrinsic peripheral lymphatic disease (Milroy’s disease) also
have intestinal lymphangiectasia and hypoproteinemia. Other than
steatorrhea and enhanced protein loss into the gastrointestinal tract, all
TREATMENT other aspects of intestinal absorptive function are normal in intestinal
Whipple’s Disease lymphangiectasia.
Other Causes Patients who appear to have idiopathic protein-
The treatment for Whipple’s disease is prolonged use of antibiotics.
losing enteropathy without evidence of gastrointestinal disease should
The current regimen of choice is ceftriaxone or meropenem for
be examined for cardiac disease—especially right-sided valvular
2 weeks followed by oral TMP-SMX (160/800 mg) twice a day for
disease and chronic pericarditis (Chaps. 263 and 265). On occasion,
1 year. PAS-positive macrophages can persist after successful treat-
hypoproteinemia can be the only presenting manifestation in these two
ment, and the presence of bacilli outside of macrophages is indica-
types of heart disease. Ménétrier’s disease (also called hypertrophic gas-
tive of persistent infection or an early sign of recurrence. Recurrence
tropathy) is an uncommon entity that involves the body and fundus of
of disease activity, especially with dementia, is an extremely poor
the stomach and is characterized by large gastric folds, reduced gastric
prognostic sign and requires an antibiotic that crosses the blood-
acid secretion, and, at times, enhanced protein loss into the stomach.
brain barrier. If trimethoprim-sulfamethoxazole is not tolerated,
chloramphenicol is an appropriate second choice.
TREATMENT
■■PROTEIN-LOSING ENTEROPATHY Protein-Losing Enteropathy
Protein-losing enteropathy is not a specific disease but rather a group of
gastrointestinal and nongastrointestinal disorders with hypoproteine- As excess protein loss into the gastrointestinal tract is most often sec-
mia and edema in the absence of either proteinuria or defects in protein ondary to a specific disease, treatment should be directed primarily
synthesis (e.g., chronic liver disease). These diseases are characterized to the underlying disease process and not to the hypoproteinemia.

For example, if significant hypoproteinemia with resulting periph- TABLE 318-9 Pathophysiology of Clinical Manifestations of 2257
eral edema is secondary to celiac disease or ulcerative colitis, a Malabsorption Disorders
gluten-free diet and mesalamine, respectively, would be the initial SYMPTOM OR SIGN MECHANISM
therapy. When enhanced protein loss is secondary to lymphatic Weight loss/malnutrition Anorexia, malabsorption of nutrients
obstruction, it is critical to establish the nature of this obstruction.
Diarrhea Impaired absorption or secretion of water and
electrolytes; colonic fluid secretion secondary to
unabsorbed dihydroxy bile acids and fatty acids
TABLE 318-8 Classification of Malabsorption Syndromes
Flatus Bacterial fermentation of unabsorbed carbohydrate
Inadequate digestion
Glossitis, cheilosis, Deficiency of iron, vitamin B12, folate, and vitamin A
Postgastrectomya stomatitis
Deficiency or inactivation of pancreatic lipase Abdominal pain Bowel distention or inflammation, pancreatitis
Exocrine pancreatic insufficiency Bone pain Calcium, vitamin D malabsorption, protein
Chronic pancreatitis deficiency, osteoporosis
Pancreatic carcinoma Tetany, paresthesia Calcium and magnesium malabsorption
Cystic fibrosis Weakness Anemia, electrolyte depletion (particularly K+)
Pancreatic insufficiency—congenital or acquired Azotemia, hypotension Fluid and electrolyte depletion
Gastrinoma—acid inactivation of lipase Amenorrhea, decreased Protein depletion, decreased calories, secondary
Drugs—orlistat libido hypopituitarism
Reduced intraduodenal bile-acid concentration/impaired micelle formation Anemia Impaired absorption of iron, folate, vitamin B12
Liver disease Bleeding Vitamin K malabsorption, hypoprothrombinemia
Parenchymal liver disease Night blindness/ Vitamin A malabsorption
xerophthalmia
Cholestatic liver disease
Peripheral neuropathy Vitamin B12 and thiamine deficiency
Bacterial overgrowth in small intestine:
Dermatitis Deficiency of vitamin A, zinc, and essential fatty
Anatomic stasis Functional stasis
acid
Afferent loop Diabetesa
Stasis/blind Sclerodermaa
Loop/strictures/fistulae Intestinal pseudo-obstruction

Identification of mesenteric nodes or lymphoma may be possible by
Interrupted enterohepatic circulation of bile salts
imaging studies. Similarly, it is important to exclude cardiac disease
Ileal resection
as a cause of protein-losing enteropathy, either by echosonography
Crohn’s disease or, on occasion, by a right-heart catheterization.
Drugs (binding or precipitating bile salts)—neomycin, cholestyramine, The increased protein loss that occurs in intestinal lymphangiec-
calcium carbonate
tasia is a result of distended lymphatics associated with lipid mal-
Impaired mucosal absorption/mucosal loss or defect absorption. The hypoproteinemia is treated with a low-fat diet and
Intestinal resection or bypassa the administration of MCTs (Table 318-3), which do not exit from the
Inflammation, infiltration, or infection: intestinal epithelial cells via lymphatics but are delivered to the body
Crohn’s diseasea Celiac disease via the portal vein.
Amyloidosis Collagenous sprue
Sclerodermaa Whipple’s diseasea
SUMMARY
Lymphomaa Radiation enteritisa The many conditions that can produce malabsorption are classified
Eosinophilic enteritis Folate and vitamin B12 deficiency by their pathophysiology in Table 318-8. The pathophysiology of the
Mastocytosis Infections—giardiasis various clinical manifestations of malabsorption is summarized in
Tropical sprue Graft versus host disease Table 318-9.
Genetic disorders
Disaccharidase deficiency ■■FURTHER READING
Agammaglobulinemia Binder HJ: Role of colonic short chain fatty acid transport in diarrhea.
Abetalipoproteinemia
Annu Rev Physiol 72:297, 2010.
Carroll RE et al: Management and complications of short bowel
Hartnup’s disease
syndrome: An updated review. Curr Gastroenterol Rep 18:40, 2016.
Cystinuria
Desnues B, Al Moussawi K, Fenollar F: New insights into Whipple’s
Impaired nutrient delivery to and/or from intestine: disease and Tropheryma whipplei infections. Microbes Infect 12:1102,
Lymphatic obstruction Circulatory disorders 2010.
Lymphomaa Congestive heart failure Ghoshal UC et al: Tropical sprue in 2014: The new face of an old dis-
Lymphangiectasia Constrictive pericarditis ease. Curr Gastroenterol Rep 16:391, 2014.
Mesenteric artery atherosclerosis Hill ID et al: NASPGHAN Clinical Report on the diagnosis and treat-
Vasculitis ment of gluten-related disorders. J Pediatr Gastroenerol Nutr 63:156,
Endocrine and metabolic disorders 2016.
Diabetesa Kelly CP et al: Advances in diagnosis and management of celiac
disease. Gastroenterology 148:1175, 2015.
Hypoparathyroidism
Korpe PS, Petri WA: Environmental enteropathy: critical implications
Adrenal insufficiency
of a poorly studied condition. Trends Mol Med 18:328, 2012.
Hyperthyroidism Rezaeie A, Pimentel M, Rao SS: How to test and treat small
Carcinoid syndrome intestinal bacterial overgrowth: An evidence-based approach. Curr
Malabsorption caused by more than one mechanism.
a Gastroenterol Rep 18:8, 2016.

2258 immigrated to Westernized countries and then returned to their
319 Inflammatory Bowel

Disease
country of birth also continue to demonstrate an increased risk of
developing IBD.
Peak incidence of UC and CD is in the second to fourth decades,
with 78% of CD studies and 51% of UC studies reporting the highest
Sonia Friedman, Richard S. Blumberg incidence among those age 20–29 years old. A second modest rise
in incidence occurs between the seventh and ninth decades of life.
The female-to-male ratio ranges from 0.51 to 1.58 for UC studies and
Inflammatory bowel disease (IBD) is an immune-mediated chronic 0.34 to 1.65 for CD studies, suggesting that the diagnosis of IBD is not
intestinal condition. Ulcerative colitis (UC) and Crohn’s disease (CD) gender-specific. Pediatric IBD (patients <18 years of age) comprises
are the two major types of IBD. ~20–25% of all IBD patients and about 5% of all IBD patients are
<10 years of age. Very early onset IBD (VEOIBD) has been defined as
■■GLOBAL CONSIDERATIONS: EPIDEMIOLOGY IBD that occurs in children <6 years of age and infantile IBD in children
The highest incidence rates of CD and UC have been reported <2 years of age. VEOIBD and infantile IBD mainly affect the colon, are
in northern Europe, the United Kingdom, and North America. resistant to standard medications, and patients often have a strong
Countries in the Pacific, including New Zealand and Australia, family history of IBD, with at least one first-degree related affected.
which share many possible environmental risk factors and similar Twenty-five percent of patients have an underlying immunodeficiency.
genetic background as northwest Europe and North America, have In some cases, infantile IBD or VEOIBD can be caused by a number of
high incidence rates of IBD. rare, single genetic mutations.
The highest reported incidence rates are in Canada (19.2 per The greatest incidence of IBD is among white and Jewish people,
1000,000 for UC and 20.2 for CD), Northern Europe (24.3 per 100,000 but the incidence of IBD in Hispanic and Asian people is increasing, as
for UC in Iceland and 10.6 per 100,000 for CD in the United Kingdom), noted above. Urban areas have a higher prevalence of IBD than rural
and Australia (17.4 per 100,000 for UC and 29.3 per 100,000 for CD). areas, and high socioeconomic classes have a higher prevalence than
Prevalence is highest in Europe (505 per 100,000 for UC in Norway and lower socioeconomic classes.
322 per 100,000 for CD in Italy) and Canada (248 per 100,000 for UC and Epidemiologic studies have identified a number of potential envi-
319 per 100,000 for CD) (Table 319-1). Based on these estimates ~0.6% ronmental factors that are associated with disease risk (Fig. 319-1).
of the Canadian population has IBD. In Caucasian populations, smoking is an important risk factor in IBD
In countries that are becoming more Westernized, including China, with opposite effects on UC (odds ratio [OR] 0.58) and CD (OR 1.76),
South Korea, India, Lebanon, Iran, Thailand, and countries in the whereas in other ethnic groups with different genetic susceptibility,
PART 10
French West Indies and North Africa, IBD appears to be emerging, smoking may play a lesser role. There is a protective effect of previous
emphasizing the importance of environmental factors in disease patho- appendectomy with confirmed appendicitis (risk reduction of 13–26%),
genesis. In Japan, the prevalence of CD has risen rapidly from 2.9 cases particularly at a young age, on the development of UC across different
per 100,000 in 1986 to 13.5 per 100,000 in 1998, whereas in South Korea, geographical regions and populations. There is a modest association
the prevalence of UC has quadrupled from 7.6 per 100,000 in 1997 to with the development of CD but this may be due to diagnostic bias.
30.9 per 100,000 in 2005. In Hong Kong, the prevalence of UC almost Oral contraceptive use is associated with the risk of CD with a reported
tripled from 2.3 in 1997 to 6.3 per 100,000 over a 9-year period. In Singa- hazard ratio as high as 2.82 among current users and 1.39 among past
pore, the prevalence of CD increased from 1.3 in 1990 to 7.2 per 100,000 users. The association between oral contraceptive use and UC is limited
in 2004. In China the number of cases of UC has increased by fourfold to women with a history of smoking. There is an association between
between 1981–1990 and 1991–2000. antibiotic use and the development of childhood IBD with children
Increasing immigration to Western societies also has an impact on who received one or more dispensations of antibiotics during the first
the incidence and prevalence of IBD. The prevalence of UC among year of life having a 2.9-fold increase in the risk of developing IBD
southern Asians who immigrated to the United Kingdom (UK) was during childhood. Breastfeeding may also protect against the develop-
higher in comparison to the European UK population (17 cases per ment of IBD. Infectious gastroenteritis with pathogens (e.g., Salmonella,
100,000 persons vs 7 per 100,000). Spanish patients who emigrated Shigella, Campylobacter spp., Clostridium difficile) increases IBD risk by
within Europe, but not those who immigrated to Latin America, two- to threefold. Diets high in animal protein, sugars, sweets, oils, fish
developed IBD more frequently than controls. Individuals who have and shellfish, and dietary fat, especially ω-6 fatty acids, and low in ω-3
fatty acids have been implicated in increasing the risk of IBD. A protec-
tive effect of vitamin D on the risk of CD has been reported.
TABLE 319-1 Epidemiology of IBD
IBD is a familial disease in 5–10% of patients (Fig. 319-2). Some of
ULCERATIVE COLITIS CROHN'S DISEASE these patients may exhibit early-onset disease during the first decade
Incidence (North 0–19.2 per 100,000 0–20.2 per 100,000 of life and, in CD, a concordance of anatomic site and clinical type
America) per within families. In the remainder of patients, IBD is observed in the
person-years
absence of a family history (i.e., sporadic disease). If a patient has IBD,
Age of onset Second to fourth Second to fourth
the lifetime risk that a first-degree relative will be affected is ~10%. If
decades and seventh to decades and seventh to
ninth decades ninth decades two parents have IBD, each child has a 36% chance of being affected.
Ethnicity Jewish > non-Jewish white > African American >
In twin studies, 38–58% of monozygotic twins are concordant for CD
Hispanic > Asian and 6–18% are concordant for UC, whereas 4% of dizygotic twins are
Female/male ratio 0.51–1.58 0.34–1.65 concordant for CD and 0–2% are concordant for UC in Swedish and
Danish cohorts. The risks of developing IBD are higher in first-degree
Smoking May prevent disease May cause disease
(odds ratio 0.58) (odds ratio 1.76) relatives of Jewish versus non-Jewish patients: 7.8% versus 5.2% for CD
Oral contraceptives No increased risk Hazard ratio 2.82
and 4.5% versus 1.6% for UC.
Appendectomy Protective (risk reduction Not protective
13–26%)
GLOBAL CONSIDERATIONS: IBD
Monozygotic twins 6–18% concordance 38–58% concordance
PHENOTYPES
There are racial differences in IBD location and behavior that
Dizygotic twins 0–2% concordance 4% concordance
may reflect underlying genetic variations and have important
Antibiotic use in the first 2.9× the risk of developing childhood IBD
implications for diagnosis and management of disease. African
year of life Americans and Hispanics tend to have an ileocolonic CD distribution.
Abbreviation: IBD, inflammatory bowel disease. Data from East Asia have observed that ileocolonic CD is the most

2259
Genetic susceptibility
TLR4
XBP1 IL23R, IL12B, JAK2, STAT3, CCR6,
DLG5 NOD2, TLR4, CARD9, IRF5,
XBP1 ATG16L1, IRGM, LRRK2
ECM1
NOD2 TNFSF15, TNFRSF6B
ITLN1
ATG16L1 TNFAIP3, PTPN2/22
SLC22A5
DMBT1 NLRP3, IL18RAP
PTGER4 ICOSL, ARPC2, STAT3, IL10
Microbial flora IEC Immune dysregulation
Enteropathogens
Antibiotics
Diet, hygiene NSAIDs, smoking
Stress
CHAPTER 319 Inflammatory Bowel Disease

Diet, hygiene
Environmental factors
FIGURE 319-1 Pathogenesis of inflammatory bowel disease (IBD). In IBD, the tridirectional relationship between the commensal flora (microbiota), intestinal epithelial
cells (IECs), and mucosal immune system is dysregulated, leading to chronic inflammation. Each of these three factors is affected by genetic and environmental factors
that determine risk for the disease. NSAIDs, nonsteroidal anti-inflammatory drugs. (Adapted from A Kaser et al: Annu Rev Immunol 28:573, 2010.)
common CD phenotype (50.5–71%) and perianal disease is more com- prevalence of IBD in African Americans, and in Asians with IBD out-
mon in East Asian patients (30.3–58.8%) than Caucasians (25.1–29.6%). side Asia. These ethnic variations implicate the importance of different
Pancolonic disease is more common than left-sided colitis or proctitis genetic and/or environmental factors in the pathogenesis of this
among African Americans, Hispanics, and Asian patients with UC. disorder.
Older Asian patients with UC (age >60) tend to have a more aggressive
disease course. Among African Americans, joint involvement is the ETIOLOGY AND PATHOGENESIS
predominant extra intestinal manifestation (EIM) reported and ranges Under physiologic conditions, homeostasis normally exists between
from 15.7 to 29.6%. Ocular involvement is also common in African the commensal microbiota, epithelial cells that line the interior of the
Americans and ranges from 7.1 to 13%. Dermatologic manifestations intestines (intestinal epithelial cells [IECs]) and immune cells within
are the most common EIM reported in Hispanics (10–13%). There are the tissues (Fig. 319-1). A consensus hypothesis is that each of these
few data on all aspects of disease in Hispanics, on the incidence and three major host compartments that function together as an integrated
“supraorganism” (microbiota, IECs, and immune cells) are affected by
Monogenic Oligogenic Polygenic specific environmental (e.g., smoking, antibiotics, enteropathogens)
and genetic factors that, in a susceptible host, cumulatively and inter-
Environment actively disrupt homeostasis during the course of one’s life, which in
Undiagnosed
infections?
so doing culminates in a chronic state of dysregulated inflammation;

Early onset
that is IBD. Although chronic activation of the mucosal immune system

may represent an appropriate response to an infectious agent, a search
for such an agent has thus far been unrewarding in IBD. As such, IBD is
currently considered an inappropriate immune response to the endoge-
Genetics
nous (autochthonous) commensal microbiota within the intestines,
with or without some component of autoimmunity. Importantly, the
Familial Sporadic normal, uninflamed intestines contain a large number of immune cells
(10%)
that are in a unique state of activation, in which the gut is restrained
FIGURE 319-2 A model for the syndromic nature of inflammatory bowel disease. from full immunologic responses to the commensal microbiota and
Genetic and environmental factors variably influence the development and dietary antigens by very powerful regulatory pathways that function
phenotypic manifestations of IBD. At the one extreme, IBD is exemplified as a
within the immune system (e.g., T-regulatory cells that express the
simple Mendelian disorder as observed in “early-onset IBD” due to single gene
defects such as IL10, IL10RA, and IL10RB; and at the other extreme, it may be FoxP3 transcription factor and suppress inflammation). During the
exemplified by as yet to be described emerging infectious diseases. (Adapted course of infections or other environmental stimuli in the normal host,
from A Kaser et al: Dig Dis 28:395, 2010.) full activation of the lymphoid tissues in the intestines occurs but is

2260 rapidly superseded by dampening of the immune response and tissue TABLE 319-2 Primary Genetic Disorders Associated with IBD
repair. In IBD such processes may not be regulated normally. NAME GENETIC ASSOCIATION PHENOTYPE
Turner’s syndrome Loss of part or all of XAssociated with UC and
GENETIC CONSIDERATIONS chromosome colonic CD
The genetic underpinning of IBD is known from its occurrence in
Hermansky-Pudlak Autosomal recessive Granulomatous colitis,
the context of several genetic syndromes and the development of chromosome 10q23 oculocutaneous
severe, refractory IBD in early life in the setting of single gene albinism, platelet
defects that affect the immune system (Table 319-2). These include dysfunction, pulmonary
mutations in genes encoding, for example, interleukin-10 (IL-10), the fibrosis
IL-10 receptor (IL-10R), cytotoxic T-lymphocyte associated protein-4 Wiskott-Aldrich syndrome X-linked recessive Colitis,
(CTLA4), neutrophil cytosolic factor 2 protein (NCF2), X-linked inhibi- (WAS) disorder, loss of WAS immunodeficiency,
tor of apoptosis protein (XIAP), lipopolysaccharide responsive and protein function severely dysfunctional
beige-like anchor protein (LRBA), or tetratricopeptide repeat domain platelets, and
thrombocytopenia
7A protein (TTC7), among many other genes that are involved in
Glycogen storage Deficiency of the Granulomatous colitis,
host-commensal interactions. In addition, IBD has a familial origin in at
disease glucose-6-phosphate presents in infancy with
least 10% of afflicted individuals (Fig. 319-2). In the majority of transport protein type hypoglycemia, growth
patients, IBD is considered to be a polygenic disorder that gives rise to B1 failure, hepatomegaly,
multiple clinical subgroups within UC and CD. A variety of genetic and neutropenia
approaches including candidate gene studies, linkage analysis, and Immune dysregulation Loss of FoxP3 UC-like autoimmune
genome-wide association studies (GWAS) that focus on the identification polyendocrinopathy, transcription factor and enteropathy, with
of disease-associated, single-nucleotide polymorphisms (SNPs) within enteropathy X-linked T regulatory cell function endocrinopathy
the human genome and, more recently, whole-genome sequencing have (IPEX) (neonatal type 1
diabetes or thyroiditis),
elucidated many of the genetic factors that affect risk for these diseases. dermatitis
GWAS have, to date, identified ~200 genetic loci with two-thirds of these
Early-onset IBD Deficient IL-10 and IL-10 Severe, refractory IBD in
loci observed to be associated with both disease phenotypes with the receptor function early life
remainder being specific for either CD or UC (Table 319-3). These
Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; IL,
genetic similarities account for the overlapping immunopathogenesis interleukin; UC, ulcerative colitis.
and consequently epidemiologic observations of both diseases in the
same families and similarities in response to therapies. Because the
PART 10
specific causal variants for each identified gene or locus are mostly risk factors associated with CD and UC that are observed are shared at
unknown as most risk loci are contained with regulatory regions of the structural or functional levels. The risk conferred by each identified
associated genes, it is not clear whether the similarities in the genetic gene or locus is unequal and generally small, such that only ~20% of
TABLE 319-3 Some Genetic Loci Associated with Crohn’s Disease and/or Ulcerative Colitis
CHROMOSOME PUTATIVE GENE GENE NAME PROTEIN FUNCTION CD UC
Unfolded Protein Response, Autophagy and Metabolism
2q37 ATG16L1 ATG16 autophagy related 16-like 1 Autophagy +
5q31 SLC22A5 Solute carrier family 22, member 5 β carnitine transporter +
5q33 IRGM Immunity-related GTPase family, M Autophagy +
7p21 AGR2 Anterior gradient 2 Unfolded protein response + +
12q12 LRRK2 Leucine-rich repeat kinase 2 Autophagy +
13q14 C13orf1 FAMIN/ LACC1 Immunometabolic regulator +
17q21 ORMDL3 Orosomucoid related member 1-like 3 Unfolded protein response and lipid synthesis + +
22q12 XBP1 X-box binding protein 1 Unfolded protein response + +
Innate Immunity
1q23 ITLN1 Intelectin 1 Bacterial binding +
16q12 NOD2 Nucleotide-binding oligomerization domain Bacterial sensing and autophagy activation +
containing 2
Adaptive Immunity
1p31 IL23R Interleukin 23 receptor Th17 cell stimulation + +
1q32 IL10 Interleukin 10 Treg-associated cytokine +
5q33 IL12B Interleukin 12B IL-12 p40 chain of IL-12/IL-23 + +
18p11 PTPN2 Protein tyrosine phosphatase, nonreceptor T cell regulation +
type 2
Inflammation
3p21 MST1 Macrophage stimulating 1 Macrophage activation + +
5p13 PTGER4 Prostaglandin E receptor 4 PGE2 receptor + +
6q23 TNFAIP3 Tumor necrosis factor, alpha-induced Toll-like receptor regulation +
protein 3 (A20)
6q27 CCR6 Chemokine (C-C motif) receptor 6 Dendritic cell migration +
9p24 JAK2 Janus kinase 2 IL-6R and IL-23R signaling + +
17q21 STAT3 Signal transducer and activator of IL-6R, IL-23R, and IL-10R signaling + +
transcription 3
Abbreviations: CD, Crohn’s disease; GTPase, guanosine triphosphatase; IL, interleukin; PGE2, prostaglandin E2; UC, ulcerative colitis.
Source: Adapted from A Kaser et al: Ann Rev Immunol 28:573, 2010; B Khor et al: Nature 474:307, 2011; and L Jostins et al: Nature 491:119, 2012.

the genetic variance is considered to be explained by the current to fecal diversion, demonstrating the ability of luminal contents to 2261
genetic information. Further, many of the genetic risk factors identified exacerbate disease.
are also observed to be associated with risk for other immune-mediated
diseases, suggesting that related immunogenetic pathways are involved ■■DEFECTIVE IMMUNE REGULATION IN IBD
in the pathogenesis of multiple different disorders accounting for the The mucosal immune system does not normally elicit an inflammatory
common responsiveness to similar types of biologic therapies (e.g., immune response to luminal contents due to oral (mucosal) tolerance.
anti–tumor necrosis factor [TNF] therapies) and possibly the simulta- Administration of soluble antigens orally, rather than subcutaneously or
neous occurrence of these disorders. The diseases and the genetic risk intramuscularly, leads to antigen-specific control of the response and the
factors that are shared with IBD include rheumatoid arthritis (TNFAIP3), host’s ability to tolerate the antigen. Multiple mechanisms are involved
psoriasis (IL23R, IL12B), ankylosing spondylitis (IL23R), type 1 diabetes in the induction of oral tolerance and include deletion or anergy of
mellitus (IL10, PTPN2), asthma (ORMDL3), and systemic lupus erythe- antigen-reactive T cells or induction of CD4+ T cells that suppress gut
matosus (TNFAIP3, IL10) among others. inflammation (e.g., T-regulatory cells expressing the FoxP3 transcription
The genetic factors defined to date that are recognized to mediate factor) that secrete anti-inflammatory cytokines such as IL-10, IL-35, and
risk for IBD have highlighted the importance of several common transforming growth factor β (TGF-β). Oral tolerance may be responsi-
mechanisms of disease (Table 319-3). These include the following: ble for the lack of immune responsiveness to dietary antigens and the
those genes that are associated with fundamental cell biologic pro- commensal microbiota in the intestinal lumen. In IBD this suppression of
cesses such as endoplasmic reticulum (ER) and metabolic stress inflammation is altered, leading to uncontrolled inflammation. The mech-
(e.g., XBP1, ORMDL3, OCTN), which serve to regulate the secretory anisms of this regulated immune suppression are incompletely known.
activity of cells involved in responses to the commensal microbiota Gene knockout (–/–) or transgenic (Tg) mouse models of IBD, which
such as Paneth and goblet cells and the manner in which intestinal include those that are directed at genes demonstrated to be associated
cells respond to the metabolic products of bacteria; those associated with risk for the human disease, have revealed that deleting specific
with innate immunity and autophagy (e.g., NOD2, ATG16L1, IRGM, cytokines (e.g., IL-2, IL-10, TGF-β) or their receptors, deleting mole-
JAK2, STAT3, C13orf31) that function in innate immune cells (both cules associated with T-cell antigen recognition (e.g., T-cell antigen
parenchymal and hematopoietic) to respond to and effectively clear receptors), or interfering with IEC barrier function and the regulation
bacteria, mycobacteria, and viruses; those that are associated with the of responses to commensal bacteria (e.g., XBP1, mucus glycoproteins,
regulation of adaptive immunity (e.g., IL23R, IL12B, IL10, PTPN2), or nuclear factor-κB [NF-κB]) leads to spontaneous colitis or enteritis.
which regulate the balance between inflammatory and anti-inflam- In the majority of circumstances, intestinal inflammation in these
matory (regulatory) cytokines; and, finally, those that are involved in animal models requires the presence of the commensal microbiota.

the development and resolution of inflammation (e.g., MST1, CCR6, However, in some cases, activation of certain elements of the intes-
TNFAIP3, PTGER4) and ultimately leukocyte recruitment and inflam- tinal immune system may be exacerbated by the absence of bacteria
matory mediator production. Some of these loci are associated with resulting in severe colitis emphasizing the presence of protective
specific subtypes of disease such as the association between NOD2 properties that are also contained within the commensal microbiota.
polymorphisms and fibrostenosing CD or ATG16L1 and fistulizing Thus, a variety of specific alterations in either the microbiota or host
disease, especially within the ileum. However, the clinical utility of can lead to uncontrolled immune activation and inflammation directed
these genetic risk factors for the diagnosis or determination of prog- at the intestines in mice. How these relate to human IBD remains to be
nosis and therapeutic responses remains to be defined. defined, but they are consistent with inappropriate responses of the
genetically susceptible host to the commensal microbiota.
■■COMMENSAL MICROBIOTA AND IBD
The endogenous commensal microbiota within the intestines plays a ■■THE INFLAMMATORY CASCADE IN IBD
central role in the pathogenesis of IBD. Humans are born sterile and In both UC and CD, inflammation thus likely emerges from the genetic
acquire their commensal microbiota initially from the mother during predisposition of the host in the context of yet-to-be defined environ-
egress through the birth canal and subsequently from environmental mental factors. Once initiated in IBD by abnormal innate immune sens-
sources. A stable configuration of up to 1000 species of bacteria that ing of bacteria by parenchymal cells (e.g., IECs) and hematopoietic cells
achieves a biomass of ~1012 colony-forming units per gram of feces is (e.g., dendritic cells), the immune inflammatory response is perpetuated
achieved by 3 years of age, which likely persists into adult life, with by T-cell activation when coupled together with inadequate regulatory
each individual human possessing a unique combination of species. pathways. A sequential cascade of inflammatory mediators extends the
In addition, the intestines contain other microbial life forms including response making each step a potential target for therapy. Inflammatory
archae, viruses, and protists. The microbiota is thus considered as a cytokines from innate immune cells such as IL-1, IL-6, and TNF have
critical and sustaining component of the human organism. The estab- diverse effects on tissues. They promote fibrogenesis, collagen produc-
lishment and maintenance of the intestinal microbiota composition tion, activation of tissue metalloproteinases, and the production of other
and function is under the control of host (e.g., immune and epithelial inflammatory mediators; they also activate the coagulation cascade in
responses), environmental (e.g., diet and antibiotics), and likely genetic local blood vessels (e.g., increased production of von Willebrand’s fac-
(e.g., NOD2) factors (Fig. 319-1). In turn, the microbiota, through its tor). These cytokines are normally produced in response to infection but
structural components and metabolic activity, has major influences on are usually turned off or inhibited at the appropriate time to limit tissue
the epithelial and immune function of the host, which, through epige- damage. In IBD their activity is not regulated, resulting in an imbalance
netic effects, may have durable consequences. During early life when between the pro-inflammatory and anti-inflammatory mediators. Some
the commensal microbiota is being established, these microbial effects cytokines activate other inflammatory cells (macrophages and B cells),
on the host may be particularly important in determining later life risk and others act indirectly to recruit other lymphocytes, inflammatory
for IBD. Specific components of the microbiota can promote or protect leukocytes, and mononuclear cells from the bloodstream into the gut
from disease. The commensal microbiota in patients with both UC and through interactions between homing receptors on leukocytes (e.g., α4β7
CD is demonstrably different from nonafflicted individuals, a state integrin) and addressins on vascular endothelium (e.g., MadCAM1).
of dysbiosis, suggesting the presence of microorganisms that drive CD4+ T-helper (TH) cells that promote inflammation are of three major
disease (e.g., Proteobacteria such as enteroinvasive and adherent Esch- types, all of which may be associated with colitis in animal models and
erichia coli) and to which the immune response is directed and/or the perhaps humans: TH1 cells (secrete interferon [IFN] γ), TH2 cells (secrete
loss of microorganisms that hinder inflammation (e.g., Firmicutes such IL-4, IL-5, IL-13), and TH17 cells (secrete IL-17, IL-21). TH17 cells may
as Faecalibacterium prausnitzii). Many of the changes in the commensal however also provide protective functions. Innate immune-like cells that
microbiota occur as a consequence of the inflammation. In addition, lack T-cell receptors are also present in intestines, polarize to the same
agents that alter the intestinal microbiota such as metronidazole, cipro- functional fates and may similarly participate in IBD. TH1 cells induce
floxacin, and elemental diets, may improve CD. CD may also respond transmural granulomatous inflammation that resembles CD; TH2 cells,

2262 and related natural killer T cells that secrete IL-4, IL-5, and IL-13, induce
superficial mucosal inflammation resembling UC in animal models; and
TH17 cells may be responsible for neutrophilic recruitment. However,
neutralization of the cytokines produced by these cells, such as IFN-γ
or IL-17, has yet to show efficacy in therapeutic trials. Each of these
T-cell subsets cross-regulate each other. The TH1 cytokine pathway is
initiated by IL-12, a key cytokine in the pathogenesis of experimental
models of mucosal inflammation. IL-4 and IL-23, together with IL-6
and TGF-β, induce TH2 and TH17 cells, respectively, and IL-23 inhibits
the suppressive function of regulatory T cells. Activated macrophages
secrete TNF and IL-6.
These characteristics of the immune response in IBD explain the
beneficial therapeutic effects of antibodies to block pro-inflammatory
cytokines or the signaling by their receptors (e.g., anti-TNF, anti-IL-12,
anti-IL-23, anti-IL-6, or Janus kinase [JAK] inhibitors) or molecules
associated with leukocyte recruitment (e.g., anti-α4β7). They also
highlight the potential usefulness of cytokines that inhibit inflamma-
tion and promote regulatory T cells or promote intestinal barrier (e.g.,
IL-10) in the treatment of IBD. Therapies such as the 5-aminosalicylic
FIGURE 319-4 Medium-power view of colonic mucosa in ulcerative colitis
acid (5-ASA) compounds and glucocorticoids are also potent inhibitors
showing diffuse mixed inflammation, basal lymphoplasmacytosis, crypt atrophy
of these inflammatory mediators through inhibition of transcription and irregularity, and superficial erosion. These features are typical of chronic
factors such as NF-κB that regulate their expression. active ulcerative colitis. (Courtesy of Dr. R. Odze, Division of Gastrointestinal
Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston,
PATHOLOGY Massachusetts; with permission.)
■■ULCERATIVE COLITIS: MACROSCOPIC FEATURES long-standing disease, inflammatory polyps (pseudopolyps) may be
UC is a mucosal disease that usually involves the rectum and extends
present as a result of epithelial regeneration. The mucosa may appear
proximally to involve all or part of the colon. About 40–50% of patients
normal in remission, but in patients with many years of disease it
have disease limited to the rectum and rectosigmoid, 30–40% have
appears atrophic and featureless, and the entire colon becomes nar-
disease extending beyond the sigmoid but not involving the whole
PART 10
rowed and shortened. Patients with fulminant disease can develop a

colon, and 20% have a total colitis. Proximal spread occurs in conti-
toxic colitis or megacolon where the bowel wall thins and the mucosa
nuity without areas of uninvolved mucosa. When the whole colon is
is severely ulcerated; this may lead to perforation.
involved, the inflammation extends 2–3 cm into the terminal ileum in
10–20% of patients. The endoscopic changes of backwash ileitis are super- ■■ULCERATIVE COLITIS: MICROSCOPIC FEATURES
ficial and mild and are of little clinical significance. Although variations Histologic findings correlate well with the endoscopic appearance and
in macroscopic activity may suggest skip areas, biopsies from normal- clinical course of UC. The process is limited to the mucosa and super-
appearing mucosa are usually abnormal. Thus, it is important to obtain ficial submucosa, with deeper layers unaffected except in fulminant
multiple biopsies from apparently uninvolved mucosa, whether prox- disease. In UC, two major histologic features suggest chronicity and
imal or distal, during endoscopy. One caveat is that effective medical
help distinguish it from infectious or acute self-limited colitis. First,
therapy can change the appearance of the mucosa such that either skip
the crypt architecture of the colon is distorted; crypts may be bifid and
areas or the entire colon can be microscopically normal.
reduced in number, often with a gap between the crypt bases and the
With mild inflammation, the mucosa is erythematous and has a fine
muscularis mucosae. Second, some patients have basal plasma cells
granular surface that resembles sandpaper. In more severe disease,
and multiple basal lymphoid aggregates. Mucosal vascular congestion,
the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 319-3). In
with edema and focal hemorrhage, and an inflammatory cell infiltrate
of neutrophils, lymphocytes, plasma cells, and macrophages may be
present. The neutrophils invade the epithelium, usually in the crypts,
giving rise to cryptitis and, ultimately, to crypt abscesses (Fig. 319-4).
Ileal changes in patients with backwash ileitis include villous atro-
phy and crypt regeneration with increased inflammation, increased
neutrophil and mononuclear inflammation in the lamina propria, and
patchy cryptitis and crypt abscesses.
■■CROHN’S DISEASE: MACROSCOPIC FEATURES

CD can affect any part of the gastrointestinal (GI) tract from the mouth
to the anus. Some 30–40% of patients have small bowel disease alone,
40–55% have disease involving both the small and large intestines, and
15–25% have colitis alone. In the 75% of patients with small intestinal
disease, the terminal ileum is involved in 90%. Unlike UC, which
almost always involves the rectum, the rectum is often spared in CD.
CD is segmental with skip areas in the midst of diseased intestine
(Fig. 319-5). Perirectal fistulas, fissures, abscesses, and anal stenosis
are present in one-third of patients with CD, particularly those with
colonic involvement. Rarely, CD may also involve the liver and the
pancreas.
FIGURE 319-3 Ulcerative colitis. Diffuse (nonsegmental) mucosal disease, with
broad areas of ulceration. The bowel wall is not thickened, and there is no Unlike UC, CD is a transmural process. Endoscopically, aphthous or
cobblestoning. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology, small superficial ulcerations characterize mild disease; in more active dis-
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; ease, stellate ulcerations fuse longitudinally and transversely to demar-
with permission.) cate islands of mucosa that frequently are histologically normal. This

accompanied by fissures that penetrate deeply into the bowel wall and 2263
sometimes form fistulous tracts or local abscesses.
CLINICAL PRESENTATION
■■ULCERATIVE COLITIS
Signs and Symptoms The major symptoms of UC are diarrhea,
rectal bleeding, tenesmus, passage of mucus, and crampy abdominal
pain. The severity of symptoms correlates with the extent of disease.
Although UC can present acutely, symptoms usually have been pres-
ent for weeks to months. Occasionally, diarrhea and bleeding are so
intermittent and mild that the patient does not seek medical attention.
Patients with proctitis usually pass fresh blood or blood-stained
mucus, either mixed with stool or streaked onto the surface of a normal
or hard stool. They also have tenesmus, or urgency with a feeling of
incomplete evacuation, but rarely have abdominal pain. With proctitis
or proctosigmoiditis, proximal transit slows, which may account for the
constipation commonly seen in patients with distal disease.
FIGURE 319-5 Crohn’s disease of the colon showing thickening of the wall, with When the disease extends beyond the rectum, blood is usually mixed
stenosis, linear serpiginous ulcers and cobblestoning of the mucosa. (Courtesy with stool or grossly bloody diarrhea may be noted. Colonic motility is
of Dr. R Odze, Division of Gastrointestinal Pathology, Department of Pathology, altered by inflammation with rapid transit through the inflamed intestine.
Brigham and Women’s Hospital, Boston, Massachusetts; with permission.) When the disease is severe, patients pass a liquid stool containing blood,
pus, and fecal matter. Diarrhea is often nocturnal and/or postprandial.
Although severe pain is not a prominent symptom, some patients with
“cobblestone” appearance is characteristic of CD, both endoscopically active disease may experience lower abdominal discomfort or mild cen-
and by barium radiography. As in UC, pseudopolyps can form in CD. tral abdominal cramping. Severe cramping and abdominal pain can occur
Active CD is characterized by focal inflammation and formation of with severe attacks of the disease. Other symptoms in moderate to severe
fistula tracts, which resolve by fibrosis and stricturing of the bowel. disease include anorexia, nausea, vomiting, fever, and weight loss.

The bowel wall thickens and becomes narrowed and fibrotic, leading to Physical signs of proctitis include a tender anal canal and blood
chronic, recurrent bowel obstructions. Projections of thickened mesen- on rectal examination. With more extensive disease, patients have
tery encase the bowel (“creeping fat”), and serosal and mesenteric tenderness to palpation directly over the colon. Patients with a toxic
inflammation promotes adhesions and fistula formation. colitis have severe pain and bleeding, and those with megacolon have
hepatic tympany. Both may have signs of peritonitis if a perforation has
■■CROHN’S DISEASE: MICROSCOPIC FEATURES occurred. The classification of disease activity is shown in Table 319-4.
The earliest lesions are aphthoid ulcerations and focal crypt abscesses
with loose aggregations of macrophages, which form noncaseating Laboratory, Endoscopic, and Radiographic Features
granulomas in all layers of the bowel wall (Fig. 319-6). Granulomas can Active disease can be associated with a rise in acute-phase reactants
be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. (C-reactive protein [CRP]), platelet count, and erythrocyte sedimen-
Granulomas are a characteristic feature of CD. They are less commonly tation rate (ESR), and a decrease in hemoglobin. Fecal lactoferrin, a
found on mucosal biopsies than on surgical resection specimens. glycoprotein present in activated neutrophils, is a highly sensitive and
Other histologic features of CD include submucosal or subserosal specific marker for detecting intestinal inflammation. Fecal calprotec-
lymphoid aggregates, particularly away from areas of ulceration, tin is present in neutrophils and monocytes and levels correlate well
gross and microscopic skip areas, and transmural inflammation that is with histologic inflammation, predict relapses, and detect pouchitis.
Both fecal lactoferrin and calprotectin are becoming an integral part
of IBD management and are used frequently to rule out active inflam-
mation versus symptoms of irritable bowel or bacterial overgrowth. In
severely ill patients, the serum albumin level will fall rather quickly.
Leukocytosis may be present but is not a specific indicator of disease
TABLE 319-4 Ulcerative Colitis: Disease Presentation

MILD MODERATE SEVERE
Bowel <4 per day 4–6 per day >6 per day
movements
Blood in stool Small Moderate Severe
Fever None <37.5°C mean >37.5°C mean
(<99.5°F) (>99.5°F)
Tachycardia None <90 mean pulse >90 mean pulse
Anemia Mild >75% of a normal ≤75% of a normal
hemoglobin hemoglobin
Sedimentation <30 mm >30 mm
rate
Endoscopic Erythema, Marked erythema, Spontaneous
appearance decreased coarse granularity, bleeding, ulcerations
FIGURE 319-6 Medium-power view of Crohn’s colitis showing mixed acute and vascular absent vascular
chronic inflammation, crypt atrophy, and multiple small epithelioid granulomas pattern, fine markings, contact
in the mucosa. (Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology, granularity bleeding, no
Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; ulcerations
with permission.)

2264 penetrating fistulous pattern, each with different treatments and prog-
noses. The site of disease influences the clinical manifestations.
ILEOCOLITIS Because the most common site of inflammation is the
terminal ileum, the usual presentation of ileocolitis is a chronic his-
tory of recurrent episodes of right lower quadrant pain and diarrhea.
Sometimes the initial presentation mimics acute appendicitis with
pronounced right lower quadrant pain, a palpable mass, fever, and
leukocytosis. Pain is usually colicky; it precedes and is relieved by defe-
cation. A low-grade fever is usually noted. High-spiking fever suggests
intraabdominal abscess formation. Weight loss is common—typically
10–20% of body weight—and develops as a consequence of diarrhea,
anorexia, and fear of eating.
An inflammatory mass may be palpated in the right lower quadrant
of the abdomen. The mass is composed of inflamed bowel, induration
of the mesentery, and enlarged abdominal lymph nodes. Extension of
the mass can cause obstruction of the right ureter or bladder inflam-
mation, manifested by dysuria and fever. The ‘’string sign’’ on barium
studies results from a severely narrowed loop of bowel, which makes
the lumen resemble a frayed cotton string. It is caused by incomplete
FIGURE 319-7 Colonoscopy with acute ulcerative colitis: severe colon filling of the lumen as the result of edema, irritability, and spasms asso-
inflammation with erythema, friability, and exudates. (Courtesy of Dr. M. Hamilton, ciated with inflammation and ulcerations. The sign may be seen in both
Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, nonstenotic and stenotic phases of the disease.
Boston, Massachusetts; with permission.) Bowel obstruction may take several forms. In the early stages of
disease, bowel wall edema and spasm produce intermittent obstruc-
tive manifestations and increasing symptoms of postprandial pain.
activity. Proctitis or proctosigmoiditis rarely causes a rise in CRP. Over several years, persistent inflammation gradually progresses to
Diagnosis relies on the patient’s history; clinical symptoms; negative fibrostenotic narrowing and stricture. Diarrhea will decrease and be
stool examination for bacteria, C. difficile toxin, and ova and parasites; replaced by chronic bowel obstruction. Acute episodes of obstruction
sigmoidoscopic appearance (see Fig. 315-4A); and histology of rectal or occur as well, precipitated by bowel inflammation and spasm or some-
PART 10
colonic biopsy specimens. times by impaction of undigested food or medication. These episodes
Sigmoidoscopy is used to assess disease activity and is usually usually resolve with intravenous fluids and gastric decompression.
performed before treatment. If the patient is not having an acute flare, Severe inflammation of the ileocecal region may lead to localized
colonoscopy is used to assess disease extent and activity (Fig. 319-7). wall thinning, with microperforation and fistula formation to the
Endoscopically mild disease is characterized by erythema, decreased adjacent bowel, the skin, or the urinary bladder, or to an abscess cavity
vascular pattern, and mild friability. Moderate disease is characterized in the mesentery. Enterovesical fistulas typically present as dysuria
by marked erythema, absent vascular pattern, friability and erosions, or recurrent bladder infections or, less commonly, as pneumaturia or
and severe disease by spontaneous bleeding and ulcerations. Histo- fecaluria. Enterocutaneous fistulas follow tissue planes of least resis-
logic features change more slowly than clinical features but can also be tance, usually draining through abdominal surgical scars. Enterovagi-
used to grade disease activity. nal fistulas are rare and present as dyspareunia or as a feculent or
foul-smelling, often painful vaginal discharge. They are unlikely to
Complications Only 15% of patients with UC present initially
develop without a prior hysterectomy.
with catastrophic illness. Massive hemorrhage occurs with severe
attacks of disease in 1% of patients, and treatment for the disease JEJUNOILEITIS Extensive inflammatory disease is associated with a
usually stops the bleeding. However, if a patient requires 6–8 units loss of digestive and absorptive surface, resulting in malabsorption
of blood within 24–48 h, colectomy is indicated. Toxic megacolon is and steatorrhea. Nutritional deficiencies can also result from poor
defined as a transverse or right colon with a diameter of >6 cm, with intake and enteric losses of protein and other nutrients. Intestinal
loss of haustration in patients with severe attacks of UC. It occurs in malabsorption can cause anemia, hypoalbuminemia, hypocalcemia,
about 5% of attacks and can be triggered by electrolyte abnormalities hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithia-
and narcotics. About 50% of acute dilations will resolve with medical sis in patients with an intact colon. Many patients need to take oral and
therapy alone, but urgent colectomy is required for those that do not often intravenous iron. Vertebral fractures are caused by a combination
improve. Perforation is the most dangerous of the local complications, of vitamin D deficiency, hypocalcemia, and prolonged glucocorticoid
and the physical signs of peritonitis may not be obvious, especially if use. Pellagra from niacin deficiency can occur in extensive small-bowel
the patient is receiving glucocorticoids. Although perforation is rare, disease, and malabsorption of vitamin B12 can lead to megaloblastic
the mortality rate for perforation complicating a toxic megacolon is anemia and neurologic symptoms. Other important nutrients to mea-
about 15%. In addition, patients can develop a toxic colitis and such sure and replete if low are folate and vitamins A, E, and K. Levels of
severe ulcerations that the bowel may perforate without first dilating. minerals such as zinc, selenium, copper, and magnesium are often low
Strictures occur in 5–10% of patients and are always a concern in UC in patients with extensive small-bowel inflammation or resections, and
because of the possibility of underlying neoplasia. Although benign these should be repleted as well. Most patients should take a daily
strictures can form from the inflammation and fibrosis of UC, stric- multivitamin, calcium, and vitamin D supplements.
tures that are impassable with the colonoscope should be presumed Diarrhea is characteristic of active disease; its causes include
malignant until proven otherwise. A stricture that prevents passage of (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-
the colonoscope is an indication for surgery. UC patients occasionally acid malabsorption due to a diseased or resected terminal ileum,
develop anal fissures, perianal abscesses, or hemorrhoids, but the and (3) intestinal inflammation with decreased water absorption and
occurrence of extensive perianal lesions should suggest CD. increased secretion of electrolytes.
COLITIS AND PERIANAL DISEASE Patients with colitis present with low-
■■CROHN’S DISEASE
grade fevers, malaise, diarrhea, crampy abdominal pain, and some-
Signs and Symptoms Although CD usually presents as acute or times hematochezia. Gross bleeding is not as common as in UC and
chronic bowel inflammation, the inflammatory process evolves toward appears in about one-half of patients with exclusively colonic disease.
one of two patterns of disease: a fibrostenotic obstructing pattern or a Only 1–2% exhibit massive bleeding. Pain is caused by passage of fecal

material through narrowed and inflamed segments of the large bowel. 2265
Decreased rectal compliance is another cause for diarrhea in Crohn’s
colitis patients. Toxic megacolon is rare but may be seen with severe
inflammation and short duration disease.
Stricturing can occur in the colon in 4–16% of patients and produce
symptoms of bowel obstruction. If the endoscopist is unable to traverse
a stricture in Crohn’s colitis, surgical resection should be considered,
especially if the patient has symptoms of chronic obstruction. Colonic
disease may fistulize into the stomach or duodenum, causing feculent
vomiting, or to the proximal or mid-small bowel, causing malabsorp-
tion by “short circuiting” and bacterial overgrowth. Ten percent of
women with Crohn’s colitis will develop a rectovaginal fistula.
Perianal disease affects about one-third of patients with Crohn’s
colitis and is manifested by incontinence, large hemorrhoidal tags,
anal strictures, anorectal fistulae, and perirectal abscesses. Not all
patients with perianal fistula will have endoscopic evidence of colonic
inflammation.
GASTRODUODENAL DISEASE Symptoms and signs of upper GI tract
disease include nausea, vomiting, and epigastric pain. Patients usually
have an Helicobacter pylori–negative gastritis. The second portion of the
duodenum is more commonly involved than the bulb. Fistulas involv-
ing the stomach or duodenum arise from the small or large bowel and
do not necessarily signify the presence of upper GI tract involvement.
Patients with advanced gastroduodenal CD may develop a chronic
gastric outlet obstruction. About 30% of children diagnosed with CD FIGURE 319-8 Wireless capsule endoscopy image in a patient with Crohn’s
have esophagogastroduodenal involvement. disease of the ileum shows ulcerations and narrowing of the intestinal lumen.
(Courtesy of Dr. S. Reddy, Gastroenterology Division, Department of Medicine,
Laboratory, Endoscopic, and Radiographic Features Brigham and Women’s Hospital, Boston, Massachusetts; with permission.)

Laboratory abnormalities include elevated ESR and CRP. In more
severe disease, findings include hypoalbuminemia, anemia, and leu-
kocytosis. Fecal calprotectin and lactoferrin levels have been used to accurate in the identification of active small-bowel inflammation, CTE
distinguish IBD from irritable bowel syndrome (IBS), assess whether and MRE have been shown to be superior to SBFT in the detection
CD is active, and to detect postoperative recurrence of CD. of extraluminal complications, including fistulas, sinus tracts, and
Endoscopic features of CD include rectal sparing, aphthous ulcera- abscesses. MRI is thought to offer superior soft tissue contrast and has
tions, fistulas, and skip lesions. Colonoscopy allows examination and the added advantage of avoiding radiation exposure changes (Figs. 319-9
biopsy of mass lesions or strictures and biopsy of the terminal ileum. and 319-10). The lack of ionizing radiation is particularly appealing in
Upper endoscopy is useful in diagnosing gastroduodenal involvement younger patients and when monitoring response to therapy where serial
in patients with upper tract symptoms. Ileal or colonic strictures may images will be obtained. Ultrasound is becoming increasingly more pop-
be dilated with balloons introduced through the colonoscope. Stric- ular, especially in Europe, for measuring CD extent and activity. Pelvic
tures ≤4 cm in length and those at anastomotic sites respond better MRI is superior to CT for demonstrating pelvic lesions such as ischiorec-
to endoscopic dilation. The perforation rate is as high as 10%. Most tal abscesses and perianal fistulae (Fig. 319-11).
endoscopists dilate only fibrotic strictures and not those associated Complications Because CD is a transmural process, serosal adhe-
with active inflammation. Wireless capsule endoscopy (WCE) allows sions develop that provide direct pathways for fistula formation and
direct visualization of the entire small-bowel mucosa (Fig. 319-8). The reduce the incidence of free perforation. Perforation occurs in 1–2%
diagnostic yield of detecting lesions suggestive of active CD is higher of patients, usually in the ileum but occasionally in the jejunum or as
with WCE than CT or magnetic resonance (MR) enterography or small- a complication of toxic megacolon. The peritonitis of free perforation,
bowel series. WCE cannot be used in the setting of a small-bowel stric- especially colonic, may be fatal. Intraabdominal and pelvic abscesses
ture. Capsule retention occurs in <1% of patients with suspected CD, occur in 10–30% of patients with CD at some time in the course of their
but retention rates of 4–6% are seen in patients with established CD. It illness. CT-guided percutaneous drainage of the abscess is standard
is helpful to give the patient with CD a patency capsule, which is made therapy. Despite adequate drainage, most patients need resection of
of barium and starts to dissolve 30 h after ingestion. An abdominal the offending bowel segment. Percutaneous drainage has an especially
x-ray can be taken at around 30 h after ingestion to see if the capsule is high failure rate in abdominal wall abscesses. Systemic glucocorticoid
still present in the small bowel, which would indicate a stricture. therapy increases the risk of intraabdominal and pelvic abscesses in
In CD, early radiographic findings in the small bowel include CD patients who have never had an operation. Other complications
thickened folds and aphthous ulcerations. “Cobblestoning” from include intestinal obstruction in 40%, massive hemorrhage, malabsorp-
longitudinal and transverse ulcerations most frequently involves the tion, and severe perianal disease.
small bowel. In more advanced disease, strictures, fistulas, inflamma-
tory masses, and abscesses may be detected. The earliest macroscopic Serologic Markers Patients with CD show a wide variation in
findings of colonic CD are aphthous ulcers. These small ulcers are often the way they present and progress over time. Some patients present
multiple and separated by normal intervening mucosa. As the disease with mild disease activity and do well with generally safe and mild
progresses, aphthous ulcers become enlarged, deeper, and occasionally medications, but many others exhibit more severe disease and can
connected to one another, forming longitudinal stellate, serpiginous, develop serious complications that will require surgery. Current and
and linear ulcers (see Fig. 315-4B). developing biologic therapies can help halt progression of disease
The transmural inflammation of CD leads to decreased luminal and give patients with moderate to severe CD a better quality of
diameter and limited distensibility. As ulcers progress deeper, they can life. There are potential risks of biologic therapies such as infection
lead to fistula formation. The segmental nature of CD results in wide and malignancy, and it would be optimal to determine by genetic or
gaps of normal or dilated bowel between involved segments. serologic markers at the time of diagnosis which patients will require
Although CT enterography (CTE), MR enterography (MRE), and more aggressive medical therapy. This same argument holds true for
small-bowel follow-through (SBFT) have been shown to be equally UC patients as well.

2266
FIGURE 319-9 A coronal magnetic resonance image was obtained using a half
Fourier single-shot T2-weighted acquisition with fat saturation in a 27-year-
FIGURE 319-10 A coronal balanced, steady-state, free precession, T2-weighted
PART 10
old pregnant (23 weeks’ gestation) woman. The patient had Crohn’s disease
image with fat saturation was obtained in a 32-year-old man with Crohn’s disease
and was maintained on 6-mercaptopurine and prednisone. She presented with
and prior episodes of bowel obstruction, fistulas, and abscesses. He was being
abdominal pain, distension, vomiting, and small-bowel obstruction. The image
treated with 6-mercaptopurine and presented with abdominal distention and
reveals a 7- to 10-cm long stricture at the terminal ileum (white arrows) causing
diarrhea. The image demonstrates a new gastrocolic fistula (solid white arrows).
obstruction and significant dilatation of the proximal small bowel (white asterisk).
Multifocal involvement of the small bowel and terminal ileum is also present
A fetus is seen in the uterus (dashed white arrows). (Courtesy of Drs. J. F. B. Chick
(dashed white arrows). (Courtesy of Drs. J. F. B. Chick and P. B. Shyn, Abdominal

and P. B. Shyn, Abdominal Imaging and Intervention, Department of Radiology,
Imaging and Intervention, Department of Radiology, Brigham and Women’s Hospital,
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts;
Harvard Medical School, Boston, Massachusetts; with permission.)
with permission.)
For success in diagnosing IBD and in differentiating between CD indeterminate colitis. Fortunately, in most cases, the true nature of the
and UC, the efficacy of these serologic tests depends on the prevalence underlying colitis becomes evident later in the course of the patient’s
of IBD in a specific population. Increased titers of anti-Saccharomyces disease. Approximately 5% (range 1–20%) of colon resection specimens
cerevisiae antibodies (ASCAs) have been associated with CD, whereas are difficult to classify as either UC or CD because they exhibit over-
increased levels of perinuclear antineutrophil cytoplasmic antibodies lapping histologic features.
(pANCA) are more commonly seen in patients with UC. However, ■■INFECTIOUS DISEASES
when evaluated in a meta-analysis of 60 studies, the sensitivity and Infections of the small intestines and colon can mimic CD or UC. They
specificity of a ASCA+/pANCA- pattern for identification of CD may be bacterial, fungal, viral, or protozoal in origin (Table 319-6).
was 55% and 93% respectively. In addition to ASCA, multiple other Campylobacter colitis can mimic the endoscopic appearance of severe
antibodies to bacterial proteins (Omp-C and I2), flagellin (CBir1) and UC and can cause a relapse of established UC. Salmonella can cause
bacterial carbohydrates have been studied and associated with CD, watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes
including laminaribioside (ALCA), chitobioside (ACCA) and manno- watery diarrhea, abdominal pain, and fever followed by rectal tene-
bioside (SMCA). These serologic markers tend to have low sensitivity smus and by the passage of blood and mucus per rectum. All three are
and specificity though due to elevation in levels cause by other autoim- usually self-limited, but 1% of patients infected with Salmonella become
mune diseases, infections and inflammation outside the GI tract. asymptomatic carriers. Yersinia enterocolitica infection occurs mainly in
Clinical factors described at diagnosis are more helpful than serolo- the terminal ileum and causes mucosal ulceration, neutrophil invasion,
gies at predicting the natural history of CD. The initial requirements for and thickening of the ileal wall. Other bacterial infections that may
glucocorticoid use, an age at diagnosis below 40 years and the presence mimic IBD include C. difficile, which presents with watery diarrhea,
of perianal disease at diagnosis, have been shown to be independently tenesmus, nausea, and vomiting; and E. coli, three categories of which
associated with subsequent disabling CD after 5 years. Except in spe- can cause colitis. These are enterohemorrhagic, enteroinvasive, and
cial circumstances (such as before consideration of an ileoanal pouch enteroadherent E. coli, all of which can cause bloody diarrhea and
anastomosis [IPAA] in a patient with indeterminate colitis), serologic abdominal tenderness. Diagnosis of bacterial colitis is made by send-
markers have only minimal clinical utility. ing stool specimens for bacterial culture and C. difficile toxin analysis.
Gonorrhea, Chlamydia, and syphilis can also cause proctitis.
DIFFERENTIAL DIAGNOSIS OF UC AND CD GI involvement with mycobacterial infection occurs primarily in
UC and CD have similar features to many other diseases. In the absence the immunosuppressed patient but may occur in patients with normal
of a key diagnostic test, a combination of features is used (Table 319-5). immunity. Distal ileal and cecal involvement predominates, and patients
Once a diagnosis of IBD is made, distinguishing between UC and present with symptoms of small-bowel obstruction and a tender abdom-
CD is impossible initially in up to 15% of cases. These are termed inal mass. The diagnosis is made most directly by colonoscopy with

TABLE 319-6 Diseases That Mimic IBD 2267
Infectious Etiologies
Bacterial Mycobacterial Viral
Salmonella Tuberculosis Cytomegalovirus
Shigella
Mycobacterium Herpes simplex
Toxigenic avium HIV
Escherichia coli Parasitic Fungal
Campylobacter Amebiasis Histoplasmosis
Yersinia Isospora Candida
Clostridium difficile Trichuris trichiura Aspergillus
Gonorrhea Hookworm
Chlamydia trachomatis Strongyloides
Noninfectious Etiologies
Inflammatory Neoplastic Drugs and Chemicals
Appendicitis Lymphoma NSAIDs
Diverticulitis Metastatic Phosphosoda
Diversion colitis Carcinoma Cathartic colon
Collagenous/ Carcinoma of the Gold
lymphocytic colitis ileum Oral contraceptives
Ischemic colitis Carcinoid Cocaine
Radiation colitis/ Familial polyposis Ipilimumab
enteritis
Mycophenolate mofetil
Solitary rectal ulcer
FIGURE 319-11 Axial T2-weighted fat-saturated image obtained in a 39-year-old syndrome
male with Crohn’s disease shows a defect in the internal sphincter at the 6:00 Eosinophilic
position of the mid anal canal (open white arrow) communicating with a 1.1-cm gastroenteritis

intersphincteric collection (black arrow). Wide defect in the external sphincter Neutropenic colitis
at the 7:00 position (solid white arrow) leads to a moderate sized perianal
abscess in the ischioanal fossa (asterisk). (Courtesy of Drs. J.S. Quon and P.B. Behçet’s syndrome
Shyn, Abdominal Imaging and Intervention, Department of Radiology, Brigham Graft-versus-host
and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; with disease
permission.)
Abbreviation: IBD, inflammatory bowel disease; NSAIDs, nonsteroidal
anti-inflammatory drugs.
TABLE 319-5 Different Clinical, Endoscopic, and Radiographic biopsy and culture. Mycobacterium avium-intracellulare complex infection
Features occurs in advanced stages of HIV infection and in other immunocompro-
ULCERATIVE COLITIS CROHN’S DISEASE mised states; it usually manifests as a systemic infection with diarrhea,
Clinical abdominal pain, weight loss, fever, and malabsorption. Diagnosis is
established by acid-fast smear and culture of mucosal biopsies.
Gross blood in stool Yes Occasionally
Although most of the patients with viral colitis are immunosup-
Mucus Yes Occasionally
pressed, cytomegalovirus (CMV) and herpes simplex proctitis may
Systemic symptoms Occasionally Frequently
occur in immunocompetent individuals. CMV occurs most commonly
Pain Occasionally Frequently in the esophagus, colon, and rectum but may also involve the small
Abdominal mass Rarely Yes intestine. Symptoms include abdominal pain, bloody diarrhea, fever,
Significant perineal No Frequently and weight loss. With severe disease, necrosis and perforation can
disease occur. Diagnosis is made by identification of characteristic intranuclear
Fistulas No Yes inclusions in mucosal cells on biopsy. Herpes simplex infection of the
Small intestinal No Frequently GI tract is limited to the oropharynx, anorectum, and perianal areas.
obstruction Symptoms include anorectal pain, tenesmus, constipation, inguinal
Colonic obstruction Rarely Frequently adenopathy, difficulty with urinary voiding, and sacral paresthesias.
Response to antibiotics No Yes Diagnosis is made by rectal biopsy with identification of characteristic
Recurrence after surgery No Yes cellular inclusions and viral culture. HIV itself can cause diarrhea,
Endoscopic nausea, vomiting, and anorexia. Small intestinal biopsies show partial
villous atrophy; small bowel bacterial overgrowth and fat malabsorp-
Rectal sparing Rarely Frequently
tion may also be noted.
Continuous disease Yes Occasionally
Protozoan parasites include Isospora belli, which can cause a self-
“Cobblestoning” No Yes limited infection in healthy hosts but causes a chronic profuse, watery
Granuloma on biopsy No Occasionally diarrhea, and weight loss in AIDS patients. Entamoeba histolytica or
Radiographic related species infect about 10% of the world’s population; symptoms
Small bowel significantly No Yes include abdominal pain, tenesmus, frequent loose stools containing
abnormal blood and mucus, and abdominal tenderness. Colonoscopy reveals
Abnormal terminal ileum No Yes focal punctate ulcers with normal intervening mucosa; diagnosis is
Segmental colitis No Yes made by biopsy or serum amebic antibodies. Fulminant amebic colitis
Asymmetric colitis No Yes is rare but has a mortality rate of >50%.
Stricture Occasionally Frequently Other parasitic infections that may mimic IBD include hookworm
(Necator americanus), whipworm (Trichuris trichiura), and Strongyloides

2268 stercoralis. In severely immunocompromised patients, Candida or Asper- has two main histologic components: increased subepithelial collagen
gillus can be identified in the submucosa. Disseminated histoplasmosis deposition and colitis with increased intraepithelial lymphocytes. The
can involve the ileocecal area. female to male ratio is 9:1, and most patients present in the sixth or
seventh decades of life. The main symptom is chronic watery diarrhea.
■■NONINFECTIOUS DISEASES Treatments range from sulfasalazine or mesalamine and diphenoxy-
Diverticulitis can be confused with CD clinically and radiographically. late/atropine (Lomotil) to bismuth to budesonide to prednisone or
Both diseases cause fever, abdominal pain, tender abdominal mass, azathioprine/6-mercaptopurine for refractory disease. Risk factors
leukocytosis, elevated ESR, partial obstruction, and fistulas. Perianal include smoking, use of NSAIDs, proton pump inhibitors, or beta
disease or ileitis on small-bowel series favors the diagnosis of CD. Sig- blockers; and a history of autoimmune disease.
nificant endoscopic mucosal abnormalities are more likely in CD than Lymphocytic colitis has features similar to collagenous colitis,
in diverticulitis. Endoscopic or clinical recurrence following segmental including age at onset and clinical presentation, but it has almost equal
resection favors CD. Diverticular-associated colitis is similar to CD, but incidence in men and women and no subepithelial collagen deposi-
mucosal abnormalities are limited to the sigmoid and descending colon. tion on pathologic section. However, intraepithelial lymphocytes are
Ischemic colitis is commonly confused with IBD. The ischemic increased. Use of sertraline (but not beta blockers) is an additional
process can be chronic and diffuse, as in UC, or segmental, as in CD. risk factor. The frequency of celiac disease is increased in lymphocytic
Colonic inflammation due to ischemia may resolve quickly or may per- colitis and ranges from 9 to 27%. Celiac disease should be excluded in
sist and result in transmural scarring and stricture formation. Ischemic all patients with lymphocytic colitis, particularly if diarrhea does not
bowel disease should be considered in the elderly following abdominal respond to conventional therapy. Treatment is similar to that of collage-
aortic aneurysm repair or when a patient has a hypercoagulable state nous colitis with the exception of a gluten-free diet for those who have
or a severe cardiac or peripheral vascular disorder. Patients usually celiac disease.
present with sudden onset of left lower quadrant pain, urgency to Diversion colitis is an inflammatory process that arises in segments
defecate, and the passage of bright red blood per rectum. Endoscopic of the large intestine that are excluded from the fecal stream. It usually
examination often demonstrates a normal-appearing rectum and a occurs in patients with ileostomy or colostomy when a mucus fistula or
sharp transition to an area of inflammation in the descending colon a Hartmann’s pouch has been created. Clinically, patients have mucus
and splenic flexure. or bloody discharge from the rectum. Erythema, granularity, friability,
The effects of radiotherapy on the GI tract can be difficult to distin- and, in more severe cases, ulceration can be seen on endoscopy. His-
guish from IBD. Acute symptoms can occur within 1–2 weeks of start- topathology shows areas of active inflammation with foci of cryptitis
ing radiotherapy. When the rectum and sigmoid are irradiated, patients and crypt abscesses. Crypt architecture is normal, which differentiates
develop bloody, mucoid diarrhea and tenesmus, as in distal UC. With it from UC. It may be impossible to distinguish from CD. Short-chain
PART 10
small-bowel involvement, diarrhea is common. Late symptoms include fatty acid enemas may help in diversion colitis, but the definitive
malabsorption and weight loss. Stricturing with obstruction and bacte- therapy is surgical reanastomosis.
rial overgrowth may occur. Fistulas can penetrate the bladder, vagina,
or abdominal wall. Flexible sigmoidoscopy reveals mucosal granu- EXTRAINTESTINAL MANIFESTATIONS
larity, friability, numerous telangiectasias, and occasionally discrete Up to one-third of IBD patients have at least one extraintestinal disease
ulcerations. Biopsy can be diagnostic. manifestation.

Solitary rectal ulcer syndrome is uncommon and can be confused
with IBD. It occurs in persons of all ages and may be caused by ■■DERMATOLOGIC
impaired evacuation and failure of relaxation of the puborectalis Erythema nodosum (EN) occurs in up to 15% of CD patients and
muscle. Single or multiple ulcerations may arise from anal sphincter 10% of UC patients. Attacks usually correlate with bowel activity;
overactivity, higher intrarectal pressures during defecation, and digital skin lesions develop after the onset of bowel symptoms, and patients
removal of stool. Patients complain of constipation with straining and frequently have concomitant active peripheral arthritis. The lesions of
pass blood and mucus per rectum. Other symptoms include abdominal EN are hot, red, tender nodules measuring 1–5 cm in diameter and are
pain, diarrhea, tenesmus, and perineal pain. Ulceration, that may be as found on the anterior surface of the lower legs, ankles, calves, thighs,
large as 5 cm in diameter, is usually observed anteriorly or anterior- and arms. Therapy is directed toward the underlying bowel disease.
laterally 3–15 cm from the anal verge. Biopsies can be diagnostic. Pyoderma gangrenosum (PG) is seen in 1–12% of UC patients and
Several types of colitis are associated with nonsteroidal anti- less commonly in Crohn’s colitis. Although it usually presents after
inflammatory drugs (NSAIDs), including de novo colitis, reactivation the diagnosis of IBD, PG may occur years before the onset of bowel
of IBD, and proctitis caused by use of suppositories. Most patients symptoms, run a course independent of the bowel disease, respond
with NSAID-related colitis present with diarrhea and abdominal pain, poorly to colectomy, and even develop years after proctocolectomy. It
and complications include stricture, bleeding, obstruction, perforation, is usually associated with severe disease. Lesions are commonly found
and fistulization. Withdrawal of these agents is crucial, and in cases of on the dorsal surface of the feet and legs but may occur on the arms,
reactivated IBD, standard therapies are indicated. chest, stoma, and even the face. PG usually begins as a pustule and
There are complications of two common drugs used in a hospital set- then spreads concentrically to rapidly undermine healthy skin. Lesions
ting that mimic IBD. The first is ipilimumab, a drug that targets cytotoxic then ulcerate, with violaceous edges surrounded by a margin of eryth-
T lymphocyte antigen 4 (CTLA-4) and reverses T cell inhibition and is ema. Centrally, they contain necrotic tissue with blood and exudates.
used to treat metastatic melanoma. Ipilimumab can cause an autoim- Lesions may be single or multiple and grow as large as 30 cm. They
mune colitis that is commonly associated with diarrhea: patients with are sometimes very difficult to treat and often require IV antibiotics, IV
diarrhea of grade 3 or greater and those who have colitis on colonos- glucocorticoids, dapsone, azathioprine, thalidomide, IV cyclosporine
copy often require glucocorticoid or infliximab therapy. The second is (CSA), infliximab or adalimumab.
mycophenolate mofetil (MMF), an immunosuppressive agent that is Other dermatologic manifestations include pyoderma vegetans,
anti-proliferative and commonly used to prevent post-transplant rejec- which occurs in intertriginous areas; pyostomatitis vegetans, which
tion. The colitis associated with MMF is common and can occur in more involves the mucous membranes; Sweet syndrome, a neutrophilic
than one-third of patients taking the drug. Treatment is dose reduction or dermatosis; and metastatic CD, a rare disorder defined by cutaneous
cessation of the drug. There have been case reports of entanercept (TNF granuloma formation. Psoriasis affects 5–10% of patients with IBD
receptor-Fc fusion protein) associated with de novo CD and UC. and is unrelated to bowel activity consistent with the potential shared
immunogenetic basis of these diseases. Perianal skin tags are found in
■■THE ATYPICAL COLITIDES 75–80% of patients with CD, especially those with colon involvement.
Two atypical colitides—collagenous colitis and lymphocytic colitis— Oral mucosal lesions, seen often in CD and rarely in UC, include
have completely normal endoscopic appearances. Collagenous colitis aphthous stomatitis and “cobblestone” lesions of the buccal mucosa.

■■RHEUMATOLOGIC lifetime risk of developing cholangiocarcinoma and then cannot be 2269
Peripheral arthritis develops in 15–20% of IBD patients, is more transplanted. Patients with IBD and PSC are at increased risk of colon
common in CD, and worsens with exacerbations of bowel activity. cancer and should be surveyed yearly by colonoscopy and biopsy.
It is asymmetric, polyarticular, and migratory and most often affects In addition, cholangiography is normal in a small percentage of
large joints of the upper and lower extremities. Treatment is directed patients who have a variant of PSC known as small duct primary scleros-
at reducing bowel inflammation. In severe UC, colectomy frequently ing cholangitis. This variant (sometimes referred to as “pericholangitis”)
cures the arthritis. is probably a form of PSC involving small-caliber bile ducts. It has
Ankylosing spondylitis (AS) occurs in about 10% of IBD patients similar biochemical and histologic features to classic PSC. It appears to
and is more common in CD than UC. About two-thirds of IBD patients have a significantly better prognosis than classic PSC, although it may
with AS express the HLA-B27 antigen. The AS activity is not related to evolve into classic PSC. Granulomatous hepatitis and hepatic amyloi-
bowel activity and does not remit with glucocorticoids or colectomy. dosis are much rarer extraintestinal manifestations of IBD.
It most often affects the spine and pelvis, producing symptoms of
diffuse low-back pain, buttock pain, and morning stiffness. The course ■■UROLOGIC
is continuous and progressive, leading to permanent skeletal damage The most frequent genitourinary complications are calculi, ureteral
and deformity. Anti-TNF therapy reduces spinal inflammation and obstruction, and ileal bladder fistulas. The highest frequency of neph-
improves functional status and quality of life. rolithiasis (10–20%) occurs in patients with CD following small bowel
Sacroiliitis is symmetric, occurs equally in UC and CD, is often resection. Calcium oxalate stones develop secondary to hyperoxaluria,
asymptomatic, does not correlate with bowel activity, and does not which results from increased absorption of dietary oxalate. Normally,
always progress to AS. Other rheumatic manifestations include hyper- dietary calcium combines with luminal oxalate to form insoluble cal-
trophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing cium oxalate, which is eliminated in the stool. In patients with ileal
polychondritis. dysfunction, however, nonabsorbed fatty acids bind calcium and leave
oxalate unbound. The unbound oxalate is then delivered to the colon,
■■OCULAR where it is readily absorbed, especially in the presence of inflammation.
The incidence of ocular complications in IBD patients is 1–10%. The
most common are conjunctivitis, anterior uveitis/iritis, and episcleritis.
■■METABOLIC BONE DISORDERS
Low bone mass occurs in 14–42% of IBD patients. The risk is increased
Uveitis is associated with both UC and Crohn’s colitis, may be found
by glucocorticoids, CSA, methotrexate (MTX), and total parenteral
during periods of remission, and may develop in patients following
nutrition (TPN). Malabsorption and inflammation mediated by IL-1,
bowel resection. Symptoms include ocular pain, photophobia, blurred
IL-6, TNF, and other inflammatory mediators also contribute to low

vision, and headache. Prompt intervention, sometimes with systemic
bone density. An increased incidence of hip, spine, wrist, and rib
glucocorticoids, is required to prevent scarring and visual impairment.
fractures has been noted: 36% in CD and 45% in UC. The absolute risk
Episcleritis is a benign disorder that presents with symptoms of mild
of an osteoporotic fracture is about 1% per person per year. Fracture
ocular burning. It occurs in 3–4% of IBD patients, more commonly in
rates, particularly in the spine and hip, are highest among the elderly
Crohn’s colitis, and is treated with topical glucocorticoids.
(age >60). One study noted an OR of 1.72 for vertebral fracture and an
■■HEPATOBILIARY OR of 1.59 for hip fracture. The disease severity predicted the risk of
Hepatic steatosis is detectable in about one-half of the abnormal liver a fracture. Only 13% of IBD patients who had a fracture were on any
biopsies from patients with CD and UC; patients usually present kind of antifracture treatment. Up to 20% of bone mass can be lost per
with hepatomegaly. Fatty liver usually results from a combination of year with chronic glucocorticoid use. The effect is dosage-dependent.
chronic debilitating illness, malnutrition, and glucocorticoid therapy. Budesonide may also suppress the pituitary-adrenal axis and thus
Cholelithiasis occurs in 10–35% of CD patients with ileitis or ileal carries a risk of causing osteoporosis.
Osteonecrosis is characterized by death of osteocytes and adipocytes
resection. Gallstone formation is caused by malabsorption of bile
and eventual bone collapse. The pain is aggravated by motion and
acids, resulting in depletion of the bile salt pool and the secretion of
swelling of the joints. It affects the hips more often than knees and
lithogenic bile.
shoulders, and in one series, 4.3% of patients developed osteonecrosis
Primary sclerosing cholangitis (PSC) is a disorder characterized by
within 6 months of starting glucocorticoids. Diagnosis is made by bone
both intrahepatic and extrahepatic bile duct inflammation and fibro-
scan or MRI, and treatment consists of pain control, cord decompres-
sis, frequently leading to biliary cirrhosis and hepatic failure; ~5% of
sion, osteotomy, and joint replacement.
patients with UC have PSC, but 50–75% of patients with PSC have
IBD. PSC occurs less often in patients with CD. Although it can be rec- ■■THROMBOEMBOLIC DISORDERS
ognized after the diagnosis of IBD, PSC can be detected earlier or even Patients with IBD have an increased risk of both venous and arte-
years after proctocolectomy. Consistent with this, the immunogenetic rial thrombosis even if the disease is not active. Factors responsible
basis for PSC appears to be overlapping but distinct from UC based on for the hypercoagulable state have included abnormalities of the
GWAS, although both IBD and PSC are commonly pANCA positive. platelet-endothelial interaction, hyperhomocysteinemia, alterations in
Most patients have no symptoms at the time of diagnosis; when symp- the coagulation cascade, impaired fibrinolysis, involvement of tissue
toms are present, they consist of fatigue, jaundice, abdominal pain, factor-bearing microvesicles, disruption of the normal coagulation
fever, anorexia, and malaise. The traditional gold standard diagnostic system by autoantibodies, and a genetic predisposition. A spectrum of
test is endoscopic retrograde cholangiopancreatography (ERCP), but vasculitides involving small, medium, and large vessels has also been
magnetic resonance cholangiopancreatography (MRCP) is sensitive, observed.
specific and safer. MRCP is reasonable as an initial diagnostic test in
children and adults and can visualize irregularities, multifocal stric- ■■OTHER DISORDERS
tures, and dilatations of all levels of the biliary tree. In patients with More common cardiopulmonary manifestations include endocarditis,
PSC, both ERCP and MRCP demonstrate multiple bile duct strictures myocarditis, pleuropericarditis, and interstitial lung disease. A second-
alternating with relatively normal segments. ary or reactive amyloidosis can occur in patients with long-standing IBD,
Gallbladder polyps in patients with PSC have a high incidence of especially in patients with CD. Amyloid material is deposited systemi-
malignancy and cholecystectomy is recommended, even if a mass lesion cally and can cause diarrhea, constipation, and renal failure. The renal
is less than 1 cm in diameter. Gallbladder surveillance with ultrasound disease can be successfully treated with colchicine. Pancreatitis is a rare
should be performed annually. Endoscopic stenting may be palliative extraintestinal manifestation of IBD and results from duodenal fistu-
for cholestasis secondary to bile duct obstruction. Patients with symp- las; ampullary CD; gallstones; PSC; drugs such as 6-mercaptopurine,
tomatic disease develop cirrhosis and liver failure over 5–10 years and azathioprine, or, very rarely, 5-ASA agents; autoimmune pancreatitis;
eventually require liver transplantation. PSC patients have a 10–15% and primary CD of the pancreas.

2270 within a hydrophilic matrix encapsulated in a polymer resistant
TREATMENT
to degradation at a low pH (<7) to delay release throughout the
Inflammatory Bowel Disease colon. The safety profile appears to be comparable to other 5-ASA
formulations.
5-ASA AGENTS Apriso is a formulation containing encapsulated mesalamine
These agents are effective at inducing and maintaining remission in granules that delivers mesalamine to the terminal ileum and colon
UC. They may have a limited role in inducing remission in CD but via a proprietary extended-release mechanism (Intellicor). The outer
no clear role in maintenance of CD. Newer sulfa-free aminosalicylate coating of this agent (Eudragit L) dissolves at a pH >6. In addition,
preparations deliver increased amounts of the pharmacologically there is a polymer matrix core that aids in sustained release through-
active ingredient of sulfasalazine (5-ASA, mesalamine) to the site out the colon. Because Lialda and Apriso are given once daily, an
of active bowel disease while limiting systemic toxicity. Peroxisome anticipated benefit is improved compliance compared with two to
proliferator activated receptor γ (PPAR-γ) may mediate 5-ASA ther- four daily doses required for other mesalamine preparations.
apeutic action by decreasing nuclear localization of NF-κB. Sulfa- Pentasa is another mesalamine formulation that uses an ethylcel-
free aminosalicylate formulations include alternative azo-bonded lulose coating to allow water absorption into small beads containing
carriers, 5-ASA dimers, and delayed-release and controlled-release the mesalamine. Water dissolves the 5-ASA, which then diffuses out
preparations. Each has the same efficacy as sulfasalazine when equi- of the bead into the lumen. Disintegration of the capsule occurs in
molar concentrations are used. the stomach. The microspheres then disperse throughout the entire
Sulfasalazine’s molecular structure provides a convenient deliv- GI tract from the small intestine through the distal colon in both
ery system to the colon by allowing the intact molecule to pass fasted and fed conditions.
through the small intestine after only partial absorption and to be Salofalk® Granu-Stix, an unencapsulated version of mesalamine,
broken down in the colon by bacterial azo reductases that cleave has been in use in Europe for induction and maintenance of remis-
the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine sion for several years.
is effective treatment for mild to moderate UC and is occasionally Appropriate doses of the 5-ASA compounds are shown in
used in Crohn’s colitis, but its high rate of side effects limits its use. Table 319-7. Some 50–75% of patients with mild to moderate UC
Although sulfasalazine is more effective at higher doses, at 6 or improve when treated with 5-ASA doses equivalent to 2 g/d of
8 g/d up to 30% of patients experience allergic reactions or intoler- mesalamine; the dose response continues up to at least 4.8 g/d.
able side effects such as headache, anorexia, nausea, and vomiting More common side effects of the 5-ASA medications include
that are attributable to the sulfapyridine moiety. Hypersensitivity headaches, nausea, hair loss, and abdominal pain. Rare side effects
reactions, independent of sulfapyridine levels, include rash, fever, of the 5-ASA medications include renal impairment, hematuria,
PART 10
hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancre- pancreatitis, and paradoxical worsening of colitis. Renal function
atitis, worsening of colitis, and reversible sperm abnormalities. tests and urinalysis should be checked yearly.
Sulfasalazine can also impair folate absorption, and patients should Topical Rowasa enemas are composed of mesalamine and are
be given folic acid supplements. effective in mild-to-moderate distal UC. Combination therapy with
Balsalazide contains an azo bond binding mesalamine to the car- mesalamine in both oral and enema form is more effective than
rier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon. either treatment alone for both distal and extensive UC.
Delzicol and Asacol HD (high dose) are enteric-coated forms of Canasa suppositories composed of mesalamine are effective in
mesalamine with the 5-ASA being released at pH >7. They disinte- treating proctitis.
grate with complete breakup of the tablet occurring in many different
parts of the gut ranging from the small intestine to the splenic flexure; GLUCOCORTICOIDS
they have increased gastric residence when taken with a meal. Asa- The majority of patients with moderate to severe UC benefit from
col has been discontinued and replaced with Delzicol, which lacks oral or parenteral glucocorticoids. Prednisone is usually started at
dibutyl phthalate (DBP), an inactive ingredient in Asacol’s enteric doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA
coating. DBP has been associated with adverse effects on the male therapy. Parenteral glucocorticoids may be administered as hydro-
reproductive system in animals at very high doses. cortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. A new
Lialda is a once-a-day formulation of mesalamine (Multi-Matrix glucocorticoid for UC, budesonide (Uceris), is released entirely in
System [MMX]) designed to release mesalamine in the colon. The the colon and has minimal to no glucocorticoid side effects. The dose
MMX technology incorporates mesalamine into a lipophilic matrix is 9 mg/d for 8 weeks, and no taper is required. Topically applied
TABLE 319-7 Oral 5-ASA Preparations

PREPARATION FORMULATION DELIVERY DOSING PER DAY
Azo-Bond
Sulfasalazine (500 mg) (Azulfidine) Sulfapyridine-5-ASA Colon 3–6 g (acute)
2–4 g (maintenance)
Balsalazide (750 mg) (Colazal) Aminobenzoyl-alanine–5-ASA Colon 6.75–9 g
Delayed-Release
Mesalamine (400, 800 mg) (Delzicol, Asacol HD) Eudragit S (pH 7) Distal ileum-colon 2.4–4.8 g (acute)
1.6–4.8 g (maintenance)
Mesalamine (1.2 g) (Lialda) MMX mesalamine (SPD476) Ileum-colon 2.4–4.8 g
Controlled-Release
Mesalamine (250, 500, 1000 mg) (Pentasa) Ethylcellulose microgranules Stomach-colon 2–4 g (acute)
1.5–4 g (maintenance)
Delayed- and Extended-Release
Mesalamine (0.375 g) (Apriso) Intellicor extended-release mechanism Ileum-colon 1.5 g (maintenance)

glucocorticoids are also beneficial for distal colitis and may serve as metabolites. Although 6-thioguanine and 6-methylmercaptopurine 2271
an adjunct in those who have rectal involvement plus more proximal levels can be followed to determine correct drug dosing and reduce
disease. Hydrocortisone enemas or foam may control active disease, toxicity, weight-based dosing is an acceptable alternative. CBCs and
although they have no proven role as maintenance therapy. These liver function tests should be monitored frequently regardless of
glucocorticoids are significantly absorbed from the rectum and can dosing strategy.
lead to adrenal suppression with prolonged administration. Topical
METHOTREXATE
5-ASA therapy is more effective than topical steroid therapy in the
treatment of distal UC. MTX inhibits dihydrofolate reductase, resulting in impaired DNA
Glucocorticoids are also effective for treatment of moderate to synthesis. Additional anti-inflammatory properties may be related
severe CD and induce a 60–70% remission rate compared to a 30% to decrease in the production of IL-1. It is used most often concom-
placebo response. The systemic effects of standard glucocorticoid itantly with biologic therapy to decrease antibody formation and
formulations have led to the development of more potent formu- improve disease response. Intramuscular (IM) or subcutaneous (SC)
lations that are less well-absorbed and have increased first-pass doses range from 15 to 25 mg/week. Potential toxicities include
metabolism. Controlled ileal-release budesonide has been nearly leukopenia and hepatic fibrosis, necessitating periodic evaluation
equal to prednisone for ileocolonic CD with fewer glucocorticoid of CBCs and liver enzymes. The role of liver biopsy in patients on
side effects. Budesonide is used for 2–3 months at a dose of 9 mg/d, long-term MTX is uncertain but is probably limited to those with
and then tapered. Glucocorticoids play no role in maintenance ther- increased liver enzymes. Hypersensitivity pneumonitis is a rare but
apy in either UC or CD. Once clinical remission has been induced, serious complication of therapy.
they should be tapered according to the clinical activity, normally CYCLOSPORINE
at a rate of no more than 5 mg/week. They can usually be tapered
CSA is a lipophilic peptide with inhibitory effects on both the cel-
to 20 mg/d within 4–5 weeks but often take several months to be
lular and humoral immune systems. CSA blocks the production of
discontinued altogether. The side effects are numerous, including
IL-2 by T helper lymphocytes. CSA binds to cyclophilin, and this
fluid retention, abdominal striae, fat redistribution, hyperglycemia,
complex inhibits calcineurin, a cytoplasmic phosphatase enzyme
subcapsular cataracts, osteonecrosis, osteoporosis, myopathy, emo-
involved in the activation of T cells. CSA also indirectly inhibits B
tional disturbances, and withdrawal symptoms. Most of these side
cell function by blocking helper T cells. CSA has a more rapid onset
effects, aside from osteonecrosis, are related to the dose and duration
of action than 6-MP and azathioprine.
of therapy.
CSA is most effective when given at 2–4 mg/kg per day IV in
ANTIBIOTICS severe UC that is refractory to IV glucocorticoids, with 82% of

Antibiotics have no role in the treatment of active or quiescent UC. patients responding. CSA can be an alternative to colectomy. The
However, pouchitis, which occurs in about 30–50% of UC patients long-term success of oral CSA is not as dramatic, but if patients
after colectomy and IPAA, usually responds to treatment with met- are started on 6-MP or azathioprine at the time of hospital dis-
ronidazole and/or ciprofloxacin. charge, remission can be maintained. For the 2 mg/kg dose, levels
Metronidazole is effective in active inflammatory, fistulizing, and as measured by monoclonal radioimmunoassay or by the high-
perianal CD and may prevent recurrence after ileal resection. The performance liquid chromatography assay should be maintained
most effective dose is 15–20 mg/kg per day in three divided doses; between 150 and 350 ng/mL.
it is usually continued for several months. Common side effects CSA may cause significant toxicity; renal function should be
include nausea, metallic taste, and disulfiram-like reaction. Periph- monitored frequently. Hypertension, gingival hyperplasia, hyper-
eral neuropathy can occur with prolonged administration (several trichosis, paresthesias, tremors, headaches, and electrolyte abnor-
months) and on rare occasions is permanent despite discontinua- malities are common side effects. Creatinine elevation calls for
tion. Ciprofloxacin (500 mg bid) is also beneficial for inflammatory, dose reduction or discontinuation. Seizures may also complicate
perianal, and fistulizing CD but has been associated with tendinitis therapy, especially if the patient is hypomagnesemic or if serum
and tendon rupture. Both ciprofloxacin and metronidazole antibi- cholesterol levels are <3.1 mmol/L (<120 mg/dL). Opportunis-
otics can be used only for short period of time due to side effects. tic infections, most notably Pneumocystis carinii pneumonia, may
occur with combination immunosuppressive treatment; prophylaxis
AZATHIOPRINE AND 6-MERCAPTOPURINE
should be given. Major adverse events occurred in 15% of patients
Azathioprine and 6-mercaptopurine (6-MP) are purine analogues in one large study, including nephrotoxicity not responding to dose
used concomitantly with biologic therapy or, less often, as the adjustment, serious infections, seizures, anaphylaxis, and death of
sole immunosuppressants. Azathioprine is rapidly absorbed and two patients. This high incidence suggests that vigorous monitoring
converted to 6-MP, which is then metabolized to the active end by experienced clinicians at tertiary care centers may be required.
product, thioinosinic acid, an inhibitor of purine ribonucleotide To compare IV CSA versus infliximab, a large trial was conducted
synthesis and cell proliferation. Efficacy can be seen as early as 3–4 in Europe by the GETAID group. The results indicated identical
weeks but can take up to 4–6 months. Adherence can be monitored 7-day response rates between CSA 2 mg/kg (with doses adjusted for
by measuring the levels of 6-thioguanine and 6-methyl-mercapto- levels of 150–250 ng/mL) and infliximab 5 mg/kg, with both groups
purine, end products of 6-MP metabolism. The doses used range achieving response rates of 85%. Serious infections occurred in 5 of
from 2–3 mg/kg per day for azathioprine and 1–1.5 mg/kg per 55 CSA patients and 4 of 56 infliximab patients. Response rates were
day for 6-MP. similar in the two groups at day 98 among patients treated with oral
Although azathioprine and 6-MP are usually well tolerated, CSA versus infliximab at the usual induction dose and maintenance
pancreatitis occurs in 3–4% of patients, typically presents within dose regimen (40 and 46%, respectively). In light of data showing
the first few weeks of therapy, and is completely reversible when equal efficacy of CSA and infliximab in severe UC, more physicians
the drug is stopped. Other side effects include nausea, fever, rash, are relying on infliximab rather than CSA in these patients.
and hepatitis. Bone marrow suppression (particularly leukopenia)
is dose-related and often delayed, necessitating regular monitoring TACROLIMUS
of the complete blood cell count (CBC). Additionally, 1 in 300 indi- Tacrolimus is a macrolide antibiotic with immunomodulatory prop-
viduals lacks thiopurine methyltransferase, the enzyme responsible erties similar to CSA. It is 100 times as potent as CSA and is not
for drug metabolism to inactive end-products (6-methylmercap- dependent on bile or mucosal integrity for absorption. These phar-
topurine); an additional 11% of the population are heterozygotes macologic properties enable tacrolimus to have good oral absorption
with intermediate enzyme activity. Both are at increased risk of despite proximal small bowel Crohn’s involvement. It has shown
toxicity because of increased accumulation of active 6-thioguanine efficacy in children with refractory IBD and in adults with extensive

2272 involvement of the small bowel. It is also effective in adults with glu- was effective for induction of clinical response in patients with active
cocorticoid-dependent or refractory UC and CD as well as refractory inflammatory CD. In the PRECISE II (Pegylated Antibody Fragment
fistulizing CD. Evaluation in Crohn’s Disease) trial of maintenance therapy with cer-
BIOLOGIC THERAPIES tolizumab in patients who responded to certolizumab induction, the
results were similar to the CHARM trial. At week 26, the subgroup
Biologic therapy is now commonly given as an initial therapy for of patients who were infliximab naïve had a response of 69% as
patients with moderate to severe CD and UC. Patients who respond compared to 44% in patients who had previously received infliximab.
to biologic therapies enjoy an improvement in clinical symptoms; Golimumab is another fully human IgG1 antibody against TNF-α
a better quality of life; less disability, fatigue, and depression; and and is currently approved for the treatment of moderately to
fewer surgeries and hospitalizations. severely active UC. Like adalimumab and certolizumab, golimumab
Anti-TNF Therapies The first biologic therapy approved for mod- is injected SC.
erate to severely active CD and also UC was infliximab, a chimeric
Side Effects of Anti-TNF Therapies • Development of Antibodies
IgG1 antibody against TNF-α,. Of active CD patients refractory to
The development of antibodies to infliximab is associated with an
glucocorticoids, 6-MP, or 5-ASA, 65% will respond to IV infliximab
increased risk of infusion reactions and a decreased response to
(5 mg/kg); one-third will enter complete remission. The ACCENT I
treatment. Current practice does not include giving on-demand
(A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New
or episodic infusions in contrast to periodic (every 8 week) infu-
Long-Term Treatment Regimen) study showed that of the patients
sions because patients are most likely to develop antibodies. Anti-
who experience an initial response, 40% will maintain remission for
infliximab antibodies are generally present when the quality of
at least 1 year with repeated infusions of infliximab every 8 weeks.
response or the response duration to infliximab infusion decreases.
Infliximab is also effective in CD patients with refractory perianal
There are commercial assays for both infliximab and adalimumab
and enterocutaneous fistulas, with the ACCENT II trial showing a
antibodies and trough levels to determine optimal dosing. If a
68% response rate (50% reduction in fistula drainage) and a 50%
patient has high anti-infliximab antibodies and a low trough level
complete remission rate. Reinfusion, typically every 8 weeks, is nec-
of infliximab, it is best to switch to another anti-TNF therapy. Most
essary to continue therapeutic benefits in many patients.
acute infusion reactions and serum sickness can be managed with
The SONIC (Study of Biologic and Immunomodulator-Naive
glucocorticoids and antihistamines. Some reactions can be serious
Patients with Crohn’s Disease) trial compared infliximab plus aza-
and would necessitate a change in therapy, especially if a patient
thioprine, infliximab alone, and azathioprine alone in immunomod-
has anti-infliximab antibodies. It is now common practice to add an
ulator- and biologic-naive patients with moderate to severe CD. At
immunomodulator such as azathioprine, 6-mercaptopurine or MTX
1 year, the infliximab plus azathioprine group had a glucocorticoid-
to anti-TNF therapy in order to prevent antibody formation.
PART 10
free remission rate of 46% compared with 35% for infliximab alone
and 24% for azathioprine alone. There was also complete mucosal Non-Hodgkin’s Lymphoma (NHL) The baseline risk of NHL in CD
healing at week 26 with the combined approach relative to either patients is 2:10,000, which is slightly higher than in the general
infliximab or azathioprine alone (44 vs 30 vs 17%). The adverse population. Azathioprine and/or 6-MP therapy increases the risk
events were equal between groups. to about 4:10,000. The highest risk for thiopurine-associated NHL
Two large trials of infliximab in moderate to severe UC also is in patients over 65 years old actively using thiopurines (yearly
showed efficacy with a response rate of 37–49%, with about one- incidence rate per 1000 patient years of 5.41), with a moderate risk
fifth of patients maintaining remission after 54 weeks. Dosing for in those between the ages of 50 and 65 (incidence rate of 2.58 com-
UC and CD are identical, with induction dosing at 0, 2, and 6 weeks pared to an incidence rate of 0.37 in patients <50 years old). It is
and every 8 weeks thereafter. There is a similar study to SONIC in difficult to assess whether anti-TNF medications are associated with
patients with moderate to severe UC. After 16 weeks of therapy, UC lymphoma because most patients are also receiving thiopurines.
patients taking azathioprine plus infliximab had a glucocorticoid- After adjustment for co-treatments, no excess risk of lymphoma was
free remission rate of 40% compared to 24% and 22% of those on found in a recent adequately powered Danish study of a cohort of
azathioprine and infliximab alone, respectively. This is even further IBD patients exposed to anti-TNF medications.
evidence for “top-down” or more aggressive therapy for both mod- Hepatosplenic T-Cell Lymphoma (HSTCL) HSTCL is a nearly uni-
erate to severe CD and UC. versally fatal lymphoma in patients with or without CD. In patients
Adalimumab is a recombinant human monoclonal IgG1 antibody with CD, events reported to the Food and Drug Administration
containing only human peptide sequences and is injected subcu- Adverse Event Reporting System (FDA AERS) and search of
taneously. Adalimumab binds TNF and neutralizes its function by PubMed and Embase published case reports demonstrate a total of
blocking the interaction between TNF and its cell-surface receptor. 37 unique cases. Eighty-six percent of the patients were male, with
Therefore, it seems to have a similar mechanism of action to inflix- a median age of 26 years. Patients had CD for a mean of 10 years
imab but with less immunogenicity. Adalimumab is approved for before the diagnosis of HSTCL. Thirty-six cases had used either
treatment of moderate to severe CD and UC. CHARM (Crohn’s Trial 6-MP or azathioprine, and 28 cases had used infliximab. Of these
of the Fully Human Adalimumab for Remission Maintenance) is an 28 cases, 27 had also used 6-MP or azathioprine. The other case had
adalimumab maintenance study in patients who responded to adali- a history of both infliximab and adalimumab exposure.
mumab induction therapy. About 50% of the patients in this trial
were previously treated with infliximab. Remission rates ranged Skin Lesions New-onset psoriasiform skin lesions develop in
from 42 to 48% of infliximab-naïve patients at 1 year compared with nearly 5% of IBD patients treated with anti-TNF therapy. Most
remission rates of 31–34% in patients who had previously received often, these can be treated topically, and occasionally, anti-TNF
infliximab. Another trial showed a remission rate of 21% at 4 weeks therapy must be decreased, switched, or stopped. Patients with IBD
in patients who had initially responded to and then failed inflixi- may have a slight unexplained intrinsic higher risk of developing
mab. UC results are similar with a sustained remission rate at one melanoma. The risk of melanoma is increased almost twofold with
year of 22% (12.4% placebo) among anti–TNF-naïve patients and anti-TNF and not thiopurine use. The risk of nonmelanoma skin
a sustained remission rate at 1 year of 10.2% (3% placebo) among cancer is increased with thiopurines and biologics, especially with
patients who had previously received anti-TNF agents. In clinical 1 year of follow-up or greater. Patients on these medications should
practice, the remission rate in both CD and UC patients taking have a skin check at least once a year.
adalimumab increases with a dose increase to 40 mg weekly instead Infections All of the anti-TNF drugs are associated with an
of every other week. increased risk of infections, particularly reactivation of latent tuber-
Certolizumab pegol is a pegylated form of an anti-TNF Fab portion culosis and opportunistic fungal infections including disseminated
of an antibody administered SC once monthly. SC certolizumab pegol histoplasmosis and coccidioidomycosis. It is recommended that

patients have a purified protein derivative (PPD) or a QuantiFER- with their receptors on T cells, natural killer cells, and antigen 2273
ON-TB gold test as well as a chest x-ray before initiation of anti-TNF presenting cells. It has recently been FDA-approved for use in
therapy. Patients >65 have a higher rate of infections and death on Crohn’s patients who have failed or were intolerant to immu-
infliximab or adalimumab than those <65 years of age. nomodulator or corticosteroid therapy but who never failed
Other Acute liver injury due to reactivation of hepatitis B virus treatment with anti-TNF therapy or who failed or were intoler-
and to autoimmune effects and cholestasis has been reported. ant to treatment with one or more anti-TNF medications. The
Rarely, infliximab and the other anti-TNF drugs have been asso- result for the highest 6 mg/kg IV induction dose and subsequent
ciated with optic neuritis, seizures, new onset or exacerbation of 90 mg every 8 week dose in one major clinical trial was 41.7%
clinical symptoms, and radiographic evidence of central nervous remission rate versus 27.4% placebo at 22 weeks in Crohn’s patients
system demyelinating disorders, including multiple sclerosis. They failing anti-TNF therapy.
may exacerbate symptoms in patients with New York Heart Associ- THERAPIES IN CLINICAL DEVELOPMENT
ation functional class III/IV heart failure.
Tofacitinib is an oral inhibitor of Janus kinases 1, 3, and, to a lesser
ANTI-INTEGRINS extent, 2. It is expected to block signaling involving common gamma
Integrins are expressed on the cell surface of leukocytes and serve as chain–containing cytokines including IL-2, IL-4, IL-7, IL-9, IL-15,
mediators of leukocyte adhesion to vascular endothelium. α4-Integrin and IL-21. These cytokines are integral to lymphocyte activation,
along with its β1 or β7 subunit interact with endothelial ligands function, and proliferation. It is effective in moderate to severe UC
termed adhesion molecules. Interaction between α4β7 and mucosal in clinical trials.
addressin cellular adhesion molecule (MAdCAM-1) is important in Biosimilars The FDA defines a biosimilar drug as a “biological
lymphocyte trafficking to gut mucosa. product that is highly similar to the reference product not with-
Natalizumab is a recombinant humanized IgG4 antibody against standing minor differences in clinically inactive components.” There
α4-integrin that has been shown to be effective in induction and are no clinically meaningful differences between the biological
maintenance of patients with CD. It has been approved since product and the reference product in terms of the safety, purity,
February 2008 for the treatment of patients with CD refractory or and potency of the product. The infliximab biosimilar CT-P13 is
intolerant to anti-TNF therapy. The rates of response and remission approved and available for use in almost 70 countries and many
at 3 months are about 60 and 40%, respectively, with a sustained other biosimilars to infliximab and adalimumab are currently being
remission rate of about 40% at 36 weeks. manufactured. Biosimilars may be approved without randomized-
Natalizumab is no longer widely used for CD due to the risk controlled trials. The FDA examines quality considerations such as

of progressive multifocal leukoencephalopathy (PML). The most the expression system, manufacturing process, assessment of phys-
important risk factor for development of PML is exposure to the iochemical properties, functional activities, receptor binding and
John Cunningham (JC) polyomavirus, seen in 50–55% of the adult immunochemical properties, measurement of impurities, stability
population. The other two risk factors for development of PML are under multiple stress conditions and effect of product formulation
longer duration of treatment, especially beyond 2 years, and prior and shipping, Since biosimilars will likely cost about a third of the
treatment with an immunosuppressant medication. Patients with all reference drug, they will likely be widely used in the near future in
three risk factors have an estimated risk of 11:1000. the United States.
The FDA approved a commercial enzyme-linked immunosorbent Ozanimod is an oral agonist of the sphingosine-1-phosphate recep-
assay (ELISA) kit to assay anti-JC viral antibodies (Stratify JCV Anti- tor subtypes 1 and 5 that causes peripheral lymphocyte sequestration,
body ELISA; Focus Diagnostics, Cypress, CA) in early 2012. The test potentially decreasing the number of activated lymphocytes circulat-
is 99% accurate in stratifying risk of PML. It is recommended that all ing to the GI tract. In a phase 2 trial of ozanimod in 197 patients with
patients be tested prior to initiating natalizumab therapy. JC virus moderate to severe UC, at 32 weeks, 21% of patients who received
serologies are then measured every 6 months because 1–2% of patients 1 mg of ozanimod versus 6% achieved clinical remission. Phase 3
will seroconvert yearly. Natalizumab is administered IV, 300 mg every trials are now in progress.
4 weeks. Labeling requirements mandate that it should not be used in
combination with any immunosuppressant medications. NUTRITIONAL THERAPIES
Vedolizumab, another leukocyte trafficking inhibitor, is a monoclo- Dietary antigens may stimulate the mucosal immune response.
nal antibody directed against α4β7 integrin specifically and has the Patients with active CD respond to bowel rest, along with TPN.
ability to convey gut-selective immunosuppression. Vedolizumab Bowel rest and TPN are as effective as glucocorticoids at inducing
is indicated for CD and UC patients who have had an inadequate remission of active CD but are not effective as maintenance therapy.
response or lost response to, or were intolerant of a TNF blocker or Enteral nutrition in the form of elemental or peptide-based prepa-
immunomodulator; or had an inadequate response or were intoler- rations is also as effective as glucocorticoids or TPN, but these diets
ant to, or demonstrated dependence on, glucocorticoids. It is also are not palatable. Enteral diets may provide the small intestine with
an option for patients who are JC antibody positive since unlike nutrients vital to cell growth and do not have the complications
natalizumab it inhibits adhesion of a discrete gut-homing subset of of TPN. In contrast to CD, dietary intervention does not reduce
T lymphocytes to MAdCAM-1, but not to vascular adhesion mole- inflammation in UC. Standard medical management of UC and CD
cule-1. Vedolizumab decreases GI inflammation without inhibiting is shown in Fig. 319-12.
systemic immune responses or affecting T-cell trafficking to the
central nervous system. Vedolizumab is given intravenously every SURGICAL THERAPY
8 weeks after 3 induction doses at 0, 2, and 6 weeks. In the GEMINI Ulcerative Colitis Nearly one-half of patients with extensive
I trial (A Phase 3, Randomized, Placebo-Controlled, Blinded, Multi- chronic UC undergo surgery within the first 10 years of their illness.
center Study of the Induction and Maintenance of Clinical Response The indications for surgery are listed in Table 319-8. Morbidity is
and Remission by MLN002 in Patients With Moderate to Severe about 20% for elective, 30% for urgent, and 40% for emergency proc-
Ulcerative Colitis), 42% of the UC patients treated every 8 weeks tocolectomy. The risks are primarily hemorrhage, contamination
and 45% of those treated every 4 weeks were in clinical remission and sepsis, and neural injury. The operation of choice is an IPAA.
at week 52 compared with 16% placebo. In the GEMINI II trial, the Because UC is a mucosal disease, the rectal mucosa can be
clinical remission rates for CD patients treated with vedolizumab dissected and removed down to the dentate line of the anus or
were 36 to 39%, compared with 22% placebo at 52 weeks. about 2 cm proximal to this landmark. The ileum is fashioned
Ustekinumab, a fully human IgG1 monoclonal antibody, blocks into a pouch that serves as a neorectum. This ileal pouch is then
the biologic activity of IL-12 and IL-23 through their common sutured circumferentially to the anus in an end-to-end fashion. If
p40 subunit by inhibiting the interaction of these cytokines performed carefully, this operation preserves the anal sphincter

2274
Infliximab/
adalimumab/
Cyclosporine IV
golimumab/
vedolizumab
Adalimumab/golimumab/
6-Mercaptopurine/ vedolizumab IV
azathioprine
6-Mercaptopurine/
Glucocorticoid oral azathioprine + infliximab
Vedolizumab Glucocorticoid IV
Glucocorticoid rectal
5-ASA oral and/or rectal Glucocorticoid oral

Infliximab/adalimumab/
certolizumab pegol
Mild to Moderate Ulcerative Colitis Moderate to Severe Ulcerative Colitis
6-Mercaptopurine/
azathioprine/methotrexate
Total Prednisone
parenteral Total
nutrition parenteral
Sulfasalazine (colon) nutrition
Budesonide (ileal and right colon)

Glucocorticoid IV
Mild to Moderate Crohn’s Disease 6-Mercaptopurine/
azathioprine/methotrexate +
Infliximab/adalimumab/
certolizumab pegol
Vedolizumab/ustekinumab
PART 10
6-Mercaptopurine/azathioprine/methotrexate + Abscess drainage and antibiotics

Infliximab/adalimumab/ certolizumab pegol
Moderate to Severe Crohn’s Disease Fistulizng Crohn’s Disease

FIGURE 319-12 Medical management of inflammatory bowel disease. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis.
and maintains continence. The overall operative morbidity is 10%, The most frequent complication of IPAA is pouchitis in about
with the major complication being bowel obstruction. Pouch failure 30–50% of patients with UC. This syndrome consists of increased
necessitating conversion to permanent ileostomy occurs in 5–10% stool frequency, watery stools, cramping, urgency, nocturnal leak-
of patients. Some inflamed rectal mucosa is usually left behind, and age of stool, arthralgias, malaise, and fever. Pouch biopsies may
thus endoscopic surveillance is necessary. Primary dysplasia of the distinguish true pouchitis from underlying CD. Although pouchitis
ileal mucosa of the pouch has occurred rarely. usually responds to antibiotics, 3–5% of patients remain refractory
Patients with IPAA usually have about 6–10 bowel movements and may require glucocorticoids, immunomodulators, biologics or
a day. On validated quality-of-life indices, they report better per- even pouch removal. A highly concentrated probiotic preparation
formance in sports and sexual activities than ileostomy patients. with four strains of Lactobacillus, three strains of Bifidobacterium, and
one strain of Streptococcus salivarius may prevent the recurrence of
pouchitis when taken daily.
TABLE 319-8 Indications for Surgery
Crohn’s Disease Most patients with CD require at least one oper-
ULCERATIVE COLITIS CROHN’S DISEASE ation in their lifetime. The need for surgery is related to duration
Intractable disease Small Intestine of disease and the site of involvement. Patients with small-bowel
Fulminant disease Stricture and obstruction disease have an 80% chance of requiring surgery. Those with colitis
Toxic megacolon unresponsive to medical therapy alone have a 50% chance. Surgery is an option only when medical
Colonic perforation Massive hemorrhage treatment has failed or complications dictate its necessity. The indi-
Massive colonic hemorrhage Refractory fistula cations for surgery are shown in Table 319-8.
Extracolonic disease Abscess Small Intestinal Disease Because CD is chronic and recurrent, with
Colonic obstruction Colon and rectum no clear surgical cure, as little intestine as possible is resected. Cur-
Colon cancer prophylaxis Intractable disease rent surgical alternatives for treatment of obstructing CD include
Colon dysplasia or cancer Fulminant disease resection of the diseased segment and strictureplasty. Surgical resec-
Perianal disease unresponsive to tion of the diseased segment is the most frequently performed oper-
medical therapy ation, and in most cases, primary anastomosis can be done to restore
Refractory fistula continuity. If much of the small bowel has already been resected and
Colonic obstruction the strictures are short, with intervening areas of normal mucosa,
Cancer prophylaxis strictureplasties should be done to avoid a functionally insufficient
Colon dysplasia or cancer
length of bowel. The strictured area of intestine is incised longitu-
dinally and the incision sutured transversely, thus widening the

narrowed area. Complications of strictureplasty include prolonged milk has been shown to contain negligible levels of 6-MP/azathioprine 2275
ileus, hemorrhage, fistula, abscess, leak, and restricture. when measured in a limited number of patients.
There is evidence that mesalamine, nitroimidazole antibiotics, Little data exist on CSA in pregnancy. In a small number of patients
6-MP/azathioprine, infliximab, and adalimumab are all supe- with severe IBD treated with IV CSA during pregnancy, 80% of preg-
rior to placebo for the prevention of postoperative recurrence of nancies were successfully completed without development of renal
CD. Mesalamine is the least effective, and the side effects of the toxicity or congenital malformations. However, because of the lack of
nitroimidazole antibiotics limit their use. Risk factors for early data, CSA should probably be avoided unless the patient would other-
recurrence of disease include cigarette smoking, penetrating dis- wise require surgery.
ease (internal fistulas, abscesses, or other evidence of penetration MTX is contraindicated in pregnancy and nursing. In a large
through the wall of the bowel), early recurrence since a previous prospective and multiple retrospective studies, no increased risk of
surgery, multiple surgeries, and a young age at the time of the stillbirths, miscarriages, or spontaneous abortions was seen with
first surgery. Aggressive postoperative treatment with 6-MP/ infliximab, adalimumab, or certolizumab. Infliximab and adalimumab
azathioprine, infliximab, or adalimumab should be considered are IgG1 antibodies and are actively transported across the placenta
for this group of patients. It is also recommended to evaluate in the late second and third trimester. Infants can have serum levels
for endoscopic recurrence of CD via a colonoscopy, if possible, 6 of infliximab and adalimumab up to 12 months of age, and live vac-
months after surgery. cines should be avoided during this time. Certolizumab crosses the
Colorectal Disease A greater percentage of patients with Crohn’s placenta by passive diffusion, and infant serum and cord blood levels
colitis require surgery for intractability, fulminant disease, and are minimal. The anti-TNF drugs are relatively safe in nursing. Min-
anorectal disease. Several alternatives are available, ranging from iscule levels of infliximab, adalimumab, and certolizumab have been
the use of a temporary loop ileostomy to resection of segments of reported in breast milk. These levels are of no clinical significance. It
diseased colon or even the entire colon and rectum. For patients with is recommended that drugs should not be switched during pregnancy
segmental involvement, segmental colon resection with primary unless necessitated by the medical condition of the IBD. Vedolizumab
anastomosis can be performed. In 20–25% of patients with extensive and natalizumab appear safe during pregnancy although the data are
colitis, the rectum is spared sufficiently to consider rectal preserva- limited. There are very little data available on ustekinemab use during
tion. Most surgeons believe that an IPAA is contraindicated in CD pregnancy.
due to the high incidence of pouch failure. A diverting colostomy Surgery in UC should be performed only for emergency indications,
may help heal severe perianal disease or rectovaginal fistulas, but including severe hemorrhage, perforation, and megacolon refractory
to medical therapy. Total colectomy and ileostomy carry a 50% risk
disease almost always recurs with reanastomosis. These patients

of postoperative spontaneous abortion. Fetal mortality is also high in
often require a total proctocolectomy and ileostomy.
CD requiring surgery. Patients with IPAAs have increased nighttime
stool frequency during pregnancy that resolves postpartum. Transient
■■IBD AND PREGNANCY small-bowel obstruction or ileus has been noted in up to 8% of patients
Patients with quiescent UC and CD have normal fertility rates; the with ileostomies.
fallopian tubes can be scarred by the inflammatory process of CD,
especially on the right side because of the proximity of the terminal CANCER IN IBD
ileum. In addition, perirectal, perineal, and rectovaginal abscesses and
fistulae can result in dyspareunia. Infertility in men can be caused by ■■ULCERATIVE COLITIS
sulfasalazine but reverses when treatment is stopped. In women who Patients with long-standing UC are at increased risk for developing
have an IPAA, most studies show that the fertility rate is reduced to colonic epithelial dysplasia and carcinoma (Fig. 319-13).
about 50–80% of normal. This is due to scarring or occlusion of the The risk of neoplasia in chronic UC increases with duration and
fallopian tubes secondary to pelvic inflammation. extent of disease. In contrast to the relatively high risk in one large
In mild or quiescent UC and CD, fetal outcome is nearly normal. The meta-analysis (2% after 10 years, 8% after 20 years, and 18% after
courses of CD and UC during pregnancy mostly correlate with disease 30 years of disease), a decrease in the risk of colorectal cancer has been
activity at the time of conception. Patients should be in remission for 6 noted over time potentially due to better control of inflammation,
months before conceiving. Most CD patients can deliver vaginally, but better colonoscopic surveillance, more frequent colectomies and use
cesarean delivery may be the preferred route of delivery for patients of 5-ASA chemoprophylaxis. The rates of colon cancer are still about
with anorectal and perirectal abscesses and fistulas to reduce the like- 1.5 to 2 × higher than in the general population, and colonoscopic sur-
lihood of fistulas developing or extending into the episiotomy scar. veillance is the standard of care.
Unless they desire multiple children, UC patients with an IPAA should
consider a cesarean delivery due to an increased risk of future fecal
incontinence.
Sulfasalazine, Lialda, Apriso, Delzicol, balsalazide and now Asacol
HD since the DBP has been removed from the capsule are safe for use
in pregnancy and nursing with the caveat that additional folate supple-
mentation must be given with sulfasalazine. Topical 5-ASA agents are
safe during pregnancy and nursing. Glucocorticoids are generally safe
for use during pregnancy and are indicated for patients with moderate
to severe disease activity. The amount of glucocorticoids received by
the nursing infant is minimal. The safest antibiotics to use for CD in
pregnancy for short periods of time (weeks, not months) are ampicillin
and cephalosporins. Metronidazole can be used in the second or third
trimester. Ciprofloxacin causes cartilage lesions in immature animals
and should be avoided because of the absence of data on its effects on
growth and development in humans.
6-MP and azathioprine pose minimal or no risk during pregnancy, FIGURE 319-13 Medium-power view of low-grade dysplasia in a patient with
chronic ulcerative colitis. Low-grade dysplastic crypts are interspersed among
but experience is limited. If the patient cannot be weaned from the regenerating crypts. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology,
drug or has an exacerbation that requires 6-MP/azathioprine during Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;
pregnancy, she should continue the drug with informed consent. Breast with permission.)

2276 Annual or biennial colonoscopy with multiple biopsies is recom-
mended for patients with >8–10 years of extensive colitis (greater than
one-third of the colon involved) or 12–15 years of proctosigmoiditis
(less than one-third but more than just the rectum) and has been widely
320 Irritable Bowel Syndrome
Chung Owyang
used to screen and survey for subsequent dysplasia and carcinoma.
Risk factors for cancer in UC include long-duration disease, extensive
disease, family history of colon cancer, PSC, a colon stricture, and the
Irritable bowel syndrome (IBS) is a functional bowel disorder charac-
presence of post inflammatory pseudopolyps on colonoscopy.
terized by abdominal pain or discomfort and altered bowel habits in
the absence of detectable structural abnormalities. No clear diagnostic
■■CROHN’S DISEASE
markers exist for IBS; thus the diagnosis of the disorder is based on clin-
Risk factors for developing cancer in Crohn’s colitis are long-duration
ical presentation. In 2016, the Rome III criteria for the diagnosis of IBS
and extensive disease, bypassed colon segments, colon strictures, PSC,
were updated to Rome IV (Table 320-1). Throughout the world, about
and family history of colon cancer. The cancer risks in CD and UC are
10–20% of adults and adolescents have symptoms consistent with IBS,
probably equivalent for similar extent and duration of disease. In the
and most studies show a female predominance. IBS symptoms tend
CESAME study, a prospective observational cohort of IBD patients in
to come and go over time and often overlap with other functional
France, the standardized incidence ratios of colorectal cancer were 2.2
disorders such as fibromyalgia, headache, backache, and genitouri-
for all IBD patients (95% confidence interval [CI], 1.5–3.0; p < 0.001) and
nary symptoms. Severity of symptoms varies and can significantly
7.0 for patients with long-standing extensive colitis (both Crohn’s and
impair quality of life, resulting in high health care costs. Advances
UC) (95% CI, 4.4–10.5; p < 0.001). Thus, the same endoscopic surveil-
in basic, mechanistic, and clinical investigations have improved our
lance strategy used for UC is recommended for patients with chronic
understanding of this disorder and its physiologic and psychosocial
Crohn’s colitis. A pediatric colonoscope can be used to pass narrow
determinants. Altered gastrointestinal (GI) motility, visceral hyperalge-
strictures in CD patients, but surgery should be considered in symp-
sia, disturbance of brain–gut interaction, abnormal central processing,
tomatic patients with impassable strictures.
autonomic and hormonal events, genetic and environmental factors,
and psychosocial disturbances are variably involved, depending on
■■MANAGEMENT OF DYSPLASIA AND CANCER
the individual. This progress may result in improved methods of
Dysplasia can be flat or polypoid. If flat high-grade dysplasia is
treatment.
encountered on colonoscopic surveillance, the usual treatment is
colectomy for UC and either colectomy or segmental resection for CD. ■■CLINICAL FEATURES
If flat low-grade dysplasia is found (Fig. 319-13), most investigators IBS is a disorder that affects all ages, although most patients have their
PART 10
recommend immediate colectomy. Adenomas may occur coincidently first symptoms before age 45. Older individuals have a lower reporting
in UC and CD patients with chronic colitis and can be removed endo- frequency. Women are diagnosed with IBS two to three times as often
scopically provided that biopsies of the surrounding mucosa are free as men and make up 80% of the population with severe IBS. As indi-
of dysplasia. High-definition and high-magnification colonoscopes and cated in Table 320-1, pain is a key symptom for the diagnosis of IBS.
dye sprays have increased the rate of dysplasia detection. This symptom should be associated with defecation and/or have their
IBD patients are also at greater risk for other malignancies. Patients onset associated with a change in frequency or form of stool. In com-
with CD may have an increased risk of NHL, leukemia, and myelodys- parison to Rome III, the Rome IV criteria is more stringent, requiring
plastic syndromes. Severe, chronic, complicated perianal disease in CD abdominal pain to occur at a minimum of once a week and eliminates
patients may be associated with an increased risk of cancer in the lower “discomfort” as one of the criteria. Painless diarrhea or constipation
rectum and anal canal (squamous cell cancers). Although the absolute does not fulfill the diagnostic criteria to be classified as IBS. Supportive
risk of small-bowel adenocarcinoma in CD is low (2.2% at 25 years in symptoms that are not part of the diagnostic criteria include defecation
one study), patients with long-standing, extensive, small-bowel disease straining, urgency or a feeling of incomplete bowel movement, passing
should consider screening. mucus, and bloating.
■■FURTHER READING Abdominal Pain According to the current IBS diagnostic criteria,
Beaugerie L, Itzkowitz SH: Cancers complicating inflammatory abdominal pain is a prerequisite clinical feature of IBS. Abdominal
bowel disease. N Engl J Med 372:15, 2014. pain in IBS is highly variable in intensity and location. It is frequently
Bonovas S: Biologic therapies and risk of infection and malignancy episodic and crampy, but it may be superimposed on a background
in patients with inflammatory bowel disease: a systemic review and of constant ache. Pain may be mild enough to be ignored or it may
network meta-analysis. Clin Gastroenetrol Hepatol 14:1385, 2016. interfere with daily activities. Despite this, malnutrition due to inade-
Columbel JF et al: The safety of vedolizumab for ulcerative colitis and quate caloric intake is exceedingly rare with IBS. Sleep deprivation is
Crohn’s disease. Gut 66:839, 2017. also unusual because abdominal pain is almost uniformly present only
Ha C, Kornbluth A: A critical review of biosimilars in IBD: The during waking hours. However, patients with severe IBS frequently
confluence of biologic drug development, regulatory requirements, wake repeatedly during the night; thus, nocturnal pain is a poor
clinical outcomes, and big business. Inflamm Bowel Dis 22:2513, 2016. discriminating factor between organic and functional bowel disease.
Julsgaard M: Concentrations of adalimumab and infliximab in moth- Pain is often exacerbated by eating or emotional stress and improved
ers and newborns and effects on infection. Gastroenterology 151:110, by passage of flatus or stools. In addition, female patients with IBS
2016. commonly report worsening symptoms during the premenstrual and
Ng SC: Geographical variability and environmental risk factors in menstrual phases.
inflammatory bowel disease. Gut 62:630, 2013.
Panes J, Jairath V, Levesque BG: Advances in use of endoscopy,
radiology and biomarkers to monitor inflammatory bowel disease. TABLE 320-1 Rome IV Diagnostic Criteria for Irritable Bowel
Gastroenterology 152:362, 2017. Syndromea
Regueiro M: Infliximab reduces endoscopic, but not clinical, recur- Recurrent abdominal pain, on average, at least 1 day per week in the last
rence of Crohn’s disease after ileocolonic resection. Gastroenterology 3 months, associated with ≥2 of the following criteria:
150:1568, 2016. 1. Related to defecation
Sandborn WJ: Ustekinumab induction and maintenance therapy in 2. Associated with a change in frequency of stool
refractory Crohn’s disease. N Engl J Med 367:12, 2012. 3. Associated with a change in form (appearance) of stool
Sandborn WJ: Tofactitinib as induction and maintenance therapy for a
Criteria fulfilled for the last 3 months with symptom onset at least 6 months
ulcerative colitis. N Engl J Med 376:1723, 2017. prior to diagnosis.

Altered Bowel Habits Alteration in bowel habits is 2277
the most consistent clinical feature in IBS. The most com-
mon pattern is constipation alternating with diarrhea, usu- Motility “Leaky” gut
ally with one of these symptoms predominating. At first, abnormalities dysbiosis Visceral
constipation may be episodic, but eventually it becomes hypersensitivity
continuous and increasingly intractable to treatment with Brain–gut
laxatives. Stools are usually hard with narrowed caliber, interactions
possibly reflecting excessive dehydration caused by pro- • HPA axis
• Autonomic IBS
longed colonic retention and spasm. Most patients also
experience a sense of incomplete evacuation, thus leading dysfxn Psychologic
to repeated attempts at defecation in a short time span. • Anxiety/panic
Patients whose predominant symptom is constipation may Genetic factors • Depression
Bile acid • Twin studies
have weeks or months of constipation interrupted with malabsorption • Somatization
• SERT polymorhisms
brief periods of diarrhea. In other patients, diarrhea may
be the predominant symptom. Diarrhea resulting from
FIGURE 320-1 Pathophysiology of IBS. The cause of IBS is likely to be multifactorial. Patients
IBS usually consists of small volumes of loose stools. Most often show evidence of visceral hypersensitivity and motility abnormalities. Many IBS patients
patients have stool volumes of <200 mL. Nocturnal diar- have increased anxiety and/or depression and their symptoms are often exacerbated by mental
rhea does not occur in IBS. Diarrhea may be aggravated or physical stress suggesting abnormal brain–gut interaction. Genetic studies suggest a few
by emotional stress or eating. Stool may be accompanied IBS patients may have genetic abnormalities affecting the serotonin transport system in the
by passage of large amounts of mucus. Bleeding is not a enteric nerves. Up to 30% of IBS patients may have bile acid malabsorption. Gut dysbiosis and
feature of IBS unless hemorrhoids are present, and malab- impaired mucosa permeability also have been reported in many IBS patients. This may lead to
subclinical mucosa inflammation.
sorption or weight loss does not occur.
Bowel pattern subtypes are highly unstable. In a patient
population with ~33% prevalence rates of IBS-diarrhea predominant GI Motor Abnormalities Studies of colonic myoelectrical and
(IBS-D), IBS-constipation predominant (IBS-C), and IBS-mixed (IBS-M) motor activity under unstimulated conditions have not shown consis-
forms, 75% of patients change subtypes and 29% switch between IBS-C tent abnormalities in IBS. In contrast, colonic motor abnormalities are
and IBS-D over 1 year. The heterogeneity and variable natural history more prominent under stimulated conditions in IBS. IBS patients may
of bowel habits in IBS increase the difficulty of conducting pathophys- exhibit increased rectosigmoid motor activity for up to 3 h after eating.
CHAPTER 320 Irritable Bowel Syndrome

iology studies and clinical trials. Similarly, inflation of rectal balloons both in IBS-D and IBS-C patients
leads to marked and prolonged distention-evoked contractile activ-
Gas and Flatulence Patients with IBS frequently complain of ity. Recordings from the transverse, descending, and sigmoid colon
abdominal distention and increased belching or flatulence, all of which showed that the motility index and peak amplitude of high-amplitude
they attribute to increased gas. Although some patients with these propagating contractions (HAPCs) in diarrhea-prone IBS patients were
symptoms actually may have a larger amount of gas, quantitative greatly increased compared to those in healthy subjects and were asso-
measurements reveal that most patients who complain of increased ciated with rapid colonic transit and accompanied by abdominal pain.
gas generate no more than a normal amount of intestinal gas. Most IBS
patients have impaired transit and tolerance of intestinal gas loads. In Visceral Hypersensitivity As with studies of motor activity, IBS
addition, patients with IBS tend to reflux gas from the distal to the more patients frequently exhibit exaggerated sensory responses to visceral
proximal intestine, which may explain the belching. Some patients with stimulation. The frequency of perceptions of food intolerance is at least
bloating may also experience visible distention with increase in abdom- twofold more common than in the general population. Postprandial
inal girth. Both symptoms are more common among female patients pain has been temporally related to entry of the food bolus into the
and in those with higher overall Somatic Symptom Checklist scores. cecum in 74% of patients. On the other hand, prolonged fasting in IBS
patients is often associated with significant improvement in symptoms.
Upper GI Symptoms Between 25 and 50% of patients with IBS Rectal balloon inflation produces nonpainful and painful sensations at
complain of dyspepsia, heartburn, nausea, and vomiting. This suggests lower volumes in IBS patients than in healthy controls without altering
that other areas of the gut apart from the colon may be involved. Pro- rectal tension, suggestive of visceral afferent dysfunction in IBS. Similar
longed ambulant recordings of small-bowel motility in patients with studies show gastric and esophageal hypersensitivity in patients with
IBS show a high incidence of abnormalities in the small bowel during nonulcer dyspepsia and noncardiac chest pain, raising the possibility
the diurnal (waking) period; nocturnal motor patterns are not different that these conditions have a similar pathophysiologic basis. Lipids
from those of healthy controls. The overlap between dyspepsia and IBS lower the thresholds for the first sensation of gas, discomfort, and pain
is great. The prevalence of IBS is higher among patients with dyspepsia in IBS patients. Hence, postprandial symptoms in IBS patients may
(31.7%) than among those who reported no symptoms of dyspepsia be explained in part by a nutrient-dependent exaggerated sensory
(7.9%). Conversely, among patients with IBS, 55.6% reported symptoms component of the gastrocolonic response. In contrast to enhanced gut
of dyspepsia. In addition, the functional abdominal symptoms can sensitivity, IBS patients do not exhibit heightened sensitivity elsewhere
change over time. Those with predominant dyspepsia or IBS can flux in the body. Thus, the afferent pathway disturbances in IBS appear
between the two. Although the prevalence of functional GI disorders to be selective for visceral innervation with sparing of somatic path-
is stable over time, the turnover in symptom status is high. Many epi- ways. The mechanisms responsible for visceral hypersensitivity are
sodes of symptom disappearance are due to subjects changing symp- still under investigation. It has been proposed that these exaggerated
toms rather than total symptom resolution. Thus it is conceivable that responses may be due to (1) increased end-organ sensitivity with
functional dyspepsia and IBS are two manifestations of a single, more recruitment of “silent” nociceptors; (2) spinal hyperexcitability with
extensive digestive system disorder. Furthermore, IBS symptoms are activation of nitric oxide and possibly other neurotransmitters; (3)
prevalent in noncardiac chest pain patients, suggesting overlap with endogenous (cortical and brainstem) modulation of caudad nocicep-
other functional gut disorders. tive transmission; and (4) over time, the possible development of long-
term hyperalgesia due to development of neuroplasticity, resulting in
■■PATHOPHYSIOLOGY
permanent or semipermanent changes in neural responses to chronic or
The pathogenesis of IBS is poorly understood, although roles of
recurrent visceral stimulation.
abnormal gut motor and sensory activity, central neural dysfunction,
psychological disturbances, mucosal inflammation, stress, and luminal Central Neural Dysregulation The role of central nervous sys-
factors such as bile acid malabsorption and gut dysbiosis have been tem (CNS) factors in the pathogenesis of IBS is strongly suggested by
proposed (Fig. 320-1). the clinical association of emotional disorders and stress with symptom

2278 exacerbation and the therapeutic response to therapies that act on cere- pain. Interestingly, clinical studies have also shown increased intestinal
bral cortical sites. Functional brain imaging studies such as magnetic permeability in patients with IBS-D. Psychological stress and anxiety
resonance imaging (MRI) have shown that in response to distal colonic can increase the release of proinflammatory cytokine, and this in turn
stimulation, the mid-cingulate cortex—a brain region concerned with may alter intestinal permeability. A clinical study shows 39% of IBS-D
attention processes and response selection—shows greater activation in patients had increased intestinal permeability as measured by the
IBS patients. Modulation of this region is associated with changes in the lactulose/mannitol ratio. These IBS patients also demonstrated higher
subjective unpleasantness of pain. In addition, IBS patients also show Functional Bowel Disorder Severity Index (FBDSI) score and increased
preferential activation of the prefrontal lobe, which contains a vigilance hypersensitivity to visceral nociceptive pain stimuli. This provides a
network within the brain that increases alertness. These may represent functional link between psychological stress, immune activation, and
a form of cerebral dysfunction leading to the increased perception of symptom generation in patients with IBS.
visceral pain.
Altered Gut Flora A high prevalence of small intestinal bacterial
Abnormal Psychological Features Abnormal psychiatric fea- overgrowth in IBS patients has been noted based on positive lactulose
tures are recorded in up to 80% of IBS patients, especially in referral hydrogen breath test. This finding, however, has been challenged by a
centers; however, no single psychiatric diagnosis predominates. Most number of other studies that found no increased incidence of bacterial
of these patients demonstrated exaggerated symptoms in response to overgrowth based on jejunal aspirate culture. Abnormal H2 breath
visceral distention, and this abnormality persists even after exclusion test can occur because of small-bowel rapid transit and may lead to
of psychological factors. erroneous interpretation. Hence, the role of testing for small intestinal
Psychological factors influence pain thresholds in IBS patients, as bacterial overgrowth in IBS patients remains unclear.
stress alters sensory thresholds. An association between prior sexual Studies using culture-independent approaches such as 16S rRNA
or physical abuse and development of IBS has been reported. Clinical gene-based analysis found significant differences between the molecular
studies suggest that IBS has a strong developmental component which profile of the fecal microbiota of IBS patients and that of healthy sub-
involves interactions of genetic and epigenetic factors early in life. jects. Twenty-two studies, comprising 827 subjects, reported significant
These may modulate brain networks related to emotional arousal and/ changes in the microbial communities of healthy individuals versus
or central autonomic control, salience and somatosensory integration. patients with different subtypes of IBS. Despite a lack of consensus on
Abuse is associated with greater pain reporting, psychological distress, the exact microbial differences between IBS patients and controls, in gen-
and poor health outcome. Brain functional MRI studies show greater eral IBS patients had decreased proportions of the genera Bifidobacterium
activation of the posterior and middle dorsal cingulate cortex, which and Lactobacillus and increased ratios of Firmicutes:Bacteroidetes. It has
is implicated in affect processing in IBS patients with a past history of been speculated that these changes may be related to stress and diet. A
sexual abuse. temporary reduction in lactobacilli has been reported in animal mod-
PART 10
Thus, patients with IBS frequently demonstrate increased motor els of early-life stress. On the other hand, Firmicutes is the dominant
reactivity of the colon and small bowel to a variety of stimuli and phylum in adults consuming a diet high in animal fat and protein. It
altered visceral sensation associated with lowered sensation thresholds. is conceivable that gut dysbiosis acting in concert with genetic sus-
These may result from CNS–enteric nervous system dysregulation. ceptibility and environmental insults may alter mucosal permeability
and increase antigen presentation to the immune cells in the lamina

Postinfectious IBS IBS may be induced by GI infection. In an propria. This may result in mast cell activation and altered enteric neu-
investigation of 544 patients with confirmed bacterial gastroenteritis, ronal and smooth muscle function causing IBS symptoms. In addition,
one-quarter developed IBS subsequently. Conversely, about a third of release of cytokines and chemokines from mucosal inflammation may
IBS patients experienced an acute “gastroenteritis-like” illness at the generate extra GI symptoms such as chronic fatigue, muscle pain, and
onset of their chronic IBS symptomatology. This group of “postinfec- anxiety (Fig. 320-2).
tive” IBS occurs more commonly in females and affects younger rather
than older patients. Risk factors for developing postinfectious IBS Abnormal Serotonin Pathways The serotonin (5-HT)-containing
include, in order of importance, prolonged duration of initial illness, enterochromaffin cells in the colon are increased in a subset of IBS-D
patients compared to healthy individuals or patients with ulcerative
toxicity of infecting bacterial strain, smoking, mucosal markers of
colitis. Furthermore, postprandial plasma 5-HT levels were signifi-
inflammation, female sex, depression, hypochondriasis, and adverse
cantly higher in this group of patients compared to healthy controls.
life events in the preceding 3 months. Age older than 60 years might
Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in
protect against postinfectious IBS, whereas treatment with antibiotics
enterochromaffin cell 5-HT biosynthesis, functional TPH1 polymor-
has been associated with increased risk. The microbes involved in
phism has been shown to be associated with IBS habit subtypes.
the initial infection are Campylobacter, Salmonella, and Shigella. Those
Because serotonin plays an important role in the regulation of GI
patients with Campylobacter infection who are toxin-positive are more
motility and visceral perception, the increased release of serotonin may
likely to develop postinfective IBS. Increased rectal mucosal enteroen-
contribute to the postprandial symptoms of these patients and pro-
docrine cells, T lymphocytes, and increased gut permeability are acute
vides a rationale for the use of serotonin antagonists in the treatment
changes following Campylobacter enteritis that could persist for more
of this disorder.
than a year and may contribute to postinfective IBS.
Immune Activation and Mucosal Inflammation Some APPROACH TO THE PATIENT
patients with IBS display persistent signs of low-grade mucosal
inflammation with activated lymphocytes, mast cells, and enhanced Irritable Bowel Syndrome
expression of proinflammatory cytokines. Other studies also indicate
Because IBS is a disorder for which no pathognomonic abnormalities
that peripheral blood mononuclear cells (PBMCs) from IBS patients
have been identified, its diagnosis relies on recognition of positive
show abnormal release of proinflammatory cytokines such as IL6, IL1β,
clinical features and elimination of other organic diseases. Symp-
and TNF. These abnormalities may contribute to abnormal epithelial
tom-based criteria have been developed for the purpose of differ-
secretion and visceral hypersensitivity. There is increasing evidence
entiating patients with IBS from those with organic diseases. These
that some members of the superfamily of transient receptor potential
include the Manning, Rome I, Rome II, Rome III, and Rome IV crite-
(TRP) cation channels such as TRPV1 (vanilloid) channels are central
ria. Rome IV criteria for the diagnosis of IBS were published in 2016
to the initiation and persistence of visceral hypersensitivity. Mucosal
(Table 320-1) and defined IBS on the basis of abdominal pain and
inflammation can lead to increased expression of TRPV1 in the enteric
altered bowel habits that occur with sufficient frequency in affected
nervous system. Enhanced expression of TRPV1 channels in the sen-
patients. A careful history and physical examination are frequently
sory neurons of the gut has been observed in IBS, and such expression
helpful in establishing the diagnosis. Clinical features suggestive of
appears to correlate with visceral hypersensitivity and abdominal

2279
-Dysbiosis
-Genetic Increased
Altered Mast cell
susceptibility antigen
permeability activation
-Environmental presentation
insults
Altered
enteric
Systemic
Extra GI neuronal &
symptoms
cytokines IBS smooth
& chemokines
muscle
function
FIGURE 320-2 Gut dysbiosis and IBS. Gut dysbiosis acting in concert with genetic and environmental factors may alter intestinal permeability, increase antigen
presentation resulting in mast cell activation. Products of mast cell degranulation may alter neuronal and smooth muscle function causing IBS symptoms. The
cytokines and chemokines generated from mucosal inflammation may cause symptoms such as fibromyalgia, chronic fatigue, and mood changes. (Adapted from NJ
Talley, AA Fodor: Gastroenterology 141: 1555, 2011.)
IBS include the following: recurrence of lower abdominal pain with the degree of psychosocial dysfunction. Thus, a younger individual
altered bowel habits over a period of time without progressive dete- with mild symptoms requires a minimal diagnostic evaluation,
rioration, onset of symptoms during periods of stress or emotional while an older person or an individual with rapidly progressive
upset, absence of other systemic symptoms such as fever and weight symptoms should undergo a more thorough exclusion of organic
loss, and small-volume stool without any evidence of blood. disease. Most patients should have a complete blood count and

On the other hand, the appearance of the disorder for the first sigmoidoscopic examination; in addition, stool specimens should
time in old age, progressive course from time of onset, persistent be examined for ova and parasites in those who have diarrhea. In
diarrhea after a 48-h fast, and presence of nocturnal diarrhea or patients with persistent diarrhea not responding to simple anti-
steatorrheal stools argue against the diagnosis of IBS. diarrheal agents, a sigmoid colon biopsy should be performed to
Because the major symptoms of IBS—abdominal pain, abdominal rule out microscopic colitis. In those age >40 years, an air-contrast
bloating, and alteration in bowel habits—are common complaints barium enema or colonoscopy should also be performed. If the main
of many GI organic disorders, the list of differential diagnoses is a symptoms are diarrhea and increased gas, the possibility of lactase
long one. The quality, location, and timing of pain may be helpful deficiency should be ruled out with a hydrogen breath test or with
to suggest specific disorders. Pain due to IBS that occurs in the evaluation after a 3-week lactose-free diet. Excessive gas with bloat-
epigastric or periumbilical area must be differentiated from bil- ing also raises the possibility of small bowel bacteria overgrowth
iary tract disease, peptic ulcer disorders, intestinal ischemia, and and should be ruled out with a glucose hydrogen breath test. Some
carcinoma of the stomach and pancreas. If pain occurs mainly in patients with IBS-D may have undiagnosed celiac sprue. Because
the lower abdomen, the possibility of diverticular disease of the the symptoms of celiac sprue respond to a gluten-free diet, testing
colon, inflammatory bowel disease (including ulcerative colitis and for celiac sprue in IBS may prevent years of morbidity and attendant
Crohn’s disease), and carcinoma of the colon must be considered. expense. Decision-analysis studies show that serology testing for
Postprandial pain accompanied by bloating, nausea, and vomiting celiac sprue in patients with IBS-D has an acceptable cost when the
suggests gastroparesis or partial intestinal obstruction. Intestinal prevalence of celiac sprue is >1% and is the dominant strategy when
infestation with Giardia lamblia or other parasites may cause similar the prevalence is >8%. In patients with concurrent symptoms of dys-
symptoms. When diarrhea is the major complaint, the possibility pepsia, upper GI radiographs or esophagogastroduodenoscopy may
of lactase deficiency, laxative abuse, malabsorption, celiac sprue, be advisable. In patients with postprandial right upper quadrant
hyperthyroidism, inflammatory bowel disease, and infectious diar- pain, an ultrasonogram of the gallbladder should be obtained.
rhea must be ruled out. On the other hand, constipation may be a Laboratory features that argue against IBS include evidence of ane-
side effect of many different drugs, such as anticholinergic, antihy- mia, elevated sedimentation rate, presence of leukocytes or blood
pertensive, and antidepressant medications. Endocrinopathies such in stool, and stool volume >200–300 mL/d. These findings would
as hypothyroidism and hypoparathyroidism must also be consid- necessitate other diagnostic considerations.
ered in the differential diagnosis of constipation, particularly if other
systemic signs or symptoms of these endocrinopathies are present.
In addition, acute intermittent porphyria and lead poisoning may TREATMENT
present in a fashion similar to IBS, with painful constipation as the
major complaint. These possibilities are suspected on the basis of Irritable Bowel Syndrome
their clinical presentations and are confirmed by appropriate serum
Patient Counseling and Dietary Alterations Reassurance and
and urine tests.
careful explanation of the functional nature of the disorder and of
Few tests are required for patients who have typical IBS symp-
how to avoid obvious food precipitants are important first steps in
toms and no alarm features. Unnecessary investigations may be
patient counseling and dietary change. Occasionally, a meticulous
costly and even harmful. The American Gastroenterological Asso-
dietary history may reveal substances (such as coffee, disaccha-
ciation has delineated factors to be considered when determining
rides, legumes, and cabbage) that aggravate symptoms. Excessive
the aggressiveness of the diagnostic evaluation. These include the
fructose and artificial sweeteners, such as sorbitol or mannitol, may
duration of symptoms, the change in symptoms over time, the
cause diarrhea, bloating, cramping, or flatulence. As a therapeutic
age and sex of the patient, the referral status of the patient, prior
trial, patients should be encouraged to eliminate any foodstuffs
diagnostic studies, a family history of colorectal malignancy, and
that appear to produce symptoms. However patients should avoid

2280 TABLE 320-2 Some Common Food Sources of FODMAPs
FOOD TYPE FREE FRUCTOSE LACTOSE FRUCTANS GALACTO-OLIGOSACCHARIDES POLYOLS
Fruits Apple, cherry, mango, Peach, persimmon, watermelon Apple, apricot, pear, avocado,
pear, watermelon blackberries, cherry, nectarine,
plum, prune
Vegetables Asparagus, Artichokes, beetroot, Brussels Cauliflower, mushroom,
artichokes, sugar sprout, chicory, fennel, garlic, snow peas
snap peas leek, onion, peas
Grains and Wheat, rye, barley
cereals
Nuts and Pistachios
seeds
Milk and milk Milk, yogurt, ice
products cream, custard,
soft cheeses
Legumes Legumes, lentils, chickpeas Legumes, chickpeas, lentils
Other Honey, high-fructose Chicory drinks
corn syrup
Food additives Inulin, FOS Sorbitol, mannitol, maltitol,
xylitol, isomalt
Abbreviations: FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; FOS, fructo-oligosaccharides.
Source: Adapted from PR Gibson et al: Am J Gastroenterol 107:657, 2012.
nutritionally depleted diets. A diet low in fermentable oligosaccha- beneficial effects of anticholinergic drugs for pain. A meta-analysis
rides, disaccharides, monosaccharides, and polyols (FODMAPs) of 26 double-blind clinical trials of antispasmodic agents in IBS
(Table 320-2) has been shown to be helpful in IBS patients (see Low reported better global improvement (62%) and abdominal pain
FODMAP Diet). reductions (64%) compared to placebo (35 and 45%, respectively),
Stool-Bulking Agents High-fiber diets and bulking agents, such suggesting efficacy in some patients. The drugs are most effective
PART 10
as bran or hydrophilic colloid, are frequently used in treating IBS. when prescribed in anticipation of predictable pain. Physiologic
The water-holding action of fibers may contribute to increased studies demonstrate that anticholinergic drugs inhibit the gastro-
stool bulk because of the ability of fiber to increase fecal output of colic reflex; hence, postprandial pain is best managed by giving
bacteria. Fiber also speeds up colonic transit in most persons. In antispasmodics 30 min before meals so that effective blood levels
are achieved shortly before the anticipated onset of pain. Most
diarrhea-prone patients, whole-colonic transit is faster than aver-

age; however, dietary fiber can delay transit. Furthermore, because anticholinergics contain natural belladonna alkaloids, which may
of their hydrophilic properties, stool-bulking agents bind water and cause xerostomia, urinary hesitancy and retention, blurred vision,
thus prevent both excessive hydration and dehydration of stool. and drowsiness. They should be used in the elderly with caution.
The latter observation may explain the clinical experience that a Some physicians prefer to use synthetic anticholinergics such as
high-fiber diet relieves diarrhea in some IBS patients. Fiber supple- dicyclomine that have less effect on mucous membrane secretions
mentation with psyllium has been shown to reduce perception of and produce fewer undesirable side effects.
rectal distention, indicating that fiber may have a positive effect on Antidiarrheal Agents Peripherally acting opiate-based agents are
visceral afferent function. the initial therapy of choice for IBS-D. Physiologic studies demon-
The beneficial effects of dietary fiber on colonic physiology sug- strate increases in segmenting colonic contractions, delays in
gest that dietary fiber should be an effective treatment for IBS fecal transit, increases in anal pressures, and reductions in rectal
patients, but controlled trials of dietary fiber have produced variable perception with these drugs. When diarrhea is severe, especially
results. This is not surprising since IBS is a heterogeneous disorder, in the painless diarrhea variant of IBS, small doses of loperamide,
with some patients being constipated and other having predomi- 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed.
nant diarrhea. Most investigations report increases in stool weight, These agents are less addictive than paregoric, codeine, or tincture
decreases in colonic transit times, and improvement in constipation. of opium. In general, the intestines do not become tolerant of the
Others have noted benefits in patients with alternating diarrhea and antidiarrheal effect of opiates, and increasing doses are not required
constipation, pain, and bloating. However, most studies observe no to maintain antidiarrheal potency. These agents are most useful if
responses in patients with diarrhea- or pain-predominant IBS. It is taken before anticipated stressful events that are known to cause
possible that different fiber preparations may have dissimilar effects diarrhea. However, not infrequently, a high dose of loperamide may
on selected symptoms in IBS. A cross-over comparison of different cause cramping because of increases in segmenting colonic contrac-
fiber preparations found that psyllium produced greater improve- tions. Another antidiarrheal agent that may be used in IBS patients
ments in stool pattern and abdominal pain than bran. Furthermore, is the bile acid binder cholestyramine resin as up to 30% of IBS-D
psyllium preparations tend to produce less bloating and distention. patients may have bile acid malabsorption.
Despite the equivocal data regarding efficacy, most gastroenterol- Antidepressant Drugs In addition to their mood-elevating effects,
ogists consider stool-bulking agents worth trying in patients with antidepressant medications have several physiologic effects that
IBS-C. Fiber should be started at a nominal dose and slowly titrated suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic
up as tolerated over the course of several weeks to a targeted dose of antidepressant imipramine slows jejunal migrating motor complex
20–30 g of total dietary and supplementary fiber per day. Even when transit propagation and delays orocecal and whole-gut transit,
used judiciously, fiber can exacerbate bloating, flatulence, constipa- indicative of a motor inhibitory effect. Some studies also suggest
tion, and diarrhea. that tricyclic agents may alter visceral afferent neural function.
Antispasmodics Clinicians have observed that anticholinergic A number of studies indicate that tricyclic antidepressants may be
drugs may provide temporary relief for symptoms such as painful effective in some IBS patients. In a 2-month study of desipramine,
cramps related to intestinal spasm. Although controlled clinical abdominal pain improved in 86% of patients compared to 59% given
trials have produced mixed results, evidence generally supports placebo. Another study of desipramine in 28 IBS patients showed

improvement in stool frequency, diarrhea, pain, and depression. modest therapeutic gain was similar to that yielded by other cur- 2281
When stratified according to the predominant symptoms, improve- rent available therapies for IBS. However, currently there are still
ments were observed in IBS-D patients, with no improvement insufficient data to recommend routine use of this antibiotic in the
being noted in IBS-C patients. The beneficial effects of the tricyclic treatment of IBS.
compounds in the treatment of IBS appear to be independent of Prebiotics These are nondigestible food ingredients that stimulate
their effects on depression. The therapeutic benefits for the bowel growth and/or activity of bacteria in the GI tract. There have been
symptoms occur faster and at a lower dosage. The efficacy of anti- four randomized trials to examine the effects of prebiotics. Three
depressant agents in other chemical classes in the management of of the four studies reported that prebiotics worsened or did not
IBS is less well evaluated. In contrast to tricyclic agents, the selective improve IBS symptoms. This is not surprising given the adverse
serotonin reuptake inhibitor (SSRI) paroxetine accelerates orocecal effects of high carbohydrate diet on IBS symptoms.
transit, raising the possibility that this drug class may be useful in
IBS-C patients. The SSRI citalopram blunts perception of rectal dis- Probiotics These are defined as live microorganisms that when
tention and reduces the magnitude of the gastrocolonic response in administered in adequate amounts confer a health benefit on the host.
healthy volunteers. A small placebo-controlled study of citalopram A meta-analysis of 10 probiotic studies in IBS patients found signifi-
in IBS patients reported reductions in pain. However, these findings cant relief of pain and bloating with the use of Bifidobacterium breve,
could not be confirmed in another randomized controlled trial that B longum, and Lactobacillus acidophilus species compared to placebo.
showed that citalopram at 20 mg/d for 4 weeks was not superior to However, there was no change in stool frequency or consistency.
placebo in treating nondepressed IBS patients. Hence, the efficacy of Large-scale studies of well-phenotyped IBS patients are needed to
SSRIs in the treatment of IBS needs further confirmation. establish the efficacy of these probiotics.
Antiflatulence Therapy The management of excessive gas is sel- Low FODMAP Diet A diet rich in FODMAP (fermentable oligo-
dom satisfactory, except when there is obvious aerophagia or saccharides, disaccharides, monosaccharides, and polyols) often
disaccharidase deficiency. Patients should be advised to eat slowly triggers symptoms in IBS patients. FODMAPs are poorly absorbed
and not chew gum or drink carbonated beverages. Bloating may by the small intestine and fermented by bacteria in the colon to
decrease if an associated gut syndrome such as IBS or constipation produce gas and osmotically active carbohydrates (Fig. 320-4).
is improved. If bloating is accompanied by diarrhea and worsens At the same time, on entering the colon, FODMAPs may serve as
after ingesting dairy products, fresh fruits, vegetables, or juices, nutrient for the colonic bacteria and promote the growth of gram
further investigation or a dietary exclusion trial may be worth- negative commensal bacteria which may induce epithelial damage
while. Avoiding flatogenic foods, exercising, losing excess weight, and subclinical mucosa inflammation. Fructose and fructans induce

and taking activated charcoal are safe but unproven remedies. A IBS symptoms in a dose-dependent manner. In contrast, a low
low FODMAP diet has been shown to be quite effective to reduce FODMAP diet reduces IBS symptoms. A randomized controlled
gas and bloating (see Low FODMAP Diet). Data regarding the use trial showed a 4-week low FODMAP diet improved symptoms in
of surfactants such as simethicone are conflicting. Antibiotics may 68% of IBS patients compared with 23% on a habitual diet. Low
help in a subgroup of IBS patients with predominant symptoms of FOMAP diets appeared to be superior to national guidelines for IBS
bloating. Beano, an over-the-counter oral β-glycosidase solution, management. These observations were confirmed by a double blind
may reduce rectal passage of gas without decreasing bloating and controlled study of 30 IBS patients and 18 healthy controls, in which
pain. Pancreatic enzymes reduce bloating, gas, and fullness during a low FODMAP diet significantly reduced bloating, pain, passage of
and after high-calorie, high-fat meal ingestion. gas, and diarrhea. A double blind randomized control trial involv-
ing 92 IBS patients showed >50% of patients on the low FODMAP
Modulation of Gut Flora Because altered colonic flora (gut dysbio- diet had major improvement of their abdominal pain compared
sis) may contribute to the pathogenesis of IBS, this has led to great
interest in using antibiotics, prebiotics, and probiotics to treat IBS
(Fig. 320-3).
Small poorly absorbed carbohydrates
Antibiotics Antibiotic treatment benefits a subset of IBS patients.
In a double-blind, randomized, placebo-controlled study, neomy-
cin dosed at 500 mg twice daily for 10 days was more effective Food source for
than placebo at improving symptom scores among IBS patients. Laxative effect
bacteria
The nonabsorbed oral antibiotic rifaximin is the most thoroughly
studies antibiotic of the treatment of IBS. In a double-blind, placebo-
controlled study, patients receiving rifaximin at a dose of 550 mg
two times daily for 2 weeks experienced substantial improvement Water in intestines Gas production
of global IBS symptoms over placebo. Rifaximin is the only antibi-
otic with demonstrated sustained benefit beyond therapy cessation
in IBS patients. The drug has a favorable safety and tolerability
profile compared with systemic antibiotics. A systemic review and
meta-analysis of five studies of IBS patients found that rifaximin
is more effective than placebo for global symptoms and bloating Abdominal
(odds ratio 1.57) with a number needed to treat (NNT) of 10.2. The distention
Probiotics
Prebiotics
Dysbiosis Bloating, abdominal discomfort, flatulence, diarrhea
Diet Antibiotics FIGURE 320-4 Pathogenesis of FODMAP-related symptoms. FODMAPs are poorly
absorbed by the small intestine and fermented by gut bacteria to produce gas and
osmotically active carbohydrates. These events act in concert to cause bloating,
flatulence, and diarrhea. FODMAP may also serve as nutrients for colonic bacteria
FIGURE 320-3 Gut dysbiosis: a potential treatment target. Prebiotics, probiotics, which may induce mucosa inflammation. (Figure created using data from http://
and low FODMAP diet may be used to modulate gut flora and treat IBS. www.nutritiontoyou.com/wp-content/uploads/2014/06/IBS-symptoms.png.)

2282 with 20% of the control group. These observations demonstrate the TABLE 320-4 Possible Drugs for a Dominant Symptom in IBS
impressive efficacy of low FODMAP diet for many IBS patients, and
SYMPTOM DRUG DOSE
if confirmed may justify the recommendation of a low FODMAP
Diarrhea Loperamide 2–4 mg when necessary/
diet as first-line treatment for IBS patients. maximum 12 g/d
Serotonin Receptor Agonist and Antagonists Serotonin receptor Cholestyramine resin 4 g with meals
antagonists have been evaluated as therapies for IBS-D. Seroto- Alosetrona 0.5–1 mg bid (for severe IBS,
nin acting on 5-HT3 receptors enhances the sensitivity of afferent women)
neurons projecting from the gut. In humans, a 5-HT3 receptor Constipation Psyllium husk 3–4 g bid with meals, then adjust
antagonist such as alosetron reduces perception of painful vis- Methylcellulose 2 g bid with meals, then adjust
ceral stimulation in IBS. It also induces rectal relaxation, increases Calcium polycarbophil 1 g qd to qid
rectal compliance, and delays colonic transit. Meta-analysis of 14 Lactulose syrup 10–20 g bid
randomized controlled trials of alosetron or cilansetron showed
70% sorbitol 15 mL bid
that these antagonists are more effective than placebo in achieving
Polyethylene glycol 3350 17 g in 250 mL water qd
global improvement in IBS symptoms and relief of abdominal pain
and discomfort. These agents are more likely to cause constipation Lubiprostone (Amitiza) 24 mg bid
in IBS patients with diarrhea alternating with constipation. Also, Magnesium hydroxide 30–60 mL qd
0.2% of patients using 5-HT3 antagonists developed ischemic col- Linaclotide 290 μg qd
itis versus none in the control group. In postrelease surveillance, Abdominal Smooth-muscle relaxant qd to qid ac
84 cases of ischemic colitis were observed, including 44 cases that pain Tricyclic antidepressants Start 25–50 mg hs, then adjust
required surgery and 4 deaths. As a consequence, the medication Selective serotonin Begin small dose, increase as
was voluntarily withdrawn by the manufacturer in 2000. Alosetron reuptake inhibitors needed
has been reintroduced under a new risk-management program Gas and Low FODMAP diet
where patients have to sign a patient-physician agreement. This has bloating Probiotics qd
significantly limited its usage. Rifaximin 550 mg bid
Novel 5-HT4 receptor agonists such as tegaserod exhibit proki-
Available only in the United States.
a
netic activity by stimulating peristalsis. In IBS patients with consti-
pation, tegaserod accelerated intestinal and ascending colon transit. Abbreviation: FODMAP, fermentable oligosaccharides, disaccharides,
monosaccharides, and polyols.
Clinical trials involving >4000 IBS-C patients reported reductions in
Source: Adapted from GF Longstreth et al: Gastroenterology 130:1480, 2006.
discomfort and improvements in constipation and bloating, com-
PART 10
pared to placebo. Diarrhea is the major side effect. However, tegase-

rod has been withdrawn from the market; a meta-analysis revealed
an increase in serious cardiovascular events. bowel movement. The only significant side effect was diarrhea,
Chloride Channel Activators Lubiprostone is a bicyclic fatty acid which occurred in 4.5% of the patients. The drug has been approved
for treatment of constipation in IBS-C patients.
that stimulates chloride channels in the apical membrane of intesti-

nal epithelial cells. Chloride secretion induces passive movement of Summary The treatment strategy of IBS depends on the severity of
sodium and water into the bowel lumen and improves bowel func- the disorder (Table 320-3). Most IBS patients have mild symptoms.
tion. Oral lubiprostone was effective in the treatment of patients They are usually cared for in primary care practices, have little
with constipation-predominant IBS in large phase II and phase III or no psychosocial difficulties, and do not seek health care often.
randomized, double-blinded, placebo-controlled multicenter trials. Treatment usually involves education, reassurance, and dietary/
Responses were significantly greater in patients receiving lubipros- lifestyle changes. A smaller portion have moderate symptoms that
tone 8 μg twice daily for 3 months than in those receiving placebo. are usually intermittent and correlate with altered gut physiology,
In general, the drug was quite well tolerated. The major side effects e.g., worsened with eating or stress and relieved by defecation. For
are nausea and diarrhea. Lubiprostone is a new class of compounds IBS-D patients, treatments include gut-acting pharmacologic agents
for treatment of chronic constipation with or without IBS. such as antispasmodics, antidiarrheals, bile acid binders, and the
Guanylate Cyclase-C Agonist Linaclotide is a minimally absorbed newer gut serotonin modulators (Table 320-4). In IBS-C patients,
14-amino-acid peptide guanylate cyclase-C (GC-C) agonist that increased fiber intake and the use of osmotic agents such as polyeth-
binds to and activates GC-C on the luminal surface of intestinal ylene glycol may achieve satisfactory results. For patients with more
epithelium. Activation of GC-C results in generation of cyclic gua- severe constipation, a chloride channel opener (lubiprostone) or
nosine monophosphate (cGMP), which triggers secretion of fluid, GC-C agonist (linaclotide) may be considered. For IBS patients with
sodium, and bicarbonate. In animal models, linaclotide accelerates predominant gas and bloating, a low-FODMAP diet may provide
GI transit and reduces visceral nociception. The analgesic action significant relief. Some patients may benefit from probiotics and
of linaclotide appears to be mediated by cGMP acting on afferent rifaximin treatment. A small proportion of IBS patients have severe
pain fibers innervating the GI tract. A phase III, double-blind, and refractory symptoms, are usually seen in referral centers, and
controlled trial showed that linaclotide, 290 μg given once daily, frequently have constant pain and psychosocial difficulties. This
significantly improved abdominal pain, bloating, and spontaneous group of patients is best managed with antidepressants and other
psychological treatments (Table 320-4). Clinical trials demonstrating
success of low FODMAP diet in improving IBS symptoms and qual-
TABLE 320-3 Spectrum of Severity in IBS ity of life provide strong evidence supporting the use of this dietary
MILD MODERATE SEVERE approach in the treatment of IBS. These observations, if confirmed,
Clinical Features may lead to the use of low FODMAP diet as the first line of treat-
Prevalence 70% 25% 5% ment of IBS patients with moderate to severe symptoms.
Correlations with gut +++ ++ +
physiology ■■FURTHER READING
Symptoms constant 0 + +++ Barbara G et al: The immune system in irritable bowel syndrome.
Psychosocial difficulties 0 + +++ J Neurogastroenterol Motil 17:349, 2011.
Health care issues + ++ +++ Drossman DA: Functional gastrointestinal disorders: History, patho-
physiology, clinical features, and Rome IV. Gastroenterology 150:1262,
Practice type Primary Specialty Referral
2016.

Eswaran SL et al: A randomized controlled trial comparing the low 2283
FODMAP diet vs. modified NICE guidelines in US adults with IBS-D.
Am J Gastroenterol 111:1824, 2016.
Mayer EA et al: Brain-gut microbiome interactions and functional
bowel disorders. Gastroenterology 146:1500; 2014.
Mayer EA et al: Towards a systems view of IBS. Nar Rev Gastroenterol
Hepatol 12:592, 2015.
Natividad JM, Verdu EF: Modulation of intestinal barrier by intestinal
microbiota: Pathological and therapeutic implications. Pharmacologi-
cal Research 69:42, 2013.
Simren M et al: Intestinal microbiota in functional bowel disorders: A
Rome foundation report. Gut 62:159, 2013.
Talley NJ, Fodor AA: Bugs, stool, and the irritable bowel syndrome:
Too much is as bad as too little? Gastroenterology 141:1555, 2011.
321 Diverticular Disease

and Common Anorectal
Disorders
Rizwan Ahmed, Susan L. Gearhart
CHAPTER 321 Diverticular Disease and Common Anorectal Disorders

■■DIVERTICULAR DISEASE
Incidence and Epidemiology In the United States,
diverticulosis affects 60% of the population aged >60 and up to
30% of individuals with diverticular disease will experience
recurrent symptoms. Diverticular disease has become the fifth most
costly gastrointestinal disorder in the United States and is the leading
indication for elective colon resection. The incidence of diverticular dis-
ease is on the rise. Fortunately, only 20% of patients with diverticulosis
develop diverticular disease and 4% require hospitalization. Previously
overlooked, the majority of patients with diverticular disease report a
lower health-related quality of life and more depression as compared to
matched controls, thus adding to health care costs. Formerly, diverticular
disease was confined to developed countries; however, with the adop- FIGURE 321-1 Gross and microscopic view of sigmoid diverticular disease.
tion of westernized diets in underdeveloped countries, diverticulosis is Arrows mark an inflamed diverticulum with the diverticular wall made up only of
on the rise across the globe. Immigrants to the United States develop mucosa.
diverticular disease at the same rate as U.S. natives. Although the preva-
lence among females and males is similar, males tend to present at a
younger age. The mean age at presentation is now shifting to affect combined with constipated, high-fat-content stool within the sigmoid
younger populations. lumen in an area of weakness in the colonic wall results in the creation
of these diverticula. Consequently, the vasa recti is either compressed
Anatomy and Pathophysiology Two types of diverticula occur or eroded, leading to either perforation or bleeding. Chronic low-grade
in the intestine: true and false (or pseudo diverticula). A true divertic-
inflammation is thought to play a key role in neuronal degeneration
ulum is a saclike herniation of the entire bowel wall, whereas a pseudo
leading to dysmotility and high intraluminal pressure. As a conse-
diverticulum involves only a protrusion of the mucosa and submucosa
quence, pockets or outpouchings develop in the colonic wall where it
through the muscularis propria of the colon (Fig. 321-1). The type
is weakest. Furthermore, better understanding of the gut microbiota
of diverticulum most commonly affecting the colon is the pseudo
suggests that dysbiosis is an important aspect of disease.
diverticulum. Diverticula commonly affect the left and sigmoid colon;
the rectum is always spared. However, in Asian populations, 70% of Presentation, Evaluation, and Management of Diverticular
diverticula are seen in the right colon and cecum as well. Yamanda Bleeding Hemorrhage from a colonic diverticulum is the most
et al. found right-side colonic diverticulosis in 22% of Japanese patients common cause of hematochezia in patients >60 years, yet only 20%
undergoing colonoscopy. Diverticulitis is inflammation of a divertic- of patients with diverticulosis will have gastrointestinal bleeding.
ulum. Previous understanding of the pathogenesis of diverticulosis Patients at increased risk for bleeding tend to be hypertensive,
attributed a low-fiber diet as the sole culprit, and onset of diverticu- have atherosclerosis, and regularly use aspirin and nonsteroidal
litis would occur acutely when these diverticula become obstructed. anti-inflammatory agents. Most bleeds are self-limited and stop spon-
However, evidence now suggests that the pathogenesis is more com- taneously with bowel rest. The lifetime risk of rebleeding is 25%.
plex and multifactorial. The diverticula occur at the point where the Initial localization of diverticular bleeding may include colonoscopy,
nutrient artery, or vasa recti, penetrates through the muscularis propria, multiplanar computed tomography (CT) angiogram, or nuclear med-
resulting in a break in the integrity of the colonic wall. This anatomic icine tagged red cell scan. If the patient is stable, ongoing bleeding is
restriction may be a result of the relative high-pressure zone within best managed by angiography. If mesenteric angiography can localize
the muscular sigmoid colon. Thus, higher-amplitude contractions the bleeding site, the vessel can be occluded successfully with a coil in

2284 80% of cases. The patient can then be followed closely with repetitive
colonoscopy, if necessary, looking for evidence of colonic ischemia.
Alternatively, a segmental resection of the colon can be undertaken to
eliminate the risk of further bleeding. This may be advantageous in
patients on chronic anticoagulation. However, with highly selective coil Abscess
embolization, the rate of colonic ischemia is <10% and the risk of acute
rebleeding is <25%. Long-term results (40 months) indicate that >50%
of patients with acute diverticular bleeds treated with highly selective
angiography have had definitive treatment. As another alternative, a
selective infusion of vasopressin can be given to stop the hemorrhage, I II
although this has been associated with significant complications,
including myocardial infarction and intestinal ischemia. Furthermore,
bleeding recurs in 50% of patients once the infusion is stopped.
If the patient is unstable or has had a 6-unit bleed within 24 h,
current recommendations are that surgery should be performed. If the
bleeding has been localized, a segmental resection can be performed.
If the site of bleeding has not been definitively identified, a subtotal Feces
colectomy may be required. In patients without severe comorbidities,
surgical resection can be performed with a primary anastomosis.
A higher anastomotic leak rate has been reported in patients who
received >10 units of blood.
Presentation, Evaluation, and Staging of Diverticulitis
Acute uncomplicated diverticulitis (also known as Symptomatic III IV
Uncomplicated Diverticular Disease, SUDD) characteristically presents FIGURE 321-2 Hinchey classification of diverticulitis. Stage I: Perforated
with fever, anorexia, left lower quadrant abdominal pain, and obstipa- diverticulitis with a confined paracolic abscess. Stage II: Perforated diverticulitis
tion (Table 321-1). In <25% of cases, patients may present with gener- that has closed spontaneously with distant abscess formation. Stage III:
alized peritonitis indicating the presence of a diverticular perforation. Noncommunicating perforated diverticulitis with fecal peritonitis (the diverticular
If a pericolonic abscess has formed, the patient may have abdominal neck is closed off, and, therefore, contrast will not freely expel on radiographic
images). Stage IV: Perforation and free communication with the peritoneum,
distention and signs of localized peritonitis. Laboratory investigations
PART 10
resulting in fecal peritonitis.

will demonstrate a leukocytosis. Rarely, a patient may present with
an air-fluid level in the left lower quadrant on plain abdominal film.
This is a giant diverticulum of the sigmoid colon and is managed with developed to predict outcomes following the surgical management of
resection to avoid impending perforation. complicated diverticular disease. In recent years, the Hinchey staging
The diagnosis of diverticulitis is best made on CT with the fol- system has been modified to include the development of a phlegmon
lowing findings: sigmoid diverticula, thickened colonic wall >4 mm, or early abscess (Hinchey stage Ia). A pericolic abscess is then consid-
and inflammation within the periodic fat ± the collection of contrast ered Hinchey stage Ib. In complicated diverticular disease with fistula
material or fluid. In up to 20% of patients, an abdominal abscess may formation, common locations include cutaneous, vaginal, or vesicle
be present. Symptoms of irritable bowel syndrome (Chap. 320) may fistulas. These conditions present with either passage of stool through
mimic those of diverticulitis. Therefore, suspected diverticulitis that the skin or vagina or the presence of air in the urinary stream (pneu-
does not meet CT criteria or is not associated with a leukocytosis maturia). Colovaginal fistulas are more common in women who have
or fever is not diverticular disease. Other conditions that can mimic undergone a hysterectomy.
diverticular disease include an ovarian cyst, endometriosis, acute
appendicitis, and pelvic inflammatory disease.
Although the benefit of colonoscopy in the evaluation of patients TREATMENT
with diverticular disease has been called into question, its use is still Diverticular Disease
considered important in the exclusion of colorectal cancer. The parallel
epidemiology of colorectal cancer and diverticular disease provides MEDICAL MANAGEMENT
enough concern for an endoscopic evaluation before operative man-
Asymptomatic diverticular disease discovered on imaging studies
agement. Therefore, a colonoscopy should be performed ~6 weeks after
or at the time of colonoscopy is best managed by lifestyle changes.
an attack of diverticular disease.
Although the data regarding dietary risks and symptomatic diver-
Complicated diverticular disease is defined as diverticular disease
ticular disease are limited (see Table 321-2), patients may benefit
associated with an abscess or perforation and less commonly with a
from a fiber-enriched diet that includes 30 g of fiber each day.
fistula (Table 321-1). Perforated diverticular disease is staged using
Supplementary fiber products such as Metamucil, Fibercon, or
the Hinchey classification system (Fig. 321-2). This staging system was
Citrucel are useful. The use of fiber increases colonic transit time,
and, therefore, preventing increased intraluminal pressure leading
TABLE 321-1 Presentation of Diverticular Disease to the development of diverticulosis. The incidence of complicated
Uncomplicated Diverticular Disease—75%
diverticular disease appears to also be increased in patients who
smoke. Therefore, patients should be encouraged to refrain from
Abdominal pain
smoking. The historical recommendation to avoid eating nuts is
Fever based on no more than anecdotal data.
Leukocytosis SUDD with confirmation of inflammation and infection within
Anorexia/obstipation the colon should be treated initially with bowel rest. The routine
Complicated Diverticular Disease—25% use of antibiotics in uncomplicated diverticular disease did not
Abscess 16% demonstrate any benefit in time to symptom resolution, compli-
Perforation 10% cations, or risk of recurrence. However, the data are limited and
antibiotics remain in the treatment paradigm. Hospitalization is
Stricture 5%
recommended if the patient is unable to take oral therapy, affected
Fistula 2%
by several comorbidities, fails to improve with outpatient therapy,

TABLE 321-2 The Use of Fiber in the Management of Diverticular Disease 2285
JOURNAL, STUDY YEAR PATIENTS (n) INTERVENTION STUDY LENGTH FINDINGS

Lancet, 1977 18 Wheat or bran crisp bread 3 months Significant reduction of symptoms score
BMJ, 1981 58 Bran, ispaghula, placebo 16 weeks No difference
J Gastroenterol, 1977 30 Methylcellulose 3 months Significant reduction in symptoms
BMJ, 2011 47,033 Vegetarian vs nonvegetarian 11.6 years Vegetarians had a 31% lower risk of DD
Gastroenterology, 2012 2104 Fiber consumption 12 years Fiber associated with great risk of DD
Jama, 2008 47,288 Nut, corn, popcorn consumption 18 years Higher nut, corn, and popcorn had lower risk of
recurrence
Ann R Coll Surg Engl, 1985 56 Fiber consumption 66 months Higher fiber associated with 19% reduction in symptom
recurrence
Modified from A Turis, A Papa, S Danese: Review Article: The pathophysiology and medical management of diverticulosis and diverticular disease of the colon. Aliment
Parmacol Ther 42:664, 2015.
and if the patient is affected by complicated diverticulitis. Nearly The goals of surgical management of diverticular disease include
75% of patients hospitalized for acute diverticulitis will respond to controlling sepsis, eliminating complications such as fistula or
nonoperative treatment with a suitable antimicrobial regimen. The obstruction, removing the diseased colonic segment, and restoring
current recommended antimicrobial coverage is a third-generation intestinal continuity. These goals must be obtained while minimiz-
cephalosporin or ciprofloxacin and metronidazole targeting aerobic ing morbidity rate, length of hospitalization, and cost in addition
gram-negative rods and anaerobic bacteria. Unfortunately, these to maximizing survival and quality of life. Table 321-4 lists the
agents do not cover enterococci, and the addition of ampicillin to operations most commonly indicated based on the Hinchey clas-
this regimen for nonresponders is recommended. Alternatively, sification and the predicted postoperative outcomes. The current
single-agent therapy with a third-generation penicillin such as IV options for uncomplicated diverticular disease include an open or
piperacillin or oral penicillin/clavulanic acid may be effective. The a laparoscopic resection of the diseased area with reanastomosis to
usual course of antibiotics is 7–10 days, although this length of time the rectosigmoid. Preservation of portions of the sigmoid colon may
is being investigated. Patients should remain on a limited diet until lead to early recurrence of the disease. The benefits of laparoscopic

their pain resolves. resection over open surgical techniques include early discharge
Once the acute attack has resolved, the mainstay medical man- (by at least 1 day), less narcotic use, less postoperative complica-
agement of diverticular disease to prevent symptoms has evolved. tions, and an earlier return to work.
Established risk factors for symptomatic recurrence include younger The options for the surgical management of complicated diver-
age, the formation of a diverticular abscess, and more frequent ticular disease (Fig. 321-3) include the following open or laparo-
attacks (>2 per year). Newer directions are targeted at colonic scopic procedures: (1) proximal diversion of the fecal stream with an
inflammation and dysbiosis. Diverticular disease is now considered ileostomy or colostomy and sutured omental patch with drainage,
a functional bowel disorder associated with low-grade inflamma- (2) resection with colostomy and mucous fistula or closure of
tion. However, the use of anti-inflammatory medications (mesala- distal bowel with formation of a Hartmann’s pouch (Hartmann’s
zine) in randomized clinical trials has not demonstrated any effect procedure), (3) resection with anastomosis (coloproctostomy), or
on recurrence rates over placebo alone. Some authors have sug- (4) resection with anastomosis and diversion (coloproctostomy
gested that the use of anti-inflammatory medications is most helpful with loop ileostomy or colostomy). (5) Laparoscopic technique
in patients with diverticular disease who also have segmental coli- of washout and drainage without diversion has been described
tis (Segmental Colitis-Associated Diverticular Disease [SCADD]). for Hinchey III patients; however, a threefold increased risk of
Treatment strategies targeting dysbiosis in diverticular disease have recurrent peritonitis requiring reoperation with washout alone has
also been evaluated using polymerase chain reaction (PCR) on been reported.
stool specimens. Stool samples from consumers of a high-fiber diet Patients with Hinchey stage Ia are managed with antibiotic
have different bacterial content than stool samples from consumers therapy only followed by resection with anastomosis at 6 weeks.
of a low-fiber, high-fat diet. Probiotics are increasingly used by Patients with Hinchey stages Ib and II disease are managed with
gastroenterologists for multiple bowel disorders and may prevent percutaneous drainage followed by resection with anastomosis
recurrence of diverticulitis. Specifically, probiotics containing about 6 weeks later. Current guidelines put forth by the American
Lactobacillus acidophilus and Bifidobacterium strains may be benefi- Society of Colon and Rectal Surgeons suggest, in addition to anti-
cial, however, a recent systematic review was unable to show any biotic therapy, CT-guided percutaneous drainage of diverticular
benefit to the use of probiotics. Rifaximin (a poorly absorbed broad- abscesses that are >3 cm and have a well-defined wall. Abscesses
spectrum antibiotic), when compared to fiber alone for the treatment that are <5 cm may resolve with antibiotic therapy alone. Con-
of SUDD, is associated with 30% less frequent recurrent symptoms traindications to percutaneous drainage are no percutaneous access
from uncomplicated diverticular disease. route, pneumoperitoneum, and fecal peritonitis. Drainage of a
SURGICAL MANAGEMENT
Preoperative risk factors influencing postoperative mortality rates
TABLE 321-3 American Society of Anesthesiologists Physical Status
include higher American Society of Anesthesiologists (ASA) phys- Classification System
ical status class (Table 321-3) and preexisting organ failure. In P1 A normal healthy patient
patients who are low risk (ASA P1 and P2), surgical therapy can be
P2 A patient with mild systemic disease
offered to those who do not rapidly improve on medical therapy.
P3 A patient with severe systemic disease
For uncomplicated diverticular disease, medical therapy can be con-
tinued beyond two attacks without an increased risk of perforation P4 A patient with severe systemic disease that is a constant threat
to life
requiring a colostomy. However, patients on immunosuppressive
therapy, in chronic renal failure, or with a collagen-vascular disease P5 A moribund patient who is not expected to survive without the
operation
have a fivefold greater risk of perforation during recurrent attacks.
P6 A declared brain-dead patient whose organs are being removed for
Surgical therapy is indicated in all low-surgical-risk patients with
donor purposes
complicated diverticular disease.

2286 TABLE 321-4 Outcome Following Surgical Therapy for Complicated Diverticular Disease Based Upon Modified Hinchey Staging
ANASTOMOTIC
HINCHEY STAGE OPERATIVE PROCEDURE LEAK RATE, % OVERALL MORBIDITY RATE, %
Ia (pericolic phlegmon) Laparoscopic or open colon resection 43 15
Ib (pericolic abscess) Percutaneous drainage followed by laparoscopic or open colon 3 15
resection
II Percutaneous drainage followed by laparoscopic or open colon 3 15
resection +/− proximal diversion with an ostomy
III Laparoscopic washout and drainage 3 30% risk of peritonitis requiring reoperation if
or no resection is performed.
Laparoscopic or open resection with proximal diversion (ostomy) Overall morbidity 50%
or Overall mortality 15%
Hartmann’s procedure
IV Hartmann’s procedure — Overall morbidity 50%
or Overall mortality 15%
Washout with proximal diversion
diverticular abscess is associated with a 20–25% failure rate. Urgent congenital hypothyroidism, Hirschsprung’s disease, dementia, mental
operative intervention is undertaken if percutaneous drainage fails retardation, and schizophrenia.
and patients develop generalized peritonitis, and most will need to
be managed with a Hartmann’s procedure (resection of the sigmoid
Anatomy and Pathophysiology Rectal prolapse (procidentia) is
a circumferential, full-thickness protrusion of the rectal wall through
colon with end colostomy and rectal stump). In selected cases, non-
the anal orifice. It is often associated with a redundant sigmoid colon,
operative therapy may be considered. In one nonrandomized study,
pelvic laxity, and a deep rectovaginal septum (pouch of Douglas).
nonoperative management of isolated paracolic abscesses (Hinchey
Initially, rectal prolapse was felt to be the result of early internal rectal
stage I) was associated with only a 20% recurrence rate at 2 years.
intussusception, which occurs in the upper to mid rectum. This was
More than 80% of patients with distant abscesses (Hinchey stage II)
considered to be the first step in an inevitable progression to full-
PART 10
required surgical resection for recurrent symptoms.

thickness external prolapse. However, only 1 of 38 patients with inter-
The management of Hinchey stage III disease is under debate.
nal prolapse followed for >5 years developed full-thickness prolapse.
In this population of patients, no fecal peritonitis is present and it
Others have suggested that full-thickness prolapse is the result of
is presumed that the perforation has sealed. Historically, Hinchey
damage to the nerve supply to the pelvic floor muscles or pudendal
stage III has been managed with a Hartmann’s procedure or with
nerves from repeated stretching with straining to defecate. Damage to

primary anastomosis and proximal diversion. Several studies have
the pudendal nerves would weaken the pelvic floor muscles, including
examined short- and long-term outcomes for laparoscopic peri-
toneal lavage to remove the peritoneal contamination and place
drainage catheters should a communication to the bowel still exist.
However, this procedure has been associated with an increased risk
of requiring reoperation for ongoing peritonitis. Overall, ostomy
rates are lower with the use of laparoscopic peritoneal lavage. No
anastomosis of any type should be attempted in Hinchey stage IV
disease, or the presence of fecal peritonitis. A limited approach to
these patients is associated with a decreased mortality rate.
Recurrent Symptoms Recurrent abdominal symptoms following

surgical resection for diverticular disease occur in 10% of patients.
Recurrent diverticular disease develops in patients following inade-
quate surgical resection. A retained segment of diseased rectosigmoid
colon is associated with twice the incidence of recurrence. The pres-
ence of irritable bowel syndrome may also cause recurrence of initial
symptoms. Patients undergoing surgical resection for presumed diver-
ticulitis and symptoms of chronic abdominal cramping and irregular
loose bowel movements consistent with irritable bowel syndrome have
poorer functional outcomes.
COMMON DISEASES OF THE ANORECTUM

■■RECTAL PROLAPSE (PROCIDENTIA)
Incidence and Epidemiology Rectal prolapse is six times
more common in women than in men. The incidence of rectal prolapse
peaks in women >60 years. Women with rectal prolapse have a higher
incidence of associated pelvic floor disorders including urinary inconti-
nence, rectocele, cystocele, and enterocele. About 20% of children with FIGURE 321-3 Methods of surgical management of complicated diverticular
rectal prolapse will have cystic fibrosis. All children presenting with disease. 1. Drainage, omental pedicle graft, and proximal diversion. 2. Hartmann’s
prolapse should undergo a sweat chloride test. Less common associa- procedure. 3. Sigmoid resection with coloproctostomy. 4. Sigmoid resection with
tions include Ehlers-Danlos syndrome, solitary rectal ulcer syndrome, coloproctostomy and proximal diversion.

the external anal sphincter muscles. Bilateral pudendal nerve injury 2287
TREATMENT
is more significantly associated with prolapse and incontinence than
unilateral injury. Rectal Prolapse
Presentation and Evaluation In external prolapse, the majority The medical approach to the management of rectal prolapse is
of patient complaints include anal mass, bleeding per rectum, and limited and includes stool-bulking agents or fiber supplementation
poor perianal hygiene. Prolapse of the rectum usually occurs follow- to ease the process of evacuation. Surgical correction of rectal pro-
ing defecation and will spontaneously reduce or require the patient lapse is the mainstay of therapy. Two approaches are commonly
to manually reduce the prolapse. Constipation occurs in ~30–67% of considered, transabdominal and transperineal. Transabdominal
patients with rectal prolapse. Differing degrees of fecal incontinence approaches have been associated with lower recurrence rates, but
occur in 50–70% of patients. Patients with internal rectal prolapse will some patients with significant comorbidities are better served by a
present with symptoms of both constipation and incontinence. Other transperineal approach.
associated findings include outlet obstruction (anismus) in 30%, colonic Common transperineal approaches include a transanal proctec-
inertia in 10%, and solitary rectal ulcer syndrome in 12%. tomy (Altmeier procedure), mucosal proctectomy (Delorme proce-
Office evaluation is best performed after the patient has been given dure), or placement of a Tirsch wire encircling the anus. The goal
an enema, which enables the prolapse to protrude. An important of the transperineal approach is to remove the redundant rectosig-
distinction should be made between full-thickness rectal prolapse moid colon. Common transabdominal approaches include presacral
and isolated mucosal prolapse associated with hemorrhoidal disease suture or mesh rectopexy (Ripstein) with (Frykman-Goldberg) or
(Fig. 321-4). Mucosal prolapse is known for radial grooves rather than without resection of the redundant sigmoid. Colon resection, in gen-
circumferential folds around the anus and is due to increased laxity eral, is reserved for patients with constipation and outlet obstruc-
of the connective tissue between the submucosa and underlying mus- tion. Ventral rectopexy is an effective method of abdominal repair
cle of the anal canal. The evaluation of prolapse should also include of full-thickness prolapse that does not require sigmoid resection
cystoproctography and colonoscopy. These examinations evaluate for (see description below). This repair may have improved functional
associated pelvic floor disorders and rule out a malignancy or a polyp as results over other abdominal repairs. Transabdominal procedures
the lead point for prolapse. If rectal prolapse is associated with chronic can be performed effectively with laparoscopic and, more recently,
constipation, the patient should undergo a defecating proctogram and a robotic techniques without increased incidence of recurrence. The
sitzmark study. This will evaluate for the presence of anismus or colonic goal of the transabdominal approach is to restore normal anatomy
inertia. Anismus is the result of attempting to defecate against a closed by removing redundant bowel and reattaching the supportive tissue
pelvic floor and is also known as nonrelaxing puborectalis. This can be of the rectum to the presacral fascia. The final alternative is abdomi-

seen when straightening of the rectum fails to occur on fluoroscopy nal proctectomy with end-sigmoid colostomy. If total colonic inertia
while the patient is attempting to defecate. In colonic inertia, a sitzmark is present, as defined by a history of constipation and a positive
study will demonstrate retention of >20% of markers on abdominal sitzmark study, a subtotal colectomy with an ileosigmoid or rectal
x-ray 5 days after swallowing. For patients with fecal incontinence, anastomosis may be required at the time of rectopexy.
endoanal ultrasound and manometric evaluation, including pudendal Previously, the presence of internal rectal prolapse identified on
nerve testing of their anal sphincter muscles, may be performed before imaging studies has been considered a nonsurgical disorder, and
surgery for prolapse (see “Fecal Incontinence,” below). biofeedback was recommended. However, only one-third of patients
will have successful resolution of symptoms from biofeedback. Two
surgical procedures more effective than biofeedback are the Stapled
Transanal Rectal Resection (STARR) and the Laparoscopic Ventral
Rectopexy (LVR). The STARR procedure (Fig. 321-5) is performed
through the anus in patients with internal prolapse. A circular
stapling device is inserted through the anus; the internal prolapse
is identified and ligated with the stapling device. LVR (Fig. 321-6)
is performed through an abdominal approach. An opening in the
A C
B D
FIGURE 321-4 Degrees of rectal prolapse. Mucosal prolapse only (A, B, sagittal
view). Full-thickness prolapse associated with redundant rectosigmoid and deep FIGURE 321-5 Stapled transanal rectal resection. Schematic of placement of
pouch of Douglas (C, D, sagittal view). the circular stapling device.

2288 TABLE 321-5 Medical Conditions That Contribute to Symptoms of
Fecal Incontinence
Neurologic Disorders
• Dementia
• Brain tumor
• Stroke
• Multiple sclerosis
• Tabes dorsalis
• Cauda equina lesions
Skeletal Muscle Disorders
• Myasthenia gravis
• Myopathies, muscular dystrophy
Miscellaneous
• Hypothyroidism
• Irritable bowel syndrome
• Diabetes
• Severe diarrhea
• Scleroderma
muscle fibers anteriorly at the time of the delivery. This results in an

obvious anterior defect on endoanal ultrasound. Injury may also be
the result of stretching of the pudendal nerves during pregnancy or
delivery of the fetus through the birth canal.
Presentation and Evaluation Patients may suffer with varying
FIGURE 321-6 Laparoscopic ventral rectopexy (LVR). To reduce the internal degrees of fecal incontinence. Minor incontinence includes inconti-
PART 10
prolapse and close any rectovaginal septal defect, the pouch of Douglas is nence to flatus and occasional seepage of liquid stool. Major inconti-
opened and mesh is secured to the anterolateral rectum, vaginal fornix, and nence is frequent inability to control solid waste. As a result of fecal
sacrum. (From A D’Hoore et al: Br J Surg 91:1500, 2004.) incontinence, patients suffer from poor perianal hygiene. Beyond the
immediate problems associated with fecal incontinence, these patients
peritoneum is created on the left side of the rectosigmoid junction, are often withdrawn and suffer from depression. For this reason, qual-
and this opening continues down anterior on the rectum into the ity-of-life measures are an important component in the evaluation of
pouch of Douglas. No rectal mobilization is performed, thus avoid- patients with fecal incontinence.
ing any autonomic nerve injury. Mesh is secured to the anterior The evaluation of fecal incontinence should include a thorough
and lateral portion of the rectum, the vaginal fornix, and the sacral history and physical examination including digital rectal examination
promontory, allowing for closure of the rectovaginal septum and (DRE). Weak sphincter tone on DRE and loss of the “anal wink” reflex
correction of the internal prolapse. In both procedures, recurrence (S1-level control) may indicate a neurogenic dysfunction. Perianal
at 1 year was low (<10%) and symptoms improved in more than scars may represent surgical injury. Other studies helpful in the diag-
three-fourths of patients. nosis of fecal incontinence include anal manometry, pudendal nerve
terminal motor latency (PNTML), and endoanal ultrasound. Centers
■■FECAL INCONTINENCE that care for patients with fecal incontinence will have an anorectal
physiology laboratory that uses standardized methods of evaluating
Incidence and Epidemiology Fecal incontinence is the invol- anorectal physiology. Anorectal manometry (ARM) measures resting
untary passage of fecal material for at least 1 month in an individual and squeeze pressures within the anal canal using an intraluminal
with a developmental age of at least 4 years. The prevalence of fecal water-perfused catheter. Current methods of ARM include use of a
incontinence in the United States is 0.5–11%. The majority of patients three-dimensional, high-resolution system with a 12-catheter perfusion
are women and aged >65. A higher incidence of incontinence is seen system, which allows physiologic delineation of anatomic abnor-
among parous women. One-half of patients with fecal incontinence malities. Pudendal nerve studies evaluate the function of the nerves
also suffer from urinary incontinence. The majority of incontinence is a innervating the anal canal using a finger electrode placed in the anal
result of obstetric injury to the pelvic floor, either while carrying a fetus canal. Stretch injuries to these nerves will result in a delayed response
or during the delivery. An anatomic sphincter defect may occur in up of the sphincter muscle to a stimulus, indicating a prolonged latency.
to 32% of women following childbirth regardless of visible damage to Finally, endoanal ultrasound will evaluate the extent of the injury to
the perineum. Risk factors at the time of delivery include prolonged the sphincter muscles before surgical repair. Unfortunately, all of these
labor, the use of forceps, and the need for an episiotomy. Symptoms of investigations are user-dependent, and very few studies demonstrate
incontinence can present after two or more decades following obstetric that these studies predict outcome following an intervention. Magnetic
injury. Medical conditions known to contribute to the development of resonance imaging (MRI) has been used, but its routine use for imaging
fecal incontinence are listed in Table 321-5. in fecal incontinence is not well established.
Anatomy and Pathophysiology The anal sphincter complex Rarely does a pelvic floor disorder exist alone. The majority of patients
is made up of the internal and external anal sphincter. The internal with fecal incontinence will have some degree of urinary incontinence.
sphincter is smooth muscle and a continuation of the circular fibers of Similarly, fecal incontinence is a part of the spectrum of pelvic organ pro-
the rectal wall. It is innervated by the intestinal myenteric plexus and lapse. For this reason, patients may present with symptoms of obstructed
is therefore not under voluntary control. The external anal sphincter defecation as well as fecal incontinence. Careful evaluation including
is formed in continuation with the levator ani muscles and is under dynamic MRI or cinedefecography should be performed to search for
voluntary control. The pudendal nerve supplies motor innervation to other associated defects. Surgical repair of incontinence without atten-
the external anal sphincter. Obstetric injury may result in tearing of the tion to other associated defects may decrease the success of the repair.

2289
TREATMENT TABLE 321-6 The Staging and Treatment of Hemorrhoids
DESCRIPTION OF
Fecal Incontinence STAGE CLASSIFICATION TREATMENT
Medical management of fecal incontinence includes strategies to I Enlargement with bleeding Fiber supplementation
bulk up the stool, which help in increasing fecal sensation. These Short course of cortisone
include fiber supplementation, loperamide, diphenoxylate, and bile suppository
acid binders. These agents harden the stool and delay frequency Sclerotherapy
of bowel movements and are helpful in patients with minimal to Infared coagulation
mild symptoms. Furthermore, patients can be offered a form of II Protrusion with spontaneous Fiber supplementation
physical therapy called biofeedback. This therapy helps strengthen reduction Short course of cortisone
the external sphincter muscle while training the patient to relax suppository
with defecation to avoid unnecessary straining and further injury to Sclerotherapy
the sphincter muscles. Biofeedback has had variable success and is Infared coagulation
dependent on the motivation of the patient. At a minimum, biofeed- III Protrusion requiring manual Fiber supplementation
back is risk-free. Most patients will have some improvement. For reduction Short course of cortisone
this reason, it should be incorporated into the initial recommenda- suppository
tion to all patients with fecal incontinence. Rubber band ligation
Historically, the “gold standard” for the treatment of fecal incon- Operative hemorrhoidectomy
tinence with an isolated sphincter defect has been the overlapping IV Irreducible protrusion Fiber supplementation
sphincteroplasty. The external anal sphincter muscle and scar tissue
Cortisone suppository
as well as any identifiable internal sphincter muscle are dissected
Operative hemorrhoidectomy
free from the surrounding adipose and connective tissue and then
an overlapping repair is performed in an attempt to rebuild the
muscular ring and restore its function. However, long-term results
following overlapping sphincteroplasty have been poor with a 50% susceptible to injury. Hemorrhoids are commonly classified as external
failure rate over 5 years. or internal. External hemorrhoids originate below the dentate line and
Alternative therapies such as Sacral Nerve Stimulation (SNS), are covered with squamous epithelium and are associated with an inter-
collagen-enhancing injectables, and magnetic “Fenix” ring are other

nal component. External hemorrhoids are painful when thrombosed.
options. SNS is an adaptation of a procedure developed for the man- Internal hemorrhoids originate above the dentate line and are covered
agement of urinary incontinence. SNS is ideally suited for patients with mucosa and transitional zone epithelium and represent the major-
with intact but weak anal sphincters. A temporary nerve stimulator ity of hemorrhoids. The standard classification of hemorrhoidal disease
is placed on the third sacral nerve. If there is at least a 50% improve- is based on the progression of the disease from their normal internal
ment in symptoms, a permanent nerve stimulator is placed under the location to the prolapsing external position (Table 321-6).
skin. Long-term results for sacral stimulation have been promising,
with nearly 80% of patients having a reduction in incontinence epi- Presentation and Evaluation Patients commonly present to
sodes by at least 50%. This reduction has been sustainable in studies a physician for two reasons: bleeding and protrusion. Pain is less
out to 5 years. Collagen-enhancing injectables have been around common than with fissures and, if present, is described as a dull ache
for several years. More than 50% of incontinent patients treated from engorgement of the hemorrhoidal tissue. Severe pain may indi-
with nonanimal stabilized hyaluronic acid (NASHA/DX) achieved cate a thrombosed hemorrhoid. Hemorrhoidal bleeding is described
a 50% reduction in incontinence episodes, and these results were as painless bright red blood seen either in the toilet or upon wiping.
sustainable up to 2 years. Currently, this injectable is not universally Occasional patients can present with significant bleeding, which may
available. The Fenix is a magnetic ring that is implanted around the be a cause of anemia; however, the presence of a colonic neoplasm must
anal sphincter muscles. Its long-term outcomes are still being studied be ruled out in anemic patients. Patients who present with a protruding
and it is currently only available for compassionate use. mass complain about inability to maintain perianal hygiene and are
Finally, the use of stem cells to increase the bulk of the sphincter often concerned about the presence of a malignancy.
muscles is currently being tested. Stem cells can be harvested from The diagnosis of hemorrhoidal disease is made on physical exami-
the patient’s own muscle, grown, and then implanted into their nation. Inspection of the perianal region for evidence of thrombosis or
sphincter complex. Concern for cost and the need for an additional excoriation is performed, followed by a careful digital examination.
procedure dampen enthusiasm. Trial results are awaited. Anoscopy is performed paying particular attention to the known
position of hemorrhoidal disease. The patient is asked to strain. If
this is difficult for the patient, the maneuver can be performed while
■■HEMORRHOIDAL DISEASE sitting on a toilet. The physician is notified when the tissue prolapses.
Incidence and Epidemiology Symptomatic hemorrhoids affect It is important to differentiate the circumferential appearance of a
>1 million individuals in the Western world per year. The prevalence full-thickness rectal prolapse from the radial nature of prolapsing hem-
of hemorrhoidal disease is not selective for age or sex. However, age orrhoids (see “Rectal Prolapse,” above). The stage and location of the
is known to be a risk factor. The prevalence of hemorrhoidal disease hemorrhoidal complexes are defined.
is less in underdeveloped countries. The typical low-fiber, high-fat
Western diet is associated with constipation and straining and the TREATMENT
development of symptomatic hemorrhoids.
Hemorrhoidal Disease
Anatomy and Pathophysiology Hemorrhoidal cushions are a
normal part of the anal canal. The vascular structures contained within The treatment for bleeding hemorrhoids is based on the stage of the
this tissue aid in continence by preventing damage to the sphincter disease (Table 321-6). In all patients with bleeding, the possibility of
muscle. Three main hemorrhoidal complexes traverse the anal canal— other causes must be considered. In young patients without a family
the left lateral, the right anterior, and the right posterior. Engorgement history of colorectal cancer, the hemorrhoidal disease may be treated
and straining lead to prolapse of this tissue into the anal canal. Over first and a colonoscopic examination performed if the bleeding con-
time, the anatomic support system of the hemorrhoidal complex weak- tinues. Older patients who have not had colorectal cancer screening
ens, exposing this tissue to the outside of the anal canal where it is should undergo colonoscopy or flexible sigmoidoscopy.

2290 With rare exceptions, the acutely thrombosed hemorrhoid can be
excised within the first 72 h by performing an elliptical excision. Sitz
baths, fiber, and stool softeners are prescribed. Additional therapy
for bleeding hemorrhoids includes the office procedures of rubber
band ligation, infrared coagulation, and sclerotherapy. Sensation Abscesses Fistula
begins at the dentate line; therefore, all procedures can be performed Supralevator
tracts
without discomfort either endoscopically or in the office. Bands are 4
placed around the engorged tissue, causing ischemia and fibrosis.
Intersphincteric
This aids in fixing the tissue proximally in the anal canal. Patients
may complain of a dull ache for 24 h following band application. Ischiorectal
During sclerotherapy, 1–2 mL of a sclerosant (usually sodium tetra- 3
Perianal
decyl sulfate) is injected using a 25-gauge needle into the submucosa 1 2
of the hemorrhoidal complex. Care must be taken not to inject the
anal canal circumferentially, or stenosis may occur.
For surgical management of hemorrhoidal disease, excisional
hemorrhoidectomy, transhemorrhoidal dearterialization (THD), or 1
stapled hemorrhoidectomy (“the procedure for prolapse or hem- Intersphincteric
orrhoids” [PPH]) is the procedure of choice. All surgical methods 2
Trans-sphincteric 3 4 Extrasphincteric
of management are equally effective in the treatment of symp-
Suprasphincteric
tomatic third- and fourth-degree hemorrhoids. However, because
the sutured hemorrhoidectomy involves the removal of redun- FIGURE 321-7 Common locations of anorectal abscess (left) and fistula in ano
(right).
dant tissue down to the anal verge, unpleasant anal skin tags are
removed as well. The stapled hemorrhoidectomy is associated with
less discomfort; however, this procedure does not remove anal skin laboratory evaluation shows an elevated white blood cell count. Diag-
tags and an increased number of complications are associated with nostic procedures are rarely necessary unless evaluating a recurrent
use of the stapling device. THD uses ultrasound guidance to ligate abscess. A CT scan or MRI has an accuracy of 80% in determining
the blood supply to the anal tissue, hence reducing hemorrhoidal incomplete drainage. If there is a concern about the presence of IBD,
engorgement. No procedures on hemorrhoids should be done a rigid or flexible sigmoidoscopic examination may be done at the
in patients who are immunocompromised or who have active time of drainage to evaluate for inflammation within the rectosigmoid
PART 10
proctitis. Furthermore, emergent hemorrhoidectomy for bleeding region. A more complete evaluation for Crohn’s disease would include
hemorrhoids is associated with a higher complication rate. a full colonoscopy and small-bowel series.
Acute complications associated with the treatment of hemor-
rhoids include pain, infection, recurrent bleeding, and urinary reten-
tion. Care should be taken to place bands properly and to avoid
TREATMENT
overhydration in patients undergoing operative hemorrhoidectomy. Anorectal Abscess

Late complications include fecal incontinence as a result of injury to
the sphincter during the dissection. Anal stenosis may develop from As with all abscesses, the “gold standard” is drainage. Office drainage
overzealous excision, with loss of mucosal skin bridges for reepithe- of an uncomplicated anorectal abscess may suffice. A small incision
lialization. Finally, an ectropion (prolapse of rectal mucosa from the close to the anal verge is made, and a Mallenkot drain is advanced
anal canal) may develop. Patients with an ectropion complain of a into the abscess cavity. For patients who have a complicated abscess
“wet” anus as a result of inability to prevent soiling once the rectal or who are diabetic or immunocompromised, drainage should be
mucosa is exposed below the dentate line. performed in an operating room under anesthesia. These patients are
at greater risk for developing necrotizing fasciitis. The role of antibi-
otics in the management of anorectal abscesses is limited. Antibiotics
■■ANORECTAL ABSCESS are only warranted in patients who are immunocompromised or
Incidence and Epidemiology The development of a perianal have prosthetic heart valves, artificial joints, diabetes, or IBD.
abscess is more common in men than women by a ratio of 3:1. The peak
incidence is in the third to fifth decade of life. Perianal pain associated ■■FISTULA IN ANO
with the presence of an abscess accounts for 15% of office visits to a
colorectal surgeon. The disease is more prevalent in immunocompro- Incidence and Epidemiology The incidence and prevalence of
mised patients such as those with diabetes, hematologic disorders, or fistulating perianal disease parallel the incidence of anorectal abscess,
inflammatory bowel disease (IBD) and persons who are HIV positive. estimating to be 1 in 10,000 individuals. Some 30–40% of abscesses
These disorders should be considered in patients with recurrent peri- will give rise to fistula in ano. Although the majority of the fistulas are
anal infections. cryptoglandular in origin, 10% are associated with IBD, tuberculosis,
malignancy, and radiation.
Anatomy and Pathophysiology An anorectal abscess is an
abnormal fluid-containing cavity in the anorectal region. Anorectal Anatomy and Pathophysiology A fistula in ano is defined as a
abscess results from an infection involving the glands surrounding communication of an abscess cavity with an identifiable internal open-
the anal canal. Normally, these glands release mucus into the anal ing within the anal canal. This identifiable opening is most commonly
canal, which aids in defecation. When stool accidentally enters the anal located at the dentate line where the anal glands enter the anal canal.
glands, the glands become infected and an abscess develops. Anorectal Patients experiencing continuous drainage following the treatment of
abscesses are perianal in 40–50% of patients, ischiorectal in 20–25%, a perianal abscess likely have a fistula in ano. These fistulas are classi-
intersphincteric in 2–5%, and supralevator in 2.5% (Fig. 321-7). fied by their relationship to the anal sphincter muscles, with 70% being
intersphincteric, 23% transsphincteric, 5% suprasphincteric, and 2%
Presentation and Evaluation Perianal pain and fever are the extrasphincteric (Fig. 321-7).
hallmarks of an abscess. Patients may have difficulty voiding and have
blood in the stool. A prostatic abscess may present with similar com- Presentation and Evaluation A patient with a fistula in ano
plaints, including dysuria. Patients with a prostatic abscess will often will complain of constant drainage from the perianal region associated
have a history of recurrent sexually transmitted diseases. On physical with a firm mass. The drainage may increase with defecation. Perianal
examination, a large fluctuant area is usually readily visible. Routine hygiene is difficult to maintain. Examination under anesthesia is the

best way to evaluate a fistula. At the time of the examination, anos- a sawtooth deformity with paradoxical contractions of the sphincter 2291
copy is performed to look for an internal opening. Diluted hydrogen muscles are pathognomonic.
peroxide will aid in identifying such an opening. In lieu of anesthesia,
MRI with an endoanal coil will also identify tracts in 80% of the cases.
After drainage of an abscess with insertion of a Mallenkot catheter, a
TREATMENT
fistulagram through the catheter can be obtained in search of an occult Anal Fissure
fistula tract. Goodsall’s rule states that a posterior external fistula will
enter the anal canal in the posterior midline, whereas an anterior fistula The management of the acute fissure is conservative. Stool softeners
will enter at the nearest crypt. A fistula exiting >3 cm from the anal for those with constipation, increased dietary fiber, topical anes-
verge may have a complicated upward extension and may not obey thetics, glucocorticoids, and sitz baths are prescribed and will heal
Goodsall’s rule. 60–90% of fissures. Chronic fissures are those present for >6 weeks.
These can be treated with modalities aimed at decreasing the anal
canal resting pressure including nifedipine ointment applied three
TREATMENT times a day and botulinum toxin type A, up to 20 units, injected into
Fistula in Ano the internal sphincter on each side of the fissure. Surgical manage-
ment includes anal dilatation and lateral internal sphincterotomy.
A newly diagnosed draining fistula is best managed with placement Usually, one-third of the internal sphincter muscle is divided; it is
of a seton, a vessel loop or silk tie placed through the fistula tract, easily identified because it is hypertrophied. Recurrence rates from
which maintains the tract open and quiets down the surrounding medical therapy are higher, but this is offset by a risk of incontinence
inflammation that occurs from repeated blockage of the tract. Once following sphincterotomy. Lateral internal sphincterotomy may lead
the inflammation is less, the exact relationship of the fistula tract to to incontinence more commonly in women.
the anal sphincters can be ascertained. A simple fistulotomy can be
performed for intersphincteric and low (less than one-third of the
muscle) transsphincteric fistulas without compromising continence. Acknowledgment
We would like to thank Cory Sandore for providing some illustrations for this
For a higher transsphincteric fistula, an anorectal advancement flap
chapter. Gregory Bulkley, MD, contributed to this chapter in an earlier edition
in combination with a drainage catheter or fibrin glue may be used.
and some of that material has been retained here.
Very long (>2 cm) and narrow tracts respond better to fibrin glue
than shorter tracts. Simple ligation of the internal fistula tract (LIFT
procedure) has also been used in the management of simple fistula ■■FURTHER READING
CHAPTER 322 Mesenteric Vascular Insufficiency

with good success. Bharucha AE , Rao SSC, Shin AS: Surgical interventions and the use
Patients should be maintained on stool-bulking agents, nonnar- of device-aided therapy for the treatment of fecal incontinence and
cotic pain medication, and sitz baths following surgery for a fistula. defecatory disorders. Clin Gastroenterol Hepatol 15:1844, 2017.
Early complications from these procedures include urinary retention Cotter TG et al: Approach to the patient with hematochezia. Mayo
and bleeding. Later complications are rare (<10%) and include tem- Clin Proc 92:797, 2017.
porary and permanent incontinence. Recurrence is 0–18% following Guttenplan M: The evaluation and office management of hemor-
fistulotomy and 20–30% following anorectal advancement flap and rhoids for the gastroenterologist. Curr Gastroenterol Rep 19:30, 2017.
the LIFT procedure. The use of stem cell implants at the time of Prichard D, Bharucha AE: Management of pelvic floor disorders:
repair for recalcitrant fistulizing disease of the anus is being studied. Biofeedback and more. Curr Treat Options Gastroenterol 12:456, 2014.
Salfity HV et al: Minimally invasive incision and drainage technique
in the treatment of simple subcutaneous abscess in adults. Am Surg
■■ANAL FISSURE 83:699, 2017.
Incidence and Epidemiology Anal fissures occur at all ages Sugrue J et al: Sphincter-sparing anal fistula repair: Are we getting
but are more common in the third through the fifth decades. A fissure is better? Dis Colon Rectum 60:1071, 2017.
the most common cause of rectal bleeding in infancy. The prevalence is Tursi A: Dietary pattern and colonic diverticulosis. Curr Opin Clin
equal in males and females. It is associated with constipation, diarrhea, Nutr Metab Care 20:409, 2017.
infectious etiologies, perianal trauma, and Crohn’s disease.
Anatomy and Pathophysiology Trauma to the anal canal
occurs following defecation. This injury occurs in the anterior or, more
commonly, the posterior anal canal. Irritation caused by the trauma to
the anal canal results in an increased resting pressure of the internal
322 Mesenteric
sphincter. The blood supply to the sphincter and anal mucosa enters
laterally. Therefore, increased anal sphincter tone results in a relative Vascular
ischemia in the region of the fissure and leads to poor healing of the
anal injury. A fissure that is not in the posterior or anterior position
Insufficiency
should raise suspicion for other causes, including tuberculosis, syphilis, Satinderjit Locham, Mahmoud Malas
Crohn’s disease, and malignancy.
Presentation and Evaluation A fissure can be easily diagnosed
on history alone. The classic complaint is pain, which is strongly associ- INTESTINAL ISCHEMIA
ated with defecation and is relentless. The bright red bleeding that can
be associated with a fissure is less extensive than that associated with ■■INCIDENCE AND EPIDEMIOLOGY
hemorrhoids. On examination, most fissures are located in either the Intestinal ischemia occurs when splanchnic perfusion fails to meet the
posterior or anterior position. A lateral fissure is worrisome because it metabolic demands of the intestines, resulting in ischemic tissue injury.
may have a less benign nature, and systemic disorders should be ruled Mesenteric ischemia affects 2–3 people per 100,000, with an increasing
out. A chronic fissure is indicated by the presence of a hypertrophied incidence in the aging population. Delay in diagnosis and management
anal papilla at the proximal end of the fissure and a sentinel pile or results in a high mortality, and prompt interventions may be lifesav-
skin tag at the distal end. Often the circular fibers of the hypertro- ing. Intestinal ischemia is further classified based on etiology, which
phied internal sphincter are visible within the base of the fissure. If dictates management: (1) arterioocclusive mesenteric ischemia, (2) non-
anal manometry is performed, elevation in anal resting pressure and occlusive mesenteric ischemia, and (3) mesenteric venous thrombosis.

2292 Risk factors for arterioocclusive mesenteric ischemia are generally Occlusive ischemia is a result of disruption of blood flow by an
acute in onset that include atrial fibrillation, recent myocardial infarction, embolus or progressive thrombosis in a major artery supplying the
valvular heart disease, and recent cardiac or vascular catheterization, all intestine. In >75% of cases, emboli originate from the heart and prefer-
of which result in embolic clots reaching the mesenteric circulation. entially lodge in the superior mesenteric artery (SMA) just distal to the
Nonocclusive mesenteric ischemia, also known as “intestinal angina,” origin of the middle colic artery. Progressive thrombosis of at least two
is generally more insidious and often seen in the aging population of the major vessels supplying the intestine is required for the develop-
affected by atherosclerotic disease. Patients with chronic atheroscle- ment of chronic intestinal angina. Nonocclusive ischemia is dispropor-
rotic disease could also suffer an acute insult from emboli leading to tionate mesenteric vasoconstriction (arteriolar vasospasm) in response
complete occlusion. Nonocclusive mesenteric ischemia is also seen in to a severe physiologic stress such as shock. If left untreated, early
patients receiving high-dose vasopressor infusions, patients presenting mucosal stress ulceration will progress to full-thickness injury. Even
with cardiogenic or septic shock, and cocaine overdose. It is the most in the early stages of ischemia, there is translocation of bacteria across
prevalent gastrointestinal disease complicating cardiovascular surgery. the intestinal mucosa, resulting in bacteremia that can lead to sepsis.
The incidence of ischemic colitis following elective aortic repair is
5–9%, and the incidence triples in patients following emergent repair. ■■PRESENTATION, EVALUATION, AND MANAGEMENT
Mesenteric venous thrombosis is less common and is associated with Intestinal ischemia remains one of the most challenging diagnoses. The
the presence of a hypercoagulable state including protein C or S defi- mortality rate is >50%. The most significant indicator of survival is the
ciency, antithrombin III deficiency, polycythemia vera, and carcinoma. timeliness of diagnosis and treatment. An overview of diagnosis and
management of each form of intestinal ischemia is given in Table 322-1.
■■ANATOMY AND PATHOPHYSIOLOGY Acute mesenteric ischemia resulting from arterial embolus or throm-
The blood supply to the intestines is depicted in Fig. 322-1. To pre- bosis presents with severe acute, nonremitting abdominal pain strik-
vent ischemic injury, extensive collateralization occurs between major ingly out of proportion to the physical findings. Associated symptoms
mesenteric trunks and branches of the mesenteric arcades. Collateral may include nausea and vomiting, transient diarrhea, anorexia, and
vessels within the small bowel are numerous and meet within the bloody stools. With the exception of minimal abdominal distention and
duodenum and the bed of the pancreas. Collateral vessels within the hypoactive bowel sounds, early abdominal examination is unimpres-
colon meet at the splenic flexure and descending/sigmoid colon. These sive. Later findings will demonstrate peritonitis and cardiovascular
areas, which are inherently at risk for decreased blood flow, are known collapse. In the evaluation of acute intestinal ischemia, routine labora-
as Griffiths’ point and Sudeck’s point, respectively, and are the most tory tests should be obtained, including complete blood count, serum
common locations for colonic ischemia (Fig. 322-1, shaded areas). The chemistry, coagulation profile, arterial blood gas, amylase, lipase, lactic
splanchnic circulation can receive up to 30% of the cardiac output. acid, blood type and cross match, and cardiac enzymes. Regardless of
Protective responses to prevent intestinal ischemia include abun-
PART 10
the need for urgent surgery, emergent admission to a monitored bed

dant collateralization, autoregulation of blood flow, and the ability to or intensive care unit is recommended for resuscitation and further
increase oxygen extraction from the blood. evaluation. If the diagnosis of intestinal ischemia is being considered,
consultation with a surgical service is necessary. Often the decision
to operate is made on a high index of suspicion from the history and
Left Phrenic a. Aorta

physical examination despite normal laboratory findings.
Other diagnostic modalities that may be useful in diagnosis but
Right Phrenic a. Splenic a. should not delay surgical therapy include electrocardiogram (ECG),
Griffiths’
echocardiogram, abdominal radiographs, computed tomography (CT),
Celiac trunk point and mesenteric angiography. More recently, mesentery duplex scan-
ning and visible light spectroscopy during colonoscopy have been
Pancreatico- demonstrated to be beneficial. The ECG may demonstrate an arrhyth-
duodenal a.
Arc of mia, indicating the possible source of the emboli. A plain abdominal
Riolan film may show evidence of free intraperitoneal air, indicating a perfo-
rated viscus and the need for emergent exploration. Earlier features of
intestinal ischemia seen on abdominal radiographs include bowel-wall
edema, known as “thumbprinting.” If the ischemia progresses, air can
be seen within the bowel wall (pneumatosis intestinalis) and within
SMA the portal venous system. Other features include calcifications of the
IMA aorta and its tributaries, indicating atherosclerotic disease. With the
administration of oral and IV contrast, dynamic CT angiography with
three-dimensional reconstruction is a highly sensitive test for intestinal
ischemia. In acute embolic disease, mesenteric angiography is best
performed intraoperatively. A mesenteric duplex scan demonstrating
a high peak velocity of flow in the SMA is associated with an ~80%
positive predictive value of mesenteric ischemia. More significantly, a
Marginal a. negative duplex scan virtually precludes the diagnosis of mesenteric
ischemia. Duplex imaging serves as a screening test; however, further
IIA investigations with angiography are usually needed. One of the biggest
limitations of duplex scanning is patients’ body habitus. The duplex
Sudeck’s imaging yields poor results in obese patients. Nevertheless, “food fear”
Hemorrhoidal aa. point
Superior in patients with chronic disease often leads to a decreased appetite and
Middle lower abdominal fat, thus, yielding high duplex imaging results. The
Inferior endoscopic techniques such as visible light spectroscopy can also be
used in the diagnosis of chronic ischemia. When suspecting mesenteric
FIGURE 322-1 Blood supply to the intestines includes the celiac artery, superior
ischemia involving the colon, performing an endoscopy to evaluate up
mesenteric artery (SMA), inferior mesenteric artery (IMA), and branches of the
internal iliac artery (IIA). Griffiths’ and Sudeck’s points, indicated by shaded areas, to the splenic flexure is high yield. This is often an excellent diagnostic
are watershed areas within the colonic blood supply and common locations for tool in patients with chronic renal insufficiency who cannot tolerate IV
ischemia. contrast.

TABLE 322-1 Overview of the Management of Acute Intestinal Ischemia 2293
TREATMENT
TREATMENT OF OF SYSTEMIC
CONDITION KEY TO EARLY DIAGNOSIS UNDERLYING CAUSE TREATMENT OF SPECIFIC LESION CONSEQUENCE
Arterioocclusive mesenteric Computed tomography (CT) Anticoagulation Laparotomy Ensure hydration
ischemia angiography Cardioversion Embolectomy Give antibiotics
1. Arterial embolus Early laparotomy Proximal thrombectomy Vascular bypass Reverse acidosis
Assess viability and resect dead bowel Optimize oxygen delivery
Avoid vasoconstrictors
2. Arterial thrombosis Duplex ultrasound Anticoagulation Endovascular approach: thrombolysis, Give antibiotics
Angiography Hydration angioplasty and stenting Reverse acidosis
Endarterectomy/thrombectomy or Optimize oxygen delivery
vascular bypass
Support cardiac output
Assess viability and resect dead bowel
Mesenteric venous Spiral CT Anticoagulation Anticoagulation ± laparotomy/ Give antibiotics
thrombosis Angiography with venous Massive hydration thrombectomy/catheter-directed Reverse acidosis
Venous thrombosis phase thrombolysis
Optimize oxygen delivery
Assess viability and resect dead bowel
Support cardiac output
Nonocclusive mesenteric Vasospasm: Ensure hydration Vasospasm Ensure hydration
ischemia Angiography Support cardiac output Intraarterial vasodilators Give antibiotics
Hypoperfusion: Avoid vasoconstrictors Hypoperfusion Reverse acidosis
Spiral CT or colonoscopy Delayed laparotomy Optimize oxygen delivery
Assess viability and resect dead bowel Support cardiac output
Source: Modified from GB Bulkley, in JL Cameron (ed): Current Surgical Therapy, 2nd ed. Toronto, BC Decker, 1986.
CHAPTER 322 Mesenteric Vascular Insufficiency

The “gold standard” for the diagnosis of acute arterial occlusive pathogens, including gram-negative and anaerobic organisms. Frequent
disease is angiography, and management is laparotomy. Surgical explo- monitoring of the patient’s vital signs, urine output, blood gases, and
ration should not be delayed if suspicion of acute occlusive mesenteric lactate levels is paramount, as is frequent abdominal examination. All
ischemia is high or evidence of clinical deterioration or frank peritonitis vasoconstricting agents should be avoided; fluid resuscitation is the
is present. The goal of operative exploration is to resect compromised intervention of choice to maintain hemodynamics.
bowel and restore blood supply. The entire length of the small and If ischemic colitis is a concern, colonoscopy should be performed to
large bowel beginning at the ligament of Treitz should be evaluated. assess the integrity of the colon mucosa. Visualization of the rectosig-
The pattern of intestinal ischemia may indicate the level of arterial moid region may demonstrate decreased mucosal integrity, associated
occlusion. In the case of SMA occlusion where the embolus usually more commonly with nonocclusive mesenteric ischemia, or, on occa-
lies just proximal to the origin of the middle colic artery, the proximal sion, occlusive disease as a result of acute loss of inferior mesenteric
jejunum is often spared while the remainder of the small bowel up arterial flow following aortic surgery. Ischemia of the colonic mucosa
to the transverse colon will be ischemic. The surgical management of is graded as mild with minimal mucosal erythema or as moderate with
acute mesenteric ischemia of the small bowel is embolectomy via arte- pale mucosal ulcerations and evidence of extension to the muscular
riotomy; a small incision is made in the artery through which the clot layer of the bowel wall. Severe ischemic colitis presents with severe
is retrieved. Another way to manage acute thrombosis is thrombolysis ulcerations resulting in black or green discoloration of the mucosa, con-
therapy and angioplasty with stent placement. However, this approach sistent with full-thickness bowel-wall necrosis. The degree of revers-
is more commonly applied to treat chronic mesenteric ischemia. If this ibility can be predicted from the mucosal findings: mild erythema is
is unsuccessful, a bypass from the aorta or iliac artery to the SMA is nearly 100% reversible, moderate is ~50% reversible, and frank necrosis
performed. is simply dead bowel. Follow-up colonoscopy can be performed to rule
Nonocclusive or vasospastic mesenteric ischemia presents with out progression of ischemic colitis.
generalized abdominal pain, anorexia, bloody stools, and abdominal Laparotomy for nonocclusive mesenteric ischemia is warranted in
distention. Often these patients are obtunded, and physical findings patients with signs of peritonitis or worsening endoscopic findings and
may not assist in the diagnosis. The presence of a leukocytosis, met- if the patient’s condition does not improve with aggressive resuscita-
abolic acidosis, elevated amylase or creatinine phosphokinase levels, tion. Ischemic colitis is optimally treated with resection of the ischemic
and/or lactic acidosis is useful in support of the diagnosis of advanced bowel and formation of a proximal stoma. Primary anastomosis should
intestinal ischemia; however, these markers may not be indicative of not be performed in patients with acute intestinal ischemia.
either reversible ischemia or frank necrosis. Investigational markers for Patients with mesenteric venous thrombosis may present with a
intestinal ischemia include d-dimer, glutathione S-transferase, platelet- gradual or sudden onset of pain. Symptoms include vague abdominal
activating factor (PAF), and mucosal pH monitoring. Regardless of the pain, nausea, and vomiting. Physical examination findings include
need for urgent surgery, emergent admission to a monitored bed or abdominal distention with mild to moderate tenderness and signs of
intensive care unit is recommended for resuscitation and further eval- dehydration. The diagnosis of mesenteric thrombosis is frequently
uation. Early manifestations of intestinal ischemia include fluid seques- made on abdominal spiral CT with oral and IV contrast. Findings on
tration within the bowel wall leading to a loss of interstitial volume. CT angiography with venous phase include bowel-wall thickening
Aggressive fluid resuscitation may be necessary. To optimize oxygen and ascites. IV contrast will demonstrate a delayed arterial phase and
delivery, nasal O2 and blood transfusions may be given. Broad-spectrum clot within the superior mesenteric vein. The goal of management
antibiotics should be given to provide sufficient coverage for enteric is to optimize hemodynamics and correct electrolyte abnormalities

2294 with massive fluid resuscitation. Intravenous antibiotics as well as
anticoagulation should be initiated. If laparotomy is performed and
mesenteric venous thrombosis is suspected, heparin anticoagulation is
immediately initiated, and compromised bowel is resected. Of all acute
323 Acute Intestinal
Obstruction
intestinal disorders, mesenteric venous insufficiency is associated with
the best prognosis. Danny O. Jacobs
Chronic intestinal ischemia presents with intestinal angina or post-
prandial abdominal pain associated with increased need of blood flow
to the intestine following meals. Patients report abdominal cramping ■■EPIDEMIOLOGY
and pain following ingestion of a meal. Weight loss and chronic diar- Morbidity and mortality from acute intestinal obstruction have been
rhea may also be noted. Abdominal pain without weight loss is not decreasing over the past several decades. Nevertheless, the diagnosis
chronic mesenteric angina. Physical examination will often reveal a can still be challenging, and the type of complications that patients suf-
malnourished patient with an abdominal bruit as well as other man- fer has not changed significantly. The extent of mechanical obstruction
ifestations of atherosclerosis. Duplex ultrasound evaluation of the is typically described as partial, high-grade, or complete—generally
mesenteric vessels has gained in popularity. It is important to perform correlating with the risk of complications and the urgency with which
the test while the patient is fasting because the presence of increased the underlying disease process must be addressed. Obstruction is also
bowel gas prevents adequate visualization of flow disturbances within commonly described as being either “simple” or, alternatively, “stran-
the vessels or the lack of a vasodilation response to feeding during gulated” if vascular insufficiency and intestinal ischemia are evident.
the test. This tool is frequently used as a screening test for patients Acute intestinal obstruction occurs either mechanically from block-
with symptoms suggestive of chronic mesenteric ischemia. The gold age or from intestinal dysmotility when there is no blockage. In
standard for confirmation of mesenteric arterial occlusion is mesen- the latter instance, the abnormality is described as being functional.
teric angiography. Evaluation with mesenteric angiography allows for Mechanical bowel obstruction may be caused by extrinsic processes,
identification and possible intervention for the treatment of athero-
intrinsic abnormalities of the bowel wall, or intraluminal abnormalities
sclerosis within the vessel lumen and will also evaluate the patency of
(Table 323-1). Within each of these broad categories are many diseases
remaining mesenteric vessels. The use of mesenteric angiography may
that can impede intestinal propulsion. Intrinsic diseases that can cause
be limited in the presence of renal failure or contrast allergy. Magnetic
intestinal obstruction are usually congenital, inflammatory, neoplastic,
resonance angiography is an alternative if the administration of
or traumatic in origin, although intussusception and radiation injury
contrast dye is contraindicated.
can also be etiologic.
The management of chronic intestinal ischemia includes medi-
Acute intestinal obstruction accounts for ~1–3% of all hospitalizations
cal management of atherosclerotic disease by exercise, cessation of
PART 10
and a quarter of all urgent or emergent general surgery admissions.

smoking, and antiplatelet and lipid-lowering medications. A full car-
Approximately 80% of cases involve the small bowel, and about one-
diac evaluation should be performed before intervention on chronic
third of these patients show evidence of significant ischemia. The mortal-
mesenteric ischemia. Newer endovascular procedures may avoid an
operative intervention in selected patient populations. Angioplasty with ity rate for patients with strangulation who are operated on within 24–30
h of the onset of symptoms is ~8% but triples shortly thereafter.
endovascular stenting in the treatment of chronic mesenteric ischemia

is associated with an 80% long-term success rate. In patients requiring Extrinsic diseases most commonly cause mechanical obstruction of
surgical exploration, the approach used is determined by findings of the the small intestine. In the United States and Europe, almost all cases
mesenteric angiogram. The entire length of the small and large bowel are caused by postoperative adhesions, carcinomatosis, or herniation
should be evaluated, beginning at the ligament of Treitz. Restoration of of the anterior abdominal wall. Carcinomatosis most often originates
blood flow at the time of laparotomy is accomplished with mesenteric from the ovary, pancreas, stomach, or colon, although rarely, metastasis
vessel endarterectomy or bypass. from distant organs like the breast and skin can occur. Adhesions are
Determination of intestinal viability intraoperatively in patients responsible for the majority of cases of early postoperative obstruction
with suspected intestinal ischemia can be challenging. After revas- that require intervention. It is important to note many patients who are
cularization, peristalsis and return of a pink color of the bowel wall successfully treated for adhesive small-bowel instruction will recur.
should be observed. Palpation of major arterial mesenteric vessels Approximately 20% of patients who were treated conservatively and
can be performed, as well as applying a Doppler flowmeter to the
antimesenteric border of the bowel wall, but neither is a definitive
indicator of viability. In equivocal cases, 1 g of IV sodium fluorescein is TABLE 323-1 Most Common Causes of Acute Intestinal Obstruction
administered, and the pattern of bowel reperfusion is observed under Extrinsic Disease
ultraviolet illumination with a standard (3600 A) Wood’s lamp. An Adhesions (especially due to previous abdominal surgery), internal or
area of nonfluorescence >5 mm in diameter suggests nonviability. If external hernias, neoplasms (including carcinomatosis and extraintestinal
doubt persists, reexploration performed 24–48 h following surgery will malignancies, mostly commonly ovarian), endometriosis or intraperitoneal
allow demarcation of nonviable bowel. Primary intestinal anastomosis abscesses, and idiopathic sclerosis
in patients with ischemic bowel is always worrisome; thus, delayed Intrinsic Disease
bowel reconstruction and reanastomosis should be deferred to the time Congenital (e.g., malrotation, atresia, stenosis, intestinal duplication, cyst
of second-look laparotomy. formation, and congenital bands—the latter rarely in adults)
Inflammation (e.g., inflammatory bowel disease, especially Crohn’s disease,
acknowledgments
but also diverticulitis, radiation, tuberculosis, lymphogranuloma venereum, and
We thank Cory Sandore for providing the illustration for this chapter. Susan schistosomiasis)
Gearhart contributed to this chapter in the 18th edition and Rizwan Ahmed Neoplasia (note: primary small-bowel cancer is rare; obstructive colon cancer
contributed to the 19th edition. may mimic small-bowel obstruction if the ileocecal valve is incompetent)
Traumatic (e.g., hematoma formation, anastomotic strictures)
Deng QW et al: Risk factors for postoperative acute mesenteric ische- Other, including intussusception (where the lead point is typically a polyp or
tumor in adults), volvulus, obstruction of duodenum by superior mesenteric
mia among adult patients undergoing cardiac surgery: A systematic artery, radiation or ischemic injury, and aganglionosis, which is Hirschsprung’s
review and meta-analysis. J Crit Care 42:294, 2017. disease
Salsano G et al: What is the best revascularization strategy for Intraluminal Abnormalities
acute occlusive arterial mesenteric ischemia: Systematic review and
Bezoars, feces, foreign bodies including inspissated barium, gallstones
meta-analysis. Cardiovasc Intervent Radiol 41:27, 2018.
(entering the lumen via a cholecystoenteric fistula), enteroliths
Sise MJ: Acute mesenteric ischemia. Surg Clin North Am 94:165–81, 2014.

TABLE 323-2 Acute Small-Intestinal and Colonic Obstruction ■■PATHOPHYSIOLOGY 2295
Incidences The manifestations of acute intestinal obstruction depend on the
CAUSE INCIDENCE nature of the underlying disease process, its location, and changes in
Postoperative adhesions >50% blood flow (Fig. 323-1). Increased intestinal contractility, which occurs
proximally and distal to the obstruction, is a characteristic response.
Neoplasms ~20%
Subsequently, intestinal peristalsis slows as the intestine or stomach
Hernias (especially ventral or internal types, where the risk ~10%
of strangulation is increased) proximal to the point of obstruction dilates and fills with gastroin-
testinal secretions and swallowed air. Although swallowed air is the
Inflammatory bowel disease, other inflammation (obstruction ~5%
may resolve if acute inflammation and edema subside) primary contributor to intestinal distension, intraluminal air may also
Intussusception, volvulus, other miscellaneous diseases <15%
accumulate from fermentation, local carbon dioxide production, and
altered gaseous diffusion.
Intraluminal dilation also increases intraluminal pressure. When
luminal pressure exceeds venous pressure, venous and lymphatic
between 5 and 30% of patients who were managed operatively will drainage is impeded. Edema ensues, and the bowel wall proximal to
require readmission within 10 years. the site of blockage may become hypoxemic. Epithelial necrosis can
Open operations of the lower abdomen, including appendectomy be identified within 12 h of obstruction. Ultimately, arterial blood
and colorectal and gynecologic procedures, are especially likely to cre- supply may become so compromised that full-thickness ischemia,
ate adhesions that can cause bowel obstruction (Table 323-2). The risk necrosis, and perforation result. Stasis increases the bacteria counts
of internal herniation is increased by abdominal procedures such as within the jejunum and ileum. Bacteria like Escherichia coli, Strepto-
laparoscopic or open Roux-en-Y gastric bypass. Although laparoscopic coccus faecalis, and Klebsiella, and other pathogens may be recovered
procedures may generate fewer postoperative adhesions compared from intestinal cultures, mesenteric lymph nodes, the blood stream,
with open surgery, the risk of obstructive adhesion formation is not and other sites.
eliminated. Other manifestations depend on the degree of hypovolemia, the
Volvulus, which occurs when bowel twists on its mesenteric axis, patient’s metabolic response, and the presence or absence of associ-
can cause partial or complete obstruction and vascular insufficiency. ated intestinal ischemia. Inflammatory edema eventually increases the
The sigmoid colon is most commonly affected, accounting for approx- production of reactive oxygen species and activates neutrophils and
imately two-thirds of all cases of volvulus and 4% of all cases of large- macrophages, which accumulate within the bowel wall. Their accumu-
bowel obstruction. The cecum and terminal ileum can also volvulize, lation, along with changes in innate immunity, disrupts secretory and
CHAPTER 323 Acute Intestinal Obstruction

or the cecum alone may be involved as a cecal bascule. Risk factors neuromotor processes. Dehydration is caused by loss of the normal
include institutionalization, the presence of neuropsychiatric condi- intestinal absorptive capacity as well as fluid accumulation in the gas-
tions requiring psychotropic medication, chronic constipation, and tric or intestinal wall and intraperitoneally.
aging; patients typically present in their seventies or eighties. Anorexia and emesis tend to exacerbate intravascular volume
Colonic volvulus is more common in Eastern Europe, Russia, and depletion. In the worst case scenario that is most commonly identified
Africa than it is in the United States. It is rare for adhesions or hernias after high-grade distal obstruction, emesis leads to losses of gastric
to obstruct the colon. Cancer of the descending colon and rectum is potassium, hydrogen, and chloride, while dehydration stimulates
responsible for approximately two-thirds of all cases, followed by proximal renal tubule bicarbonate reabsorption. Intraperitoneal fluid
diverticulitis and volvulus. accumulation, especially in patients with severe distal bowel obstruc-
Functional obstruction, also known as ileus and pseudo-obstruction, is tion, may increase intraabdominal pressure enough to elevate the dia-
present when dysmotility prevents intestinal contents from being pro- phragm, inhibit respiration and to impede systemic venous return and
pelled distally and no mechanical blockage exists. Ileus that occurs after promote vascular instability. Severe hemodynamic compromise may
intraabdominal surgery is the most commonly identified form of func- elicit a systemic inflammatory response and generalized microvascu-
tional bowel obstruction, but there are many other causes (Table 323-3). lar leakage.
Although postoperative ileus is most often transient, it is often the most Closed-loop obstruction results when the proximal and distal
common reason why hospital discharge is delayed. Pseudo-obstruction openings of a given bowel segment are both occluded, for example,
of the colon, also known as Ogilvie’s syndrome, is a relatively rare dis- due to volvulus or a hernia. It is the most common precursor for
ease. Some patients with Ogilvie’s syndrome have colonic dysmotility strangulation, but not every closed loop strangulates. The risk of vas-
due to abnormalities of their autonomic nervous system that may be cular insufficiency, systemic inflammation, hemodynamic compromise,
inherited. and irreversible intestinal ischemia is much greater in patients with
closed-loop obstruction. Pathologic changes may occur more rapidly,
TABLE 323-3 Most Common Causes of Ileus (Functional or and emergency intervention is indicated. Irreversible bowel ischemia
Pseudo-Obstruction of the Intestine) may progress to transmural necrosis even if obstruction is relieved.
Intraabdominal procedures, lumbar spinal injuries, or surgical procedures on It is also important to remember that patients with high-grade distal
the lumbar spine and pelvis colonic obstruction who have competent ileocecal valves may present
Metabolic or electrolyte abnormalities, especially hypokalemia and with closed-loop obstruction. In the latter instance, the cecum may
hypomagnesemia, but also hyponatremia, uremia, and severe hyperglycemia progressively dilate such that ischemic necrosis results in perforation
Drugs such as opiates, antihistamines, and some psychotropic (e.g., especially when the cecal diameter exceeds 10–12 cm, as informed by
haloperidol, tricyclic antidepressants) and anticholinergic agents
Laplace’s law. Patients with distal colonic obstruction whose ileocecal
Intestinal ischemia valves are incompetent tend to present later in the course of disease
Intraabdominal or retroperitoneal inflammation or hemorrhage and mimic patients with distal small-bowel obstruction.
Lower lobe pneumonias
Intraoperative radiation (likely due to muscle damage) ■■HISTORY AND PHYSICAL FINDINGS
Systemic sepsis Even though the presenting signs and symptoms can be misleading,
Hyperparathyroidism many patients with acute obstruction can be accurately diagnosed after
a thorough history and physical examination is performed. However,
Pseudo-obstruction (Ogilvie’s syndrome)
small-bowel obstruction with strangulation can be especially difficult
Ileus secondary to hereditary or acquired visceral myopathies and
neuropathies that disrupt myocellular neural coordination
to diagnosis promptly. Early recognition allows earlier treatment that
decreases the risk of progression or other excess morbidity.
Some collagen vascular diseases such as lupus erythematosus or
scleroderma The cardinal signs are colicky abdominal pain, abdominal disten-
tion, emesis, and obstipation. More intraluminal fluid accumulates

2296
Abnormal Inflammatory
bacteria mediators
colonization released
Fluid and air

accumulate bacteria
overgrowth may occur
Air
Epithelial
necrosis
Fluid
Proximal
bowel
Inflammatory dilatation
wall edema
Point of obstruction
from extrinsic, intrinsic,
or intraluminal disease
Collapsed
bowel distal
PART 10
to obstruction
Patients with distal

obstruction may still
discharge intraluminal
contents
Note: intraluminal obstruction is displayed
FIGURE 323-1 Pathophysiologic changes of small-bowel obstruction.
in patients with distal obstruction, which typically leads to greater obstruction. It is important to remember that the discomfort may be out
distention, more discomfort, and delayed emesis. This emesis is fecu- of proportion to physical findings mimicking the complaints of patients
lent when there is bacterial overgrowth. Patients with more proximal with acute mesenteric ischemia. Patients with colonic volvulus pres-
obstruction commonly present with less abdominal distention but ent with the classic manifestations of closed-loop obstruction: severe
more pronounced vomiting. Elements of the history that might be abdominal pain, vomiting, and obstipation. Asymmetrical abdominal
helpful include any prior history of surgery, including herniorrhaphy, distension and a tympanic mass may be evident.
as well as any history of cancer or inflammatory bowel disease. Patients with ileus or pseudo-obstruction may have signs and
Most patients, even those with simple obstruction, appear to be crit- symptoms similar to those of bowel obstruction. Although abdominal
ically ill. Many may be oliguric, hypotensive, and tachycardic because distention is present, colicky abdominal pain is typically absent, and
of severe intravascular volume depletion. Fever is worrisome for stran- patients may not have nausea or emesis. Ongoing, regular discharge of
gulation or systemic inflammation. Bowel sounds and bowel functional stool or flatus can sometimes help distinguish patients with ileus from
activity are notoriously difficult to interpret. Classically, many patients those with complete mechanical bowel obstruction.
with early small-bowel obstruction will have high-pitched, “musical”
tinkling bowel sounds and peristaltic “rushes” known as borborygmi. ■■LABORATORY AND IMAGING STUDIES
Later in the course of disease, the bowel sounds may be absent or Laboratory testing should include a complete blood count and serum
hypoactive as peristaltic activity decreases. This is in contrast to the electrolyte and creatinine measurements. Serial assessments are often use-
common findings in patients with ileus or pseudo-obstruction where ful. Mild hemoconcentration and slight elevation of the white blood cell
bowel sounds are typically absent or hypoactive from the beginning. count commonly occur after simple bowel obstruction. Emesis and dehy-
Lastly, patients with partial blockage may continue to pass flatus and dration may cause hypokalemia, hypochloremia, elevated blood urea
stool, and those with complete blockage may evacuate bowel contents nitrogen–to–creatinine ratios, and metabolic alkalosis. Patients may be
present downstream beyond their obstruction. hyponatremic on admission because many have attempted to rehydrate
All surgical incisions should be examined and the presence of a themselves with hypotonic fluids. The presence of guaiac-positive stools
tender abdominal or groin mass strongly suggests that an incarcerated and iron-deficiency anemia are strongly suggestive of malignancy.
hernia may be the cause of obstruction. The presence of tenderness Higher white blood cell counts with the presence of immature forms
should increase the concern about the presence of complications such as or the presence of metabolic acidosis are worrisome for severe vol-
ischemia, necrosis, or peritonitis. Severe pain with localization or signs ume depletion or ischemic necrosis and sepsis. Presently, there are no
of peritoneal irritation is suspicious for strangulated or closed-loop laboratory tests that are especially useful for identifying the presence

of simple or strangulated obstruction, although increases in serum 2297
d-lactate, creatine kinase BB isoenzymes, or intestinal fatty acid bind-
ing protein levels may be suggestive of the latter.
Recommendations for diagnostic imaging continue to evolve. In all
cases, the key is not to operative intervention unnecessarily when the
patient’s signs or symptoms strongly suggest that high-grade or com-
plete obstruction or bowel compromise is present. Abdominal radiog-
raphy, which must include upright or cross-table lateral views, can be
completed quickly and may indicate the need for emergency surgical
intervention in patients who are not in the immediate postoperative
period. A “staircasing” pattern of dilated air and fluid-filled small-
bowel loops >2.5 cm in diameter with little or no air seen in the colon
are classical findings in patients with small-bowel obstruction, although
findings may be equivocal in some patients with documented disease.
Little bowel gas appears in patients with proximal bowel obstruction or
in patients whose intestinal lumens are filled with fluid. Upright plain
films of the abdomen of patients with large-bowel obstruction typically
show colon dilatation. Small-bowel air-fluid levels will not be obvious
if the ileocecal valve is competent. Although it can be difficult to distin-
guish from ileus, small-bowel obstruction is more likely when air-fluid
levels are seen without significant colonic distension. Free air suggests
that perforation has occurred in patients who have not recently under-
gone surgical procedures. A gas-filled, “coffee bean”–shaped dilated
shadow may be seen in patients with volvulus.
More sophisticated imaging, which may be unnecessarily time con-
suming and expensive, can nevertheless be beneficial when the diag-
nosis is unclear. Computed tomography (CT) is the most commonly
used imaging modality. Its sensitivity for detecting bowel obstruction
CHAPTER 323 Acute Intestinal Obstruction

is ~95% (78–100%) in patients with high-grade obstruction, with a
specificity of 96% and an accuracy of ≥95%. Its accuracy in diagnosing
closed-loop obstruction is much lower (60%). CT may also provide
useful information regarding location or to identify particular circum-
stances where surgical intervention is needed urgently. Patients who
have evidence of contrast appearing within the cecum within 4–24 h
of oral administration of water-soluble contrast can be expected to
improve with high sensitivity and specificity (~95% each). For exam-
ple, contrast studies may demonstrate a “bird’s beak,” a “c-loop,” or
“whorl” deformity on CT imaging at the site where twisting obstructs
the lumen when a colonic volvulus is present. Although abdominal
radiography is usually the initial examination, unlike CT imaging, it
may not accurately distinguish obstruction from other causes of colonic
dysmotility. Examples of some CT images are reproduced in Fig. 323-2.
Ultrasonographic evaluations are especially difficult to interpret but
may be sensitive and appropriate studies to evaluate patients who are
pregnant or for whom x-ray exposure is otherwise contraindicated or
inappropriate.
CT imaging with enteral and IV contrast can also identify ischemia.
Altered bowel wall enhancement is the most specific early finding, but
its sensitivity is low. Mesenteric venous gas, pneumoperitoneum, and
pneumatosis intestinalis are late findings indicating the presence of
bowel necrosis. CT scanning after a water-soluble contrast enema may
help distinguish ileus or pseudo-obstruction from distal large-bowel
FIGURE 323-2 Computed tomography with oral and intravenous contrast
obstruction in patients who present with evidence of small-bowel demonstrating (A) evidence of small-bowel dilatation with air-fluid levels
and colonic distention. CT enteroclysis, though rarely performed, can consistent with a small-bowel obstruction; (B) a partial small-bowel obstruction
accurately identify neoplasia as a cause of bowel obstruction. Contrast from an incarcerated ventral hernia (arrow); and (C) decompressed bowel seen
enemas or colonoscopies are almost always needed to identify causes distal to the hernia (arrow). (From W Silen: Acute intestinal obstruction, in DL Longo
of acute colonic obstruction. et al [eds]: Harrison’s Principles of Internal Medicine, 18th ed. New York, McGraw-
Barium studies are generally contraindicated in patients with firm Hill, 2012.)
evidence of complete or high-grade bowel obstruction, especially
when they present acutely. Barium should never be given orally
to a patient with possible obstruction until that diagnosis has been TREATMENT
excluded. In every other case, such investigations should only be per- Acute Intestinal Obstruction
formed in exceptional circumstances and with great caution because
patients with significant obstruction may develop barium concretions An improved understanding of the pathophysiology of bowel
as an additional source of blockage and some who would have oth- obstruction and the importance of fluid resuscitation, electrolyte
erwise recovered will require operative intervention. Barium opaci- repletion, intestinal decompression, and the selected use of antibi-
fication also renders cross-sectional imaging studies or angiography otics have likely contributed to a reduction in mortality from acute
uninterpretable. bowel obstruction. Every patient should be stabilized as quickly

2298 as possible. Nasogastric tube suction decompresses the stomach, ADULT INTUSSUSCEPTION AND GALLSTONE ILEUS
minimizes further distention from swallowed air, improves patient Primary resection is prudent. Careful manual reduction of any
comfort, and reduces the risk of aspiration. Urine output should involved bowel may limit the amount of intestine that needs to be
be assessed using a Foley catheter. In some cases, for example, in removed. A proximal ostomy may be required if unprepped colon is
patients with cardiac disease, central venous pressures should be involved. The most common site of intestinal obstruction in patients
monitored. The use of antibiotics is controversial, although prophy- with gallstone “ileus” is the ileum (60% of patients). The gallstone
lactic administration may be warranted if operation is anticipated. enters the intestinal tract most often via a cholecystoduodenal
Complete bowel obstruction is an indication for intervention. Stent- fistula. It can usually be removed by operative enterolithotomy.
ing may be possible and warranted for some patients with high- Addressing the gallbladder disease during urgent or emergent
grade obstruction due to unresectable stage IV malignancy. Stenting surgery is not recommended.
may also allow elective mechanical bowel preparation before sur-
gery is undertaken. Because treatment options are so variable, it is POSTOPERATIVE BOWEL OBSTRUCTION
helpful to make as precise a diagnosis as possible preoperatively. Early postoperative mechanical bowel obstruction is that which
occurs within the first 6 weeks of operation. Most are partial and can
ILEUS be expected to resolve spontaneously. It tends to respond and behave
Patients with ileus are treated supportively with intravenous fluids differently from classic mechanical bowel obstruction and may
and nasogastric decompression while any underlying pathology is be very difficult to distinguish from postoperative ileus. A higher
treated. Pharmacologic therapy is not yet proven to be efficacious index of suspicion for a definitive site of obstruction is warranted
or cost-effective. However, peripherally active μ-opioid receptor for patients who undergo laparoscopic surgical procedures. Patients
antagonists (e.g., alvimopan and methylnaltrexone) may accelerate who first had ileus and then subsequently develop obstructive
gastrointestinal recovery in some patients who have undergone symptoms after an initial return of normal bowel function are more
abdominal surgery. likely to have true postoperative small-bowel obstruction. The longer
COLONIC PSEUDO-OBSTRUCTION (OGILVIE’S DISEASE) it takes for a patient’s obstructive symptoms to resolve after hospital-
ization, the more likely the patient is to require surgical intervention.
Neostigmine is an acetylcholinesterase inhibitor that increases cho-
linergic (parasympathetic) activity, which can stimulate colonic
motility. Some studies have shown it to be moderately effective in Acknowledgment
alleviating acute colonic pseudo-obstruction. It is the most common The wisdom and expertise of Dr. William Silen are gratefully acknowledged.
therapeutic approach and can be used once it is certain that there
is no mechanical obstruction. Cardiac monitoring is required, and
PART 10
Catena F et al: Adhesive small bowel adhesions obstruction: Evolu-

atropine should be immediately available. Intravenous adminis-
tions in diagnosis, management and prevention. World J Gastrointest
tration induces defecation and flatus within 10 min in the majority
Surg 27:222, 2016.
of patients who will respond. Sympathetic blockade by epidural
Ferrada P et al: Surgery or stenting for colonic obstruction: A practice
anesthesia can successfully ameliorate pseudo-obstruction in some
management guideline from the Eastern Association for the Surgery
patients.
of Trauma. J Trauma Acute Care Surg 80:659, 2016.
VOLVULUS Jaffe T, Thompson WM: Large-bowel obstruction in the adults: Clas-
Patients with sigmoid volvulus can often be decompressed using a sic radiographic and CT findings, etiology and mimics. Radiology
flexible tube inserted through a rigid proctoscope or using a flexible 275:651, 2015.
sigmoidoscope. Successful decompression results in sudden release Paulson EK, Thompson WM: Review of small-bowel obstruction: The
of gas and fluid with evidence of decreased abdominal distension diagnosis and when to worry. Radiology 275:332, 2015.
and allows definitive correction to be scheduled electively. Cecal Perry H et al: Relative accuracy of emergency CT in adults with
volvulus most often requires laparotomy or laparoscopic correction. non-traumatic abdominal pain. Brit Inst Rad 89:20150416, 2016.
Taylor MR, Lalani N: Adult small bowel obstruction. Acad Emerg
INTRAOPERATIVE STRATEGIES Med 20:528, 2013.
Approximately 60–80% of selected patients with mechanical bowel
obstruction can be successfully treated conservatively. Indeed, most
cases of radiation-induced obstruction should also be managed
nonoperatively if possible. In most circumstances, early consultation
with a surgeon is prudent when there is concern about strangula-
tion obstruction or other abnormality that needs to be addressed
urgently. Deterioration signifies a need for intervention. At this time,
the decision as to whether the patient can continue to be treated
nonoperatively can only be based on clinical judgment, although,
324 Acute Appendicitis and
Peritonitis
as described earlier, imaging studies can sometimes be helpful. The
frequency of major complications after operation ranges from 12 to Danny O. Jacobs
47%, with greater risk being attributed to resection therapies and the
patient’s overall health. Risk is increased for patients with American
Society of Anesthesiologists (ASA) class III or higher. ACUTE APPENDICITIS
At operation, dilation proximal to the site of blockage with distal
collapse is a defining feature of bowel obstruction. Intraoperative ■■INCIDENCE AND EPIDEMIOLOGY
strategies depend on the underlying problem and range from lysis Appendicitis occurs more frequently in Westernized societies but its
of adhesions to resection with or without diverting ostomy to pri- incidence is decreasing for uncertain reasons. Nevertheless, acute
mary resection with anastomosis. Resection is warranted when there appendicitis remains the most common emergency general surgical
is concern about the bowel’s viability after the obstructive process is disease affecting the abdomen, with a rate of ~100 per 100,000 per-
relieved. Laparoscopic approaches can be useful for patients with son-years in Europe and the Americas or about 11 cases per 10,000
early obstruction when extensive adhesions are not expected to be people annually. Approximately 9% of men and 7% of women will
present. Some patients with high-grade obstruction secondary to experience an episode during their lifetime. Appendicitis occurs most
malignant disease that is not amendable to resection will benefit commonly in 10- to 19-year-olds; however, the average age at diag-
from bypass procedures. nosis appears to be gradually increasing, as is the frequency of the

disease in African Americans, Asians, and Native Americans. Overall, TABLE 324-1 Some Conditions That Mimic Appendicitis 2299
70% of patients are <30 years old and most are men. Crohn’s disease Meckel’s diverticulitis
One of the more common complications and most important causes
Cholecystitis or other gallbladder Mittelschmerz
of excess morbidity and mortality is perforation, whether it is contained disease Mesenteric adenitis
and localized or unconstrained within the peritoneal cavity. In contrast Diverticulitis Omental torsion
to the trend observed for appendicitis and appendectomy, the incidence
Ectopic pregnancy Pancreatitis
of perforated appendicitis (~20 cases per 100,000 person-years) is
Endometriosis Lower lobe pneumonia
increasing. The explanation for this trend is unknown. Approximately
Gastroenteritis or colitis Pelvic inflammatory disease
20% of all patients will present with evidence of perforation, but the per-
centage risk is much higher in patients under 5 or over 65 years of age. Gastric or duodenal ulceration Ruptured ovarian cyst or other cystic
Hepatitis disease of the ovaries
■■PATHOGENESIS OF APPENDICITIS AND Kidney disease, including Small-bowel obstruction
APPENDICEAL PERFORATION nephrolithiasis Urinary tract infection
Appendicitis was first described in 1886 by Reginald Fitz. Its etiology is Liver abscess
still not completely understood. Fecaliths, incompletely digested food
residue, lymphoid hyperplasia, intraluminal scarring, tumors, bacteria,
viruses, and inflammatory bowel disease have all been associated with The appendix’s anatomical location, which varies, may directly
inflammation of the appendix and appendicitis. influence how the patient presents. Where the appendix can be “found”
Although not proven, obstruction of the appendiceal lumen is ranges from local differences in how the appendiceal body and tip lie
believed to be an important step in the development of appendicitis— relative to its attachment to the cecum (Figs. 324-1 and 324-2), to where
at least in some cases. Here, obstruction leads to bacterial overgrowth the appendix is actually situated in the peritoneal cavity—for example,
and luminal distension, with an increase in intraluminal pressure that from its typical location in the right lower quadrant, to the pelvis, right
can inhibit the flow of lymph and blood. Then, vascular thrombosis flank, right upper quadrant (as may be observed during pregnancy), or
and ischemic necrosis with perforation of the distal appendix may even the left side of the abdomen for patients with malrotation or who
occur. Therefore, perforation that occurs near the base of the appendix have severely redundant colons.
should raise concerns about another disease process. Most patients Because the differential diagnosis of appendicitis is so extensive,
who will perforate do so before they are evaluated by surgeons. deciding if a patient has appendicitis can be difficult (Table 324-2).
Appendiceal fecaliths (or appendicoliths) are found in ~50% of Many patients may not present with the classically described history
CHAPTER 324 Acute Appendicitis and Peritonitis

patients with gangrenous appendicitis who perforate but are rarely or physical findings and some may not have any abdominal discomfort
identified in those who have simple disease. As mentioned earlier, early in the disease process. Soliciting an appropriate history requires
the incidence of perforated, but not simple, appendicitis is increasing. detecting and evaluating symptoms that might suggest alternative
The rate of perforated and nonperforated appendicitis is correlated in diagnoses.
men but not in women. Together these observations suggest that the What is the classic history? Nonspecific complaints occur first.
underlying pathophysiologic processes are different and that simple Patients may notice changes in bowel habits or malaise and vague,
appendicitis does not always progress to perforation. It appears that perhaps intermittent, crampy, abdominal pain in the epigastric or peri-
some cases of simple acute appendicitis may resolve spontaneously or umbilical region. The pain subsequently migrates to the right lower
with antibiotic therapy with limited risk of recurrent disease. The use quadrant over 12–24 h, where it is sharper and can be definitively local-
of antibiotics to treat uncomplicated appendicitis is currently being ized as transmural inflammation when the appendix irritates the pari-
studied intensively. Preliminary data indicate that as many as 70% of etal peritoneum. Parietal peritoneal irritation may be associated with
patients who present with uncomplicated appendicitis based on com- local muscle rigidity and stiffness. Patients with appendicitis will most
puted tomography (CT) and who are treated with antibiotics alone will often observe that their nausea, if present, followed the development
be free of recurrent disease for at least a year. These findings highlight of abdominal pain, which can help distinguish them from patients with
the importance of clinical decision-making and risk assessment when gastroenteritis, for example, where nausea occurs first. Emesis, if pres-
deciding and discussing treatment options with patients who presum- ent, also occurs after the onset of pain and is typically mild and scant.
ably have simple disease, for example, deciding who is an appropriate Thus, timing of the onset of symptoms and the characteristics of the
candidate for non-operative management and who is not. The latter patient’s pain and any associated findings must be rigorously assessed.
is especially pertinent given the difficulty in assessing which patients Anorexia is so common that the diagnosis of appendicitis should be
might progress to perforation and which will not. questioned in its absence.
Increasingly it appears that there are two broad categories of
patients with appendicitis—those with complicated disease like gan-
grene or perforation and those without. When perforation occurs, the
resultant leak may be contained by the omentum or other surrounding
tissues to form an abscess. Free perforation normally causes severe
peritonitis. These patients may also develop infective suppurative
thrombosis of the portal vein and its tributaries along with intrahepatic 0.5%
abscesses. The prognosis of the very unfortunate patients who develop
this rare but dreaded complication is very poor.
■■CLINICAL MANIFESTATIONS
Improved diagnosis, supportive care, and surgical interventions are 64%
likely responsible for the remarkable decrease in the risk of mortality
from simple appendicitis to currently <1%. Nevertheless, it is still
important to identify patients who might have appendicitis as early 1%
as possible. Patients who have persistent symptoms that haven’t
improved over 48 h may be more likely to perforate or develop other
complications. 32%
Appendicitis should be included in the differential diagnosis of
abdominal pain for every patient in any age group unless it is certain 2%
that the organ has been previously removed (Table 324-1). FIGURE 324-1 Regional anatomical variations of the appendix.

2300 TABLE 324-3 Relative Frequency of Some Presenting Signs
SIGNS FREQUENCY (%)
Abdominal tenderness >95%
Right lower quadrant tenderness >90%
Rebound tenderness 30–70%
Rectal tenderness 30–40%
Cervical motion tenderness 30%
Rigidity ~10%
Psoas sign 3–5%
Obturator sign 5–10%
Rovsing’s sign 5%
Palpable mass <5%
Patients with simple appendicitis normally only appear mildly ill

with a pulse and temperature that are usually only slightly above nor-
mal. The provider should be concerned about other disease processes
beside appendicitis or the presence of complications such as perfo-
ration, phlegmon, or abscess formation if the temperature is >38.3°C
(~101°F) and if there are rigors.
Patients with appendicitis will be found to lie quite still to avoid
peritoneal irritation caused by movement, and some will report dis-
comfort caused by a bumpy car ride on the way to the hospital or
clinic, coughing, sneezing, or other actions that replicate a Valsalva
maneuver. The entire abdomen should be examined systematically
starting in an area where the patient does not report discomfort if
possible. Classically, maximal tenderness is identified in the right
lower quadrant at or near McBurney’s point, which is located approx-
PART 10
FIGURE 324-2 Locations of the appendix and cecum.

imately one-third of the way along a line originating at the anterior
iliac spine and running to the umbilicus. Gentle pressure in the left
Arriving at the correct diagnosis is even more challenging when the lower quadrant may elicit pain in the right lower quadrant if the
appendix is not located in the right lower quadrant, in women of child- appendix is located there. This is Rovsing’s sign (Table 324-4). Evi-
bearing age, and in the very young or elderly. Because the differential dence of parietal peritoneal irritation is often best elicited by gentle
diagnosis of appendicitis is so broad, often the key question to answer abdominal percussion, jiggling the patient’s gurney or bed, or mildly
expeditiously is whether the patient has appendicitis or some other con- bumping the feet.
dition that requires immediate operative intervention. A major concern Atypical presentation and pain patterns are common, especially in
is that the likelihood of a delay in diagnosis is greater if the appendix is the very old or the very young. Diagnosing appendicitis in children can
unusually positioned. All patients should undergo a rectal examination. be especially challenging because they tend to respond so dramatically
An inflamed appendix located behind the cecum or below the pelvic to stimulation and obtaining an accurate history may be difficult. In
brim may prompt very little tenderness of the anterior abdominal wall. addition, it is important to remember that the smaller omentum found
Patients with pelvic appendicitis are more likely to present with in children may be less likely to wall off an appendiceal perforation.
dysuria, urinary frequency, diarrhea, or tenesmus. They may only Observing the child in a quiet surrounding may be helpful.
experience pain in the suprapubic region on palpation or on rectal Signs and symptoms of appendicitis can be subtle in the elderly
or pelvic examination. A pelvic examination in women is mandatory who may not react as vigorously to appendicitis as younger people.
to rule out conditions affecting urogynecologic organs that can cause Pain, if noticed, may be minimal and have originated in the right lower
abdominal pain and mimic appendicitis such as pelvic inflammatory quadrant or, otherwise, where the appendix is located. It may never
disease, ectopic pregnancy, and ovarian torsion. Interest in the ability of have been noticed to be intermittent, or there may only be significant
various clinical scoring systems to predict appendicitis or the need for discomfort with deep palpation. Nausea, anorexia, and emesis may be
imaging studies continues. However, none of the currently available the predominant complaints. The rare patient may even present with
decision tools yet appear to be able to circumvene or obviate the need signs and symptoms of distal bowel obstruction secondary to appendi-
for expert clinical opinion. The relative frequencies of some presenting ceal inflammation and phlegmon or abscess formation.
signs are displayed in Table 324-3.
■■LABORATORY TESTING
Laboratory testing does not identify patients with appendicitis. The white
blood cell count is only mildly to moderately elevated in ~70% of patients
TABLE 324-2 Relative Frequency of Common Presenting Symptoms
SYMPTOMS FREQUENCY
Abdominal pain >95% TABLE 324-4 Classic Signs of Appendicitis in Patients with
Anorexia >70% Abdominal Pain
Constipation 4–16% MANEUVER FINDINGS
Diarrhea 4–16% Rovsing’s sign Palpating in the left lower quadrant causes pain in the
Fever 10–20% right lower quadrant
Migration of pain to right lower 50–60% Obturator sign Internal rotation of the hip causes pain, suggesting the
quadrant possibility of an inflamed appendix located in the pelvis
Nausea >65% Iliopsoas sign Extending the right hip causes pain along posterolateral
Vomiting 50–75% back and hip, suggesting retrocecal appendicitis

with simple appendicitis (with a leukocytosis of 10,000–18,000 cells/μL). 2301
A “left shift” toward immature polymorphonuclear leukocytes is present
in >95% of cases. A sickle cell preparation may be prudent to obtain in
those of African, Spanish, Mediterranean, or Indian ancestry. Serum amy-
lase and lipase levels should be measured.
Urinalysis is indicated to help exclude genitourinary conditions that
may mimic acute appendicitis, but a few red or white blood cells may
be present as a nonspecific finding. However, an inflamed appendix
that abuts the ureter or bladder may cause sterile pyuria or hematuria.
Every woman of childbearing age should have a pregnancy test. Cer-
vical cultures are indicated if pelvic inflammatory disease is suspected.
Anemia and guaiac-positive stools should raise concern about the pres-
ence of other diseases or complications such as cancer.
■■IMAGING
Plain films of the abdomen are rarely helpful and so are not routinely
obtained unless the clinician is worried about other conditions such as
intestinal obstruction, perforated viscus, or ureterolithiasis. Less than
5% of patients will present with an opaque fecalith in the right lower
quadrant. The presence of a fecalith is not diagnostic of appendicitis,
although its presence in an appropriate location where the patient com- FIGURE 324-3 Computed tomography with oral and intravenous contrast
plains of pain is suggestive and is associated with a greater likelihood of acute appendicitis. There is thickening of the wall of the appendix and
of complications. periappendiceal stranding (arrow).
The effectiveness of ultrasonography as a tool to diagnosis appen-
dicitis is highly operator dependent. Even in very skilled hands, the
appendix may not be visualized. Its overall sensitivity is 0.86, with a in patients who present with abdominal pain, fever, and neutropenia
specificity of 0.81. Ultrasonography, especially intravaginal techniques, due to chemotherapy. CT imaging may be very helpful, although it is
appears to be most useful for identifying pelvic pathology in women. important not to be overly cautious and delay operative intervention
CHAPTER 324 Acute Appendicitis and Peritonitis

Ultrasonographic findings suggesting the presence of appendicitis for those patients who are believed to have appendicitis.
include wall thickening, an increased appendiceal diameter, and the
presence of free fluid. Current practice in many institutions is to first
perform ultrasonography and progress to other imaging studies only if
TREATMENT
the findings are equivocal. Acute Appendicitis
The sensitivity and specificity of CT are at least 0.94 and 0.95,
respectively. Thus, CT imaging, given its high negative predictive In the absence of contraindications, most patients who have strongly
value, may be helpful if the diagnosis is in doubt, although studies suggestive medical histories and physical examinations with sup-
performed early in the course of disease may not have any typical portive laboratory findings are candidates for appendectomy. In
radiographic findings. In patients where the diagnosis is uncertain, many instances, imaging studies are not required but are often
delaying operation at the time of presentation to obtain CT does not obtained before surgical consultation is requested. Certainly, imag-
appear to increase the risk of perforation. CT scanning is a superior ing and further study is appropriate in patients whose evaluations
method for assessing the severity of acute appendicitis in the absence are suggestive but not convincing.
of peritoneal findings indicative of perforation, abscess, or suspicion of CT may accurately indicate the presence of appendicitis or other
an associated malignancy. intraabdominal processes that warrant intervention. Whenever the
Suggestive findings on CT examination include dilatation >6 mm diagnosis is uncertain, it is prudent to observe the patient and repeat
with wall thickening, a lumen that does not fill with enteric contrast, the abdominal examination over 6–8 h. Any evidence of progression
and fatty tissue stranding or air surrounding the appendix, which
suggests inflammation (Figs. 324-3 and 324-4). The presence of lumi-
nal air or contrast is not consistent with a diagnosis of appendicitis.
Furthermore, nonvisualization of the appendix is a nonspecific finding
that should not be used to rule out the presence of appendiceal or peri-
appendiceal inflammation.
■■SPECIAL PATIENT POPULATIONS

Appendicitis in the most common extrauterine general surgical emer-
gency observed during pregnancy. Early symptoms of appendicitis
such as nausea and anorexia may be overlooked. Diagnosing appen-
dicitis in pregnant patients may be especially difficult because as the
uterus enlarges the appendix may be pushed higher along the right
flank even to the right upper quadrant or because the gravid uterus
may obscure typical physical findings. Ultrasonography may facilitate
early diagnosis. A high index of suspicion is required because of the
effects of unrecognized and untreated appendicitis on the fetus. For
example, the fetal mortality rate is four times greater (from 5 to 20%) in
patients with perforation.
Immunocompromised patients may present with only mild tender-
ness and may have many other disease processes in their differential
diagnosis, including atypical infections from mycobacteria, Cytomega-
lovirus, or other fungi. Enterocolitis is a concern and may be present FIGURE 324-4 Appendiceal fecalith (arrow).

2302 is an indication for operation. Narcotics can be given to patients with TABLE 324-5 Conditions Leading to Secondary Bacterial Peritonitis
severe discomfort. Bowel perforation Perforation or leakage of other organs
All patients should be fully prepared for surgery and have any Appendicitis trauma (blunt or Biliary leakage (e.g., after liver biopsy)
fluid and electrolyte abnormalities corrected. Either laparoscopic or penetrating) Cholecystitis
open appendectomy is a satisfactory choice for patients with uncom- Anastomotic leakage Intraperitoneal bleeding
plicated appendicitis though most procedures are performed in a
Adhesion Pancreatitis
minimally invasive fashion. Management of those who present with
Diverticulitis Salpingitis
a mass representing a phlegmon or abscess can be more difficult.
Such patients are best served by treatment with broad-spectrum Iatrogenic (including endoscopic Traumatic or other rupture of urinary
perforation) bladder
antibiotics, drainage if there is an abscess >3 cm in diameter, and
Ingested foreign body Loss of peritoneal integrity
parenteral fluids and bowel rest if they appear to respond to conser-
vative management. The appendix can then be more safely removed Inflammation Intraperitoneal chemotherapy
6–12 weeks later when inflammation has diminished. Intussusception Iatrogenic (e.g., postoperative foreign
Laparoscopic appendectomy now accounts for the majority of all Neoplasms body)
appendectomies performed in Western cultures and is associated with Obstruction Perinephric abscess
less postoperative pain, shorter lengths of stay, faster return to normal Peptic ulcer disease Peritoneal dialysis or other indwelling
activity and likely fewer superficial wound complications—although Strangulated hernia devices
the risk of intraabdominal abscess formation may be higher. Vascular (including ischemia or Trauma
A laparoscopic approach may also be useful when the exact embolus)
diagnosis is uncertain. A laparoscopic approach may also facilitate
exposure in those who are very obese. Absent complications, most
patients can be discharged within 24–40 h of operation. The most
as diffuse abdominal tenderness with local guarding, rigidity, and
common postoperative complications are fever and leukocytosis.
other evidence of parietal peritoneal irritation. Physical findings may
Continuation of these findings beyond 5 days should raise concern
only be identified in a specific region of the abdomen if the intraperi-
for the presence of an intraabdominal abscess. The mortality rate
toneal inflammatory process is limited or otherwise contained as may
for uncomplicated, nonperforated appendicitis is 0.1–0.5%, which
occur in patients with uncomplicated appendicitis or diverticulitis.
approximates the overall risk of general anesthesia. The mortal-
Bowel sounds are usually absent to hypoactive.
ity rate for perforated appendicitis or other complicated disease
Most patients present with tachycardia and signs of volume deple-
is much higher, ranging from 3% overall to a high as 15% in the
tion with hypotension. Laboratory testing typically reveals a signifi-
PART 10
elderly.
cant leukocytosis, and patients may be severely acidotic. Radiographic
studies may show dilatation of the bowel and associated bowel wall
ACUTE PERITONITIS edema. Free air, or other evidence of leakage, requires attention and
Acute peritonitis, or inflammation of the visceral and parietal perito- could represent a surgical emergency. In stable patients in whom
neum, is most often but not always infectious in origin, resulting from
ascites is present, diagnostic paracentesis is indicated, where the fluid

perforation of a hollow viscus. This is called secondary peritonitis, as is tested for protein and lactate dehydrogenase and the cell count is
opposed to primary or spontaneous peritonitis, when a specific intraab- measured.
dominal source cannot be identified. In either instance, the inflamma-
tion can be localized or diffuse. ■■THERAPY AND PROGNOSIS
Whereas mortality rates can be <10% for reasonably healthy patients
■■ETIOLOGY with relatively uncomplicated, localized peritonitis, mortality rates
Infective organisms may contaminate the peritoneal cavity after >40% have been reported for the elderly or immunocompromised.
spillage from a hollow viscus, because of a penetrating wound of the Successful treatment depends on correcting any electrolyte abnormali-
abdominal wall, or because of the introduction of a foreign object like ties, restoration of fluid volume and stabilization of the cardiovascular
a peritoneal dialysis catheter or port that becomes infected. Secondary system, appropriate antibiotic therapy, and surgical correction of any
peritonitis most commonly results from perforation of the appendix, underlying abnormalities.
colonic diverticuli, or the stomach and duodenum. It may also occur as
a complication of bowel infarction or incarceration, cancer, inflamma- Acknowledgment
tory bowel disease, and intestinal obstruction or volvulus. Conditions The wisdom and expertise of Dr. William Silen is gratefully acknowledged in
that may cause secondary bacterial peritonitis and their mechanisms this updated chapter on acute appendicitis and peritonitis.
are listed in Table 324-5. Over 90% of the cases of primary or sponta-
neous bacterial peritonitis occur in patients with ascites or hypopro- ■■FURTHER READING
teinemia (<1 g/L). Andersson RE: Short-term complications and long-term morbidity of
Aseptic peritonitis is most commonly caused by the abnormal pres- laparoscopic and open appendicectomy in a national cohort. Br J Surg
ence of physiologic fluids like gastric juice, bile, pancreatic enzymes, 101:1135, 2014.
blood, or urine. It can also be caused by the effects of normally sterile Buckius MT et al: Changing epidemiology of acute appendicitis in the
foreign bodies like surgical sponges or instruments. More rarely, it United States: Study period 1993–2008. J Surg Res 175:185, 2012.
occurs as a complication of systemic diseases like lupus erythematosus, Drake FT et al: Time to appendectomy and risk of perforation in acute
porphyria, and familial Mediterranean fever. The chemical irritation appendicitis. JAMA Surg 149:837, 2014.
caused by stomach acid and activated pancreatic enzymes is extreme Flum DR: Acute appendicitis—appendectomy of the “antibiotics first”
and secondary bacterial infection may occur. strategy. N Engl J Med 372:1937, 2015.
Ohle R et al: The Alvarado score for predicting acute appendicitis:
■■CLINICAL FEATURES A systematic review. BMC Med 9:139, 2011.
The cardinal signs and symptoms of peritonitis are acute, typically Salminen P et al: Antibiotic therapy versus appendectomy for treat-
severe, abdominal pain with tenderness and fever. How the patient’s ment of uncomplicated acute appendicitis: The APPAC Randomized
complaints of pain are manifested depends on their overall physical Clinical Trial. JAMA 313:2340, 2015.
health and whether the inflammation is diffuse or localized. Elderly Vons C et al: Amoxicillin plus clavulanic acid versus appendicectomy
and immunosuppressed patients may not respond as aggressively to for treatment of acute uncomplicated appendicitis: An open-label,
the irritation. Diffuse, generalized peritonitis is most often recognized non-inferiority, randomised controlled trial. Lancet 377:1573, 2011.

from protein. Most American diets provide at least those amounts. 2303
Section 2 Nutrition Biological value tends to be highest for animal proteins, followed by
proteins from legumes (beans), cereals (rice, wheat, corn), and roots.
Combinations of plant proteins that complement one another in their
325 Nutrient Requirements

and Dietary Assessment
essential amino acid profiles or combinations of animal and plant
proteins can increase biological value and lower total protein intakes
necessary to meet requirements. In healthy people with adequate diets,
the timing of protein intake over the course of the day has little effect.
Johanna Dwyer Protein needs increase during growth, pregnancy, lactation, and
rehabilitation after injury or malnutrition. Tolerance to dietary protein
is decreased in renal insufficiency (with consequent uremia) and in
Nutrients are substances that are not synthesized in sufficient amounts liver failure. Usual protein intakes can precipitate encephalopathy in
in the body and therefore must be supplied by the diet. Nutrient patients with cirrhosis of the liver.
requirements for groups of healthy persons have been determined Fat and Carbohydrate Fats are a concentrated source of energy
experimentally. The absence of essential nutrients leads to growth and constitute, on average, 34% of calories in U.S. diets. However, for
impairment, organ dysfunction, and failure to maintain nitrogen bal- optimal health, fat intake should total no more than 30% of calories.
ance or adequate status of protein and other nutrients. For good health, Saturated fat and trans fat should be limited to <10% of calories and
we require energy-providing nutrients (protein, fat, and carbohydrate), polyunsaturated fats to <10% of calories, with monounsaturated fats
vitamins, minerals, and water. Requirements for organic nutrients accounting for the remainder of fat intake. At least 45–55% of total
include 9 essential amino acids, several fatty acids, glucose, 4 fat- calories should be derived from carbohydrates. The brain requires
soluble vitamins, 10 water-soluble vitamins, dietary fiber, and choline. ~100 g of glucose per day for fuel; other tissues use about 50 g/d. Some
Several inorganic substances, including 4 minerals, 7 trace minerals, 3 tissues (e.g., brain and red blood cells) rely on glucose supplied either
electrolytes, and the ultratrace elements, must also be supplied by diet. exogenously or from muscle proteolysis. Over time, during hypoca-
The amounts of essential nutrients required by individuals differ by loric states, adaptations in carbohydrate needs are possible. Like fat
their age and physiologic state. Conditionally essential nutrients are (9 kcal/g), carbohydrate (4 kcal/g), and protein (4 kcal/g), alcohol
not required in the diet but must be supplied to certain individuals (ethanol) provides energy (7 kcal/g). However, it is not a nutrient.
who do not synthesize them in adequate amounts, such as those with
genetic defects, those with pathologies such as infection, disease or Water For adults, 1–1.5 mL of water per kilocalorie of energy expen-
CHAPTER 325 Nutrient Requirements and Dietary Assessment

trauma with nutritional implications, and developmentally immature diture is sufficient under usual conditions to allow for normal varia-
infants. For example, inositol, taurine, arginine, and glutamine may tions in physical activity, sweating, and solute load of the diet. Water
be needed by premature infants. Many other organic and inorganic losses include 50–100 mL/d in the feces; 500–1000 mL/d by evapo-
compounds that are present in foods, such as pesticides, lead, phyto- ration or exhalation; and, depending on the renal solute load, ≥1000
chemicals, zoochemicals, and microbial products may also have health mL/d in the urine. If external losses increase, intakes must increase
effects. accordingly to avoid underhydration. Fever increases water losses by
~200 mL/d per °C; diarrheal losses vary but may be as great as 5 L/d
■■ESSENTIAL NUTRIENT REQUIREMENTS in severe diarrhea. Heavy sweating, vigorous exercise, and vomiting
Energy For weight to remain stable, energy intake must match also increase water losses. When renal function is normal and solute
energy output. The major components of energy output are resting intakes are adequate, the kidneys can adjust to increased water intake
energy expenditure (REE) and physical activity; minor components by excreting up to 18 L of excess water per day (Chap. 374). However,
include the energy cost of metabolizing food (thermic effect of food, obligatory urine outputs can compromise hydration status when there
or specific dynamic action) and shivering thermogenesis (e.g., cold- is inadequate water intake or when losses increase in disease or kidney
induced thermogenesis). The average energy intake is ~2600 kcal/d damage.
for American men and ~1800 kcal/d for American women, although Infants have high requirements for water because of their large sur-
these estimates vary with body size and activity level. Formulas for face area to volume ratios, their inability to communicate their thirst,
roughly estimating REE are useful in assessing the energy needs of an and the limited capacity of the immature kidney to handle high renal
individual whose weight is stable. Thus, for males, REE = 900 + 10m, solute loads. Increased water needs during pregnancy are ~30 mL/d.
and for females, REE = 700 + 7m, where m is mass in kilograms. The During lactation, milk production increases daily water requirements
calculated REE is then adjusted for physical activity level by multiply- so that ~1000 mL of additional water is needed, or 1 mL for each milli-
ing by 1.2 for sedentary, 1.4 for moderately active, or 1.8 for very active liter of milk produced. Special attention must also be paid to the water
individuals. The final figure, the estimated energy requirement (EER), needs of the elderly, who have reduced total body water and blunted
provides an approximation of total caloric needs in a state of energy thirst sensation and are more likely to be taking medications such as
balance for a person of a certain age, sex, weight, height, and physical diuretics.
activity level. For further discussion of energy balance in health and Other Nutrients See Chap. 326 for detailed descriptions of vita-
disease, see Chap. 327. mins and minerals.
Protein Dietary protein consists of both essential and nonessential
amino acids that are required for protein synthesis. The nine essential ■■DIETARY REFERENCE INTAKES AND RDAS
amino acids are histidine, isoleucine, leucine, lysine, methionine/ Fortunately, human life and well-being can be maintained within a
cystine, phenylalanine/tyrosine, threonine, tryptophan, and valine. fairly wide range with most nutrient intakes. However, the capacity
Certain amino acids, such as alanine, can also be used for energy and for adaptation is not infinite—too much, as well as too little, intake of a
gluconeogenesis. When energy intake is inadequate, protein intake nutrient can have adverse effects or alter the health benefits conferred
must be increased, because ingested amino acids are diverted into by another nutrient. Therefore, benchmark recommendations regard-
pathways of glucose synthesis and oxidation. In extreme energy depri- ing nutrient intakes have been developed to guide clinical practice.
vation, protein-calorie malnutrition may ensue (Chap. 327). These quantitative estimates of nutrient intakes are collectively referred
For adults, the recommended dietary allowance (RDA) for protein to as the dietary reference intakes (DRIs). The DRIs have supplanted the
is ~0.8 g/kg desirable body mass per day, assuming that energy needs RDAs—the single reference values used in the United States until the
are met and that the protein is of relatively high biologic value. Current early 1990s. DRIs include an estimated average requirement (EAR) for
recommendations for a healthy diet call for at least 10–14% of calories nutrients as well as other reference values used for dietary planning:

2304 the RDA, the adequate intake (AI), and the tolerable upper level (UL). daily) that is unlikely to pose a risk of adverse health effects for most
The DRIs also include acceptable macronutrient distribution ranges of the population. Data on the adverse effects of large amounts of many
(AMDRs) for protein, fat, and carbohydrate. The current DRIs for nutrients are unavailable or too limited to establish a UL. Therefore, the
vitamins and elements are provided in Tables 325-1 and 325-2, respec- lack of a UL does not mean that the risk of adverse effects from high
tively. Table 325-3 provides DRIs for water and macronutrients. EERs intake is nonexistent. Nutrient levels in commonly eaten foods rarely
are discussed in Chap. 327 on energy balance in health and disease. exceed the UL. However, very highly fortified foods and dietary sup-
plements provide more concentrated amounts of nutrients per serving
Estimated Average Requirement When florid manifestations
and thus pose a potential risk of toxicity. Nutrient dietary supplements
of the classic dietary-deficiency diseases such as rickets (deficiency of
are labeled with Supplement Facts that express the amount of nutrient
vitamin D and calcium), scurvy (deficiency of vitamin C), xerophthal-
in absolute units or as the percentage of the DV provided per recom-
mia (deficiency of vitamin A), and protein-calorie malnutrition were
mended serving size. Total nutrient consumption, including that in
common, nutrient adequacy was inferred from the absence of their clin-
foods, supplements, and over-the-counter medications (e.g., antacids),
ical deficiency signs. Later, biochemical and other changes were used
should not exceed RDA levels.
that became evident long before the deficiency was clinically apparent.
Consequently, criteria of adequacy are now based on biological mark- Acceptable Macronutrient Distribution Ranges The
ers when they are available. Priority is given to sensitive biochemical, AMDRs are not experimentally determined; rather they are rough
physiologic, or behavioral tests that reflect early changes in regulatory ranges for energy-providing macronutrient intakes (protein, carbo-
processes; maintenance of body stores of nutrients; or, if available, the hydrate, and fat) that the National Academy of Medicine’s (formerly
amount of a nutrient that minimizes the risk of chronic degenerative Institute of Medicine, IOM) Food and Nutrition Board considers to
disease. Current efforts focus on this last variable, but relevant markers be healthful. These ranges are 10–35% of calories for protein, 20–35%
often are not available, and long time lags between intake and disease of calories for fat, and 45–65% of calories for carbohydrate. Alcohol,
outcomes further complicate the picture. which also provides energy, is not a nutrient; therefore, no recommen-
The types of evidence and criteria used to establish nutrient require- dations are not provided.
ments vary by nutrient, age, and physiologic group. The EAR is the
amount of a nutrient estimated to be adequate for half of the healthy ■■FACTORS ALTERING NUTRIENT NEEDS
individuals of a specific age and sex. The EAR is not an effective The DRIs are affected by age, sex, growth rate, pregnancy, lactation,
estimate of nutrient adequacy in individuals because it is a median physical activity level, concomitant diseases, drugs, and dietary com-
requirement for a group; 50% of individuals in a group fall below the position. If requirements for nutrient sufficiency are close to intake
requirement and 50% fall above it. Thus, a person with a usual intake levels indicating excess of a nutrient, dietary planning is difficult.
at the EAR has a 50% risk of inadequate intake. For these reasons the
PART 10
other standards described below are more useful for clinical purposes. Physiologic Factors Growth, strenuous physical activity, preg-
nancy, and lactation all increase needs for energy and several essential
Recommended Dietary Allowances The RDA, the nutrient nutrients. Energy needs rise during pregnancy due to fetal growth
intake goal for planning diets of individuals, is the average daily demands and increased energy required for milk production during
dietary intake level that meets the nutrient requirements of nearly all lactation. Energy needs decrease with loss of lean body mass, the major
healthy persons of a specific sex, age, life stage, or physiologic condition determinant of REE. The energy needs of older persons, especially
(e.g., pregnancy or lactation). It is defined statistically as two standard those aged >70 years, tend to be lower than those of younger persons
deviations above the EAR to ensure that the needs of any given indi- because lean tissue, physical activity, and health often decline with age.
vidual are met. The online tool at http://fnic.nal.usda.gov/interactiveDRI/
allows health professionals to calculate individualized daily nutrient Dietary Composition Dietary composition affects the biological
recommendations for dietary planning based on the DRIs. The RDAs availability and use of nutrients. For example, iron absorption may be
are used to formulate food guides such as the U.S. Department of Agri- impaired by large amounts of calcium or lead; likewise, non-heme iron
culture (USDA) MyPlate Food Guide for individuals (www.supertracker uptake may be impaired by a lack of ascorbic acid and amino acids in
.usda.gov/default.aspx), to create food-exchange lists for therapeutic diet the meal. Bodily protein may be decreased when essential amino acids
planning, and as a standard for describing the nutritional content of are not present in sufficient amounts—a rare scenario in U.S. diets.
foods and nutrient-containing dietary supplements on labels. Animal foods, such as milk, eggs, and meat, have high biologic values,
The risk of dietary inadequacy increases as one’s intake falls below with most of the needed amino acids present in adequate amounts.
the RDA. However, the RDA is an overly generous criterion for evalu- Plant proteins in corn (maize), soy, rice, and wheat have lower biolog-
ating nutrient adequacy. For example, by definition, the RDA exceeds ical values and must be combined with other plant or animal proteins
the actual requirements of all but ~2–3% of the population. Therefore, or fortified with the amino acids that are deficient to achieve optimal
many people whose intake fall below the RDA are still getting enough use by the body.
of the nutrient. On food labels, the nutrient content in a food is stated
Route of Intake The RDAs apply only to oral intakes. When nutri-
by weight or as a percent of the daily value (DV), a variant of the RDA
ents are administered parenterally, similar values can sometimes be
used on the nutrition facts panel that, for an adult, represents the high-
used for amino acids, glucose (carbohydrate), fats, sodium, chloride,
est RDA for an adult consuming 2000 kcal.
potassium, and most vitamins because their intestinal absorption rate
Adequate Intake It is not possible to set an RDA for some nutri- is nearly 100%. However, the oral bioavailability of most mineral ele-
ents that lack an established EAR. In this circumstance, the AI is based ments may be only half that obtained by parenteral administration. For
on observed or experimentally determined approximations of nutrient some nutrients that are not readily stored in the body or that cannot be
intakes in healthy people. In the DRIs, AIs rather than RDAs are pro- stored in large amounts, timing of administration may also be impor-
posed for nutrients consumed by infants (up to age 1 year) as well as tant. For example, amino acids cannot be used for protein synthesis if
for chromium, fluoride, manganese, sodium, potassium, pantothenic they are not supplied together; instead, they will be used for energy
acid, biotin, choline, and water consumed by persons of all ages. Vita- production, although in healthy individuals eating adequate diets, the
min D and calcium recommendations were recently revised, and more distribution of protein intake over the course of the day has little effect
precise estimates are now available. on health.
Tolerable Upper Levels of Nutrient Intake Healthy indi- Disease Dietary deficiency diseases include protein-calorie malnu-
viduals gain no established benefit from consuming nutrient levels trition, iron-deficiency anemia, goiter (due to iodine deficiency), rickets
above the RDA or AI. In fact, excessive nutrient intake can disturb and osteomalacia (vitamin D deficiency), and xeropthalmia (vitamin A
body functions and cause acute, progressive, or permanent disabilities. deficiency), megaloblastic anemia (vitamin B12 or folic acid deficiency),
The tolerable UL is the highest level of chronic nutrient intake (usually scurvy (vitamin C/ascorbic acid deficiency), beriberi (thiamin deficiency),

TABLE 325-1 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Vitamins
LIFE-STAGE VITAMIN A VITAMIN C VITAMIN D VITAMIN E VITAMIN K THIAMIN RIBOFLAVIN NIACIN VITAMIN B6 FOLATE VITAMIN PANTOTHENIC BIOTIN CHOLINE
GROUP (lg/d)a (mg/d) (lg/d)b,c (mg/d)d (lg/d) (mg/d) (mg/d) (mg/d)e (mg/d) (lg/d)f B12 (lg/d) ACID (mg/d) (lg/d) (mg/d)g
Infants
Birth to 6 mo 400* 40* 10 4* 2.0* 0.2* 0.3* 2* 0.1* 65* 0.4* 1.7* 5* 125*
6–12 mo 500* 50* 10 5* 2.5* 0.3* 0.4* 4* 0.3* 80* 0.5* 1.8* 6* 150*
Children
Harrisons_20e_Part10_p2177-p2450.indd 2305
1–3 y 300 15 15 6 30* 0.5 0.5 6 0.5 150 0.9 2* 8* 200*
4–8 y 400 25 15 7 55* 0.6 0.6 8 0.6 200 1.2 3* 12* 250*
Males
9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375*
14–18 y 900 75 15 15 75* 1.2 1.3 16 1.3 400 2.4 5* 25* 550*
19–30 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550*
31–50 y 900 90 15 15 120* 1.2 1.3 16 1.3 400 2.4 5* 30* 550*
51–70 y 900 90 15 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550*
>70 y 900 90 20 15 120* 1.2 1.3 16 1.7 400 2.4h 5* 30* 550*
Females
9–13 y 600 45 15 11 60* 0.9 0.9 12 1.0 300 1.8 4* 20* 375*
14–18 y 700 65 15 15 75* 1.0 1.0 14 1.2 400i 2.4 5* 25* 400*
19–30 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425*
31–50 y 700 75 15 15 90* 1.1 1.1 14 1.3 400i 2.4 5* 30* 425*
51–70 y 700 75 15 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425*
>70 y 700 75 20 15 90* 1.1 1.1 14 1.5 400 2.4h 5* 30* 425*
Pregnant Women
14–18 y 750 80 15 15 75* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
19–30 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
31–50 y 770 85 15 15 90* 1.4 1.4 18 1.9 600j 2.6 6* 30* 450*
Lactating Women
14–18 y 1200 115 15 19 75* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
19–30 y 1300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
31–50 y 1300 120 15 19 90* 1.4 1.6 17 2.0 500 2.8 7* 35* 550*
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily
dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available
to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy
individuals in those groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake.
a
As retinol activity equivalents (RAEs). 1 RAE = 1 μg retinol, 12 μg β-carotene, 24 μg α-carotene, or 24 μg β-cryptoxanthin. The RAE for dietary provitamin A carotenoids is twofold greater than the retinol equivalent (RE), whereas the
RAE for preformed vitamin A is the same as the RE. bAs cholecalciferol. 1 μg cholecalciferol = 40 IU vitamin D. cUnder the assumption of minimal sunlight. dAs α-tocopherol. α-Tocopherol includes RRR-α-tocopherol, the only form of
α-tocopherol that occurs naturally in foods, and the 2R-stereoisomeric forms of α-tocopherol (RRR-, RSR-, RRS-, and RSS-α-tocopherol) that occur in fortified foods and supplements. It does not include the 2S-stereoisomeric forms
of α-tocopherol (SRR-, SSR-, SRS-, and SSS-α-tocopherol) also found in fortified foods and supplements. eAs niacin equivalents (NEs). 1 mg of niacin = 60 mg of tryptophan; 0–6 months = preformed niacin (not NE). fAs dietary folate
equivalents (DFEs). 1 DFE = 1 μg food folate = 0.6 μg of folic acid from fortified food or as a supplement consumed with food = 0.5 μg of a supplement taken on an empty stomach. gAlthough AIs have been set for choline, there
are few data to assess whether a dietary supply of choline is needed at all stages of the life cycle, and it may be that the choline requirement can be met by endogenous synthesis at some of these stages. hBecause 10–30% of
older people may malabsorb food-bound B12, it is advisable for those >50 years of age to meet their RDA mainly by consuming foods fortified with B12 or a supplement containing B12. iIn view of evidence linking inadequate folate
intake with neural tube defects in the fetus, it is recommended that all women capable of becoming pregnant consume 400 μg of folate from supplements or fortified foods in addition to intake of food folate from a varied diet. j It is
assumed that women will continue consuming 400 μg from supplements or fortified food until their pregnancy is confirmed and they enter prenatal care, which ordinarily occurs after the end of the periconceptional period—the critical
time for formation of the neural tube.
Source: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx).
2305
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Disorders of the Gastrointestinal System PART 10
2306
TABLE 325-2 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Elements
LIFE-STAGE CALCIUM CHROMIUM COPPER FLUORIDE IODINE IRON MAGNESIUM MANGANESE MOLYBDENUM PHOSPHORUS SELENIUM ZINC POTASSIUM SODIUM CHLORIDE
GROUP (mg/d) (lg/d) (lg/d) (mg/d) (lg/d) (mg/d) (mg/d) (mg/d) (lg/d) (mg/d) (lg/d) (mg/d) (g/d) (g/d) (g/d)
Infants
Birth to 6 200* 0.2* 200* 0.01* 110* 0.27* 30* 0.003* 2* 100* 15* 2* 0.4* 0.12* 0.18*
mo
6–12 mo 260* 5.5* 220* 0.5* 130* 11 75* 0.6* 3* 275* 20* 3 0.7* 0.37* 0.57*
Children
Harrisons_20e_Part10_p2177-p2450.indd 2306
1–3 y 700 11* 340 0.7* 90 7 80 1.2* 17 460 20 3 3.0* 1.0* 1.5*
4–8 y 1000 15* 440 1* 90 10 130 1.5* 22 500 30 5 3.8* 1.2* 1.9*
Males
9–13 y 1300 25* 700 2* 120 8 240 1.9* 34 1250 40 8 4.5* 1.5* 2.3*
14–18 y 1300 35* 890 3* 150 11 410 2.2* 43 1250 55 11 4.7* 1.5* 2.3*
19–30 y 1000 35* 900 4* 150 8 400 2.3* 45 700 55 11 4.7* 1.5* 2.3*
31–50 y 1000 35* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.5* 2.3*
51–70 y 1000 30* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.3* 2.0*
>70 y 1200 30* 900 4* 150 8 420 2.3* 45 700 55 11 4.7* 1.2* 1.8*
Females
9–13 y 1300 21* 700 2* 120 8 240 1.6* 34 1250 40 8 4.5* 1.5* 2.3*
14–18 y 1300 24* 890 3* 150 15 360 1.6* 43 1250 55 9 4.7* 1.5* 2.3*
19–30 y 1000 25* 900 3* 150 18 310 1.8* 45 700 55 8 4.7* 1.5* 2.3*
31–50 y 1000 25* 900 3* 150 18 320 1.8* 45 700 55 8 4.7* 1.5* 2.3*
51–70 y 1200 20* 900 3* 150 8 320 1.8* 45 700 55 8 4.7* 1.3* 2.0*
>70 y 1200 20* 900 3* 150 8 320 1.8* 45 700 55 8 4.7* 1.2* 1.8*
Pregnant Women
14–18 y 1300 29* 1000 3* 220 27 400 2.0* 50 1250 60 12 4.7* 1.5* 2.3*
19–30 y 1000 30* 1000 3* 220 27 350 2.0* 50 700 60 11 4.7* 1.5* 2.3*
31–50 y 1000 30* 1000 3* 220 27 360 2.0* 50 700 60 11 4.7* 1.5* 2.3*
Lactating Women
14–18 y 1300 44* 1300 3* 290 10 360 2.6* 50 1250 70 13 5.1* 1.5* 2.3*
19–30 y 1000 45* 1300 3* 290 9 310 2.6* 50 700 70 12 5.1* 1.5* 2.3*
31–50 y 1000 45* 1300 3* 290 9 320 2.6* 50 700 70 12 5.1* 1.5* 2.3*
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type followed by an asterisk (*). An RDA is the average daily
dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available
to establish an EAR and thus to calculate an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the needs of all healthy
individuals in those groups, but lack of data or uncertainty in the data makes it impossible to specify with confidence the percentage of individuals covered by this intake.
Sources: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin
D, and Fluoride (1997); Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (1998); Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids
(2000); and Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc (2001); Dietary Reference Intakes for Water, Potassium, Sodium,
Chloride, and Sulfate (2005); and Dietary Reference Intakes for Calcium and Vitamin D (2011). These reports can be accessed via www.nap.edu.
6/1/18 2:14 PM
TABLE 325-3 Dietary Reference Intakes (DRIs): Recommended Dietary Allowances and Adequate Intakes for Total Water and Macronutrients 2307
LIFE-STAGE TOTAL WATER a

CARBOHYDRATE TOTAL FIBER LINOLEIC ACID `-LINOLENIC
GROUP (L/d) (g/d) (g/d) FAT (g/d) (g/d) ACID (g/d) PROTEINb (g/d)
Infants
Birth to 6 mo 0.7* 60* NDc 31* 4.4* 0.5* 9.1*
6–12 mo 0.8* 95* ND 30* 4.6* 0.5* 11.0
Children
1–3 y 1.3* 130 19* ND 7* 0.7* 13
4–8 y 1.7* 130 25* ND 10* 0.9* 19
Males
9–13 y 2.4* 130 31* ND 12* 1.2* 34
14–18 y 3.3* 130 38* ND 16* 1.6* 52
19–30 y 3.7* 130 38* ND 17* 1.6* 56
31–50 y 3.7* 130 38* ND 17* 1.6* 56
51–70 y 3.7* 130 30* ND 14* 1.6* 56
>70 y 3.7* 130 30* ND 14* 1.6* 56
Females
9–13 y 2.1* 130 26* ND 10* 1.0* 34
14–18 y 2.3* 130 26* ND 11* 1.1* 46
19–30 y 2.7* 130 25* ND 12* 1.1* 46
31–50 y 2.7* 130 25* ND 12* 1.1* 46
51–70 y 2.7* 130 21* ND 11* 1.1* 46
>70 y 2.7* 130 21* ND 11* 1.1* 46
Pregnant Women
14–18 y 3.0* 175 28* ND 13* 1.4* 71

19–30 y 3.0* 175 28* ND 13* 1.4* 71
31–50 y 3.0* 175 28* ND 13* 1.4* 71
Lactating Women
14–18 3.8* 210 29* ND 13* 1.3* 71
19–30 y 3.8* 210 29* ND 13* 1.3* 71
31–50 y 3.8* 210 29* ND 13* 1.3* 71
Note: This table (taken from the DRI reports; see www.nap.edu) presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary
type followed by an asterisk (*). An RDA is the average daily dietary intake level sufficient to meet the nutrient requirements of nearly all healthy individuals (97–98%) in
a group. The RDA is calculated from an estimated average requirement (EAR). If sufficient scientific evidence is not available to establish an EAR and thus to calculate
an RDA, an AI is usually developed. For healthy breast-fed infants, an AI is the mean intake. The AI for other life-stage and sex-specific groups is believed to cover the
needs of all healthy individuals in those groups, but lack of data or uncertainty in the data make it impossible to specify with confidence the percentage of individuals
covered by this intake.
a
Total water includes all water contained in food, beverages, and drinking water. bBased on grams of protein per kilogram of body weight for the reference body weight
(e.g., for adults: 0.8 g/kg body weight for the reference body weight). cNot determined.
Source: Food and Nutrition Board, Institute of Medicine, National Academies (http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx), based on: Dietary
Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (2002/2005) and Dietary Reference Intakes for Water, Potassium,
Sodium, Chloride, and Sulfate (2005). These reports can be accessed via www.nap.edu.
and pellagra (niacin and tryptophan deficiency) (Chaps. 326 and 327). they have been consumed. Some disease states affect the bioavailability,
Each deficiency disease is characterized by imbalances at the cellular requirements, use, or excretion of specific nutrients. In these circum-
level between the supply of nutrients or energy and the body’s nutri- stances, specific measurements of various nutrients or their biomarkers
tional needs for growth, maintenance, and other functions. Imbalances may be required to ensure adequate replacement (Chap. 326).
and excesses in nutrient intakes are recognized as risk factors for certain Most health care facilities have nutrition-screening processes in
chronic degenerative diseases, such as saturated fat and cholesterol in place for identifying possible malnutrition after hospital admission.
coronary artery disease; sodium in hypertension; obesity in hormone- Nutritional screening is required by the Joint Commission, which
dependent cancers (endometrial and breast); and ethanol in alcoholism. accredits and certifies health care organizations in the United States.
Diet is only one of many risk factors because the etiology and pathogen- However, no universally recognized or validated standards exist. The
esis of these disorders are multifactorial. Osteoporosis, for example, is factors that are usually assessed include abnormal weight for height
associated with calcium deficiency, sometimes secondary to vitamin D or body mass index (e.g., BMI <19 or >25); reported weight change
deficiency, as well as with environment related risk factors (e.g., smok- (involuntary loss or gain of >5 kg in the past 6 months) (Chap. 43);
ing, sedentary lifestyle), physiology (e.g., estrogen deficiency), genetic diagnoses with known nutritional implications (e.g., metabolic disease,
determinants (e.g., defects in collagen metabolism), and drug use (chronic any disease affecting the gastrointestinal tract, alcoholism); present
steroid and aromatase inhibitors) (Chap. 404). therapeutic dietary prescription; chronic poor appetite; presence of
chewing and swallowing problems or major food intolerances; need for
assistance with preparing or shopping for food, eating, or other aspects
■■DIETARY ASSESSMENT of self-care; and social isolation. The nutritional status of hospitalized
Nutrition assessment in clinical situations is an iterative process that patients should be reassessed periodically—at least once every week.
involves: (1) screening for malnutrition, (2) assessing the diet and other A more complete dietary assessment is indicated for patients who
data to establish either the absence or the presence of malnutrition and exhibit a high risk of or frank malnutrition on nutritional screening.
its possible causes, (3) planning and implementing the most appropri- The type of assessment varies with the clinical setting, the severity of
ate nutritional therapy, and (4) reassessing intakes to make sure that the patient’s illness, and the stability of the patient’s condition.

2308 Acute-Care Settings In acute-care settings, anorexia, various TABLE 325-4 Choose My Plate: A Guide to Individualized Dietary
other diseases, test procedures, and medications can compromise Planning
dietary intake. Under such circumstances, the goal is to identify and EXAMPLES OF STANDARD PORTION SIZES AT
avoid inadequate intake and to assure appropriate alimentation. Dietary INDICATED ENERGY LEVEL
assessment focuses on what patients are currently eating, whether or DIETARY FACTOR, UNIT LOWER: MODERATE: HIGHER:
not they are able and willing to eat, and whether or not they experi- OF MEASURE (ADVICE) 1600 kcal 2200 kcal 2800 kcal
ence any problems with eating. Dietary intake assessment is based on Fruits, cups (Focus on 1.5 2 2.5
information from observed intakes; medical records; history; clinical fruits.)
examination; and anthropometric, biochemical, and functional status Vegetables, cups (Vary 2 3 3.5
evaluations. The objective is to gather enough information to establish vegetables.)
the likelihood of malnutrition due to poor dietary intake or other causes Grains, oz eq (Make 5 7 10
in order to assess whether nutritional therapy is indicated (Chap. 328). at least half of grains
Simple observations may suffice to suggest inadequate oral intake. whole.)a
These include dietitians’ and nurses’ notes; observation of a patient’s Protein foods, oz eq (Go 5 6 7
frequent refusal to eat or the amount of food eaten on trays; the frequent lean with protein.)b
performance of tests and procedures that are likely to cause meals to be Dairy, cups or ozc 3 3 3
skipped; adherence to nutritionally inadequate diet orders (e.g., clear (Choose calcium-rich
liquids or full liquids) for more than a few days; the occurrence of fever, foods.)
gastrointestinal distress, vomiting, diarrhea, or a comatose state; and “Empty” calories, kcald 120 260 400
the presence of diseases or use of treatments that involve any part of Sodium, mg <2300 at all energy
the alimentary tract. Acutely ill patients with diet-related diseases such levels
as diabetes need assessment because an inappropriate diet may exac- Physical activity, min At least 150 min vigorous physical activity per week
erbate these conditions and adversely affect other therapies. Abnormal at all energy levels
biochemical values (serum albumin levels <35 g/L [<3.5 mg/dL]; Note: Oils (formerly listed with portions of 5, 6, and 8 teaspoons for the lower,
serum cholesterol levels <3.9 mmol/L [<150 mg/dL]) are nonspecific moderate, and higher energy levels, respectively) are no longer singled out in
Choose My Plate, but rather are included in the empty calories/added sugar
but may indicate a need for further nutritional assessment. category with SOFAS (calories from solid fats and added sugars). The limit is
Most therapeutic diets offered in hospitals are calculated to meet the remaining number of calories in each food pattern above after intake of the
individual nutrient requirements and the RDA if they are eaten. Excep- recommended amounts of the nutrient-dense foods.
tions include clear liquids, some full-liquid diets, and test diets (such as a
For example, 1 serving equals 1 slice bread, 1 cup ready-to-eat cereal, or 0.5
cup cooked rice, pasta, or cooked cereal. bFor example, 1 serving equals 1 oz
PART 10
those adhered to in preparation for gastrointestinal procedures), which

lean meat, poultry, or fish; 1 egg; 1 tablespoon peanut butter; 0.25 cup cooked
are inadequate for several nutrients and should not be used, if possi- dry beans; or 0.5 oz nuts or seeds. cFor example, 1 serving equals 1 cup milk
ble, for more than 24 h. However, because as much as half of the food or yogurt, 1.5 oz natural cheese, or 2 oz processed cheese. dFormerly called
served to hospitalized patients is not eaten, it cannot be assumed that “discretionary calorie allowance.” Portions are calculated as the number of
calories remaining after all of the above allotments are accounted for.
the intakes of hospitalized patients are adequate. Dietary assessment
should compare how much and what kinds of food the patient has Abbreviation: oz eq, ounce equivalent.
consumed with the diet that has been provided. Major deviations in Source: Data from U.S. Department of Agriculture (http://www.Choosemyplate.gov).
intakes of energy, protein, fluids, or other nutrients of special concern
for the patient’s illness should be noted and corrected, especially for
long-staying patients. sodium and high-calorie sugary drinks. The Web version of the guide
Nutritional monitoring is especially important for patients who are provides a calculator that tailors the number of servings suggested for
very ill and who have extended lengths of hospital stay. Patients who healthy patients of different weights, sexes, ages, and life-cycle stages to
are fed by enteral and parenteral routes also require special nutritional help them to meet their needs while avoiding excess (http://www.super-
assessment and monitoring by physicians and/or dietitians with certi- tracker.usda.gov/default.aspx and www.ChooseMyPlate.gov). Patients who
fication in nutritional support (Chap. 328). follow ethnic or unusual dietary patterns may need extra instruction
on how foods should be categorized and on the appropriate portion
Ambulatory Settings The aim of dietary assessment in the outpa- sizes that constitute a serving. The process of reviewing the guide with
tient setting is to determine whether or not the patient’s usual diet is a patients helps them transition to healthier dietary patterns and identi-
health risk in itself or if it contributes to existing chronic disease-related fies food groups eaten in excess of recommendations or in insufficient
problems. Dietary assessment also provides the basis for planning a quantities. For persons on therapeutic diets, assessment against food-
diet that fulfills therapeutic goals while ensuring patient adherence. exchange lists may be useful. These include, for example, American
The outpatient’s dietary assessment should review the adequacy of Diabetes Association food-exchange lists for diabetes and the Academy
present and usual food intakes, including vitamin and mineral sup- of Nutrition and Dietetics food-exchange lists for renal disease.
plements, oral nutritional supplements, medical foods, other dietary
supplements, medications, and alcohol, because all of these may affect ■■NUTRITIONAL STATUS ASSESSMENT
the patient’s nutritional status. The assessment should focus on the Full nutritional status assessment is reserved for seriously ill patients
dietary constituents that are most likely to be involved or compromised and those at very high nutritional risk when the cause of malnutri-
by a specific diagnosis as well as on any comorbidities that are present. tion is still uncertain after the initial clinical evaluation and dietary
More than one day’s intake should be reviewed to provide a better assessment. It involves multiple dimensions, including documentation
representation of the usual diet, upon which personalized dietary rec- of dietary intake, anthropometric measurements, biochemical mea-
ommendations can be based. surements of blood and urine, clinical examination, health history
There are many ways to assess the adequacy of a patient’s habitual elicitation, and functional status evaluation. Therapeutic dietary pre-
diet. These include use of a food guide, a food-exchange list, a diet his- scriptions and menu plans for most diseases are available from most
tory, or a food-frequency questionnaire. A commonly used food guide hospitals and from the Academy of Nutrition and Dietetics. For further
for healthy persons is the USDA’s Choose My Plate, which is useful as discussion of nutritional assessment, see Chap. 327.
a rough guide for avoiding inadequate intakes of essential nutrients as
well as likely excesses in the amounts of fat (especially saturated and ■■GLOBAL CONSIDERATIONS
trans fats), sodium, sugar, and alcohol consumed (Table 325-4). The The DRIs (e.g., the EAR, the UL, and energy needs) are esti-
Choose My Plate graphic emphasizes a balance between calories and mates of physiologic requirements based on experimental
nutritional needs, encouraging increased intake of fruits and vegetables, evidence. Assuming that appropriate adjustments are made
whole grains, and low-fat milk in conjunction with reduced intake of for age, sex, body size, and physical activity level, these estimates

should be applicable to individuals in most parts of the world. How- After gastric bypass surgery, patients are at high risk for multiple nutri- 2309
ever, other values are not transportable. The AIs are based on custom- ent deficiencies. Moreover, subclinical vitamin and trace mineral defi-
ary and adequate intakes in U.S. and Canadian populations, which ciencies, as diagnosed by laboratory testing, are quite common in the
appear to be compatible with good health, rather than on a large body normal population, especially in the geriatric age group. Conversely,
of direct experimental evidence. Similarly, the AMDRs represent expert because of the widespread use of nutrient supplements, nutrient toxic-
opinion regarding the approximate intakes of energy-providing nutri- ities are gaining pathophysiologic and clinical importance.
ents that are healthful in these North American populations. Thus these Victims of famine, emergency-affected and displaced popula-
measures should be used with caution in other settings. Nutrient-based tions, and refugees are at increased risk for protein-energy
standards like the DRIs have also been developed by the World Health malnutrition and classic micronutrient deficiencies (vitamin A,
Organization/Food and Agricultural Organization of the United iron, iodine) as well as for overt deficiencies in thiamine (beriberi),
Nations and are available on the Web (http://www.who.int/nutrition/top- riboflavin, vitamin C (scurvy), and niacin (pellagra).
ics/nutrecomm/en/index.html). The European Food Safety Authority Body stores of vitamins and minerals vary tremendously. For exam-
(EFSA) Panel on Dietetic Products, Nutrition and Allergies periodically ple, stores of vitamins B12 and A are large, and an adult may not become
publishes its recommendations in the EFSA’s on-line journal. Other deficient until ≥1 year after beginning to eat a deficient diet. However,
countries have promulgated similar recommendations. The different folate and thiamine may become depleted within weeks among those
standards have many similarities in their basic concepts, definitions, eating a deficient diet. Therapeutic modalities can deplete essential
and nutrient recommendation levels, but there are some differences nutrients from the body; for example, hemodialysis or diuretics remove
from the DRIs as a result of the functional criteria chosen, environmen- water-soluble vitamins, which must be replaced by supplementation.
tal differences, the timeliness of the evidence reviewed, and expert Vitamins and trace minerals play several roles in diseases: (1) Defi-
judgment. ciencies of vitamins and minerals may be caused by disease states such
as malabsorption; (2) either deficiency or excess of vitamins and min-
■■FURTHER READING erals can cause disease in and of itself (e.g., vitamin A intoxication and
Brannon PM et al: Scanning for new evidene to prioritize updates to liver disease); and (3) vitamins and minerals in high doses may be used
the Dietary Reference Intakes: Case studies for thiamin and phospho- as drugs (e.g., niacin for hypercholesterolemia). Since they are covered
rus. Am J Clin Nur 104:1366, 2016. elsewhere, the hematologic-related vitamins and minerals (Chaps. 93
Forster H et al: Personalised nutrition: The role of new dietary assess- and 95) either are not considered or are considered only briefly in this
ment methods. Proc Nutr Soc 75:96, 2016. chapter, as are the bone-related vitamins and minerals (vitamin D, cal-
Gibson RS: Principles of Nutritional Assessment, 2nd ed. Oxford, Oxford cium, phosphorus, magnesium; Chap. 402).
CHAPTER 326 Vitamin and Trace Mineral Deficiency and Excess

University Press, 2005.
Lupton JR et al: Nutrient reference value: Non-communicable disease VITAMINS
endpoints—A conference report. Eur J Nutr 55 SUPPL 1:S1–10, 2016. See also Table 326-1 and Fig. 326-1.
Ocke MC: Evaluation of methodologies for assessing the overall diet:
Dietary quality scales and dietary pattern analysis. Proc Nutr Soc ■■THIAMINE (VITAMIN B1)
72:191, 2013. Thiamine was the first B vitamin to be identified and therefore is
Otten JJ et al: Dietary Reference Intakes: The Essential Guide to Nutrient referred to as vitamin B1. Thiamine functions in the decarboxylation of
Requirements. Washington, DC, National Academies Press, 2006. α-ketoacids (e.g., pyruvate α-ketoglutarate) and branched-chain amino
Potischman N, Freudenheim JL: Biomarkers of nutritional exposure acids and thus is essential for energy generation. In addition, thiamine
and nutritional status: An overview. J Nutr 133:873S, 2003. pyrophosphate acts as a coenzyme for a transketolase reaction that medi-
Report of the Subcommittee on Interpretation and Uses of ates the conversion of hexose and pentose phosphates. It has been postu-
Dietary Reference Intakes and Upper Reference Levels of lated that thiamine plays a role in peripheral nerve conduction, although
Nutrients, and the Steering Committtee on the Scientific the exact chemical reactions underlying this function are not known.
Evaluation of Dietary Reference Intakes, Food and Nutrition
Board: Dietary Reference Intakes: Applications in Dietary Assess- Food Sources The median intake of thiamine in the United States
ment. Washington, DC, National Academies Press, 2008. from food alone is 2 mg/d. Primary food sources for thiamine include
Willett WC: Nutritonal Epidemiology, 3rd ed. Oxford, Oxford Univer- yeast, organ meat, pork, legumes, beef, whole grains, and nuts. Milled
sity Press, 2012. rice and grains contain little thiamine. Thiamine deficiency is therefore
Yetley EA et al: Options for basing Dietary Reference Intakes (DRIs) more common in cultures that rely heavily on a rice-based diet. Tea,
on chronic disease endpoints report from a joint US-/Canadian- coffee (regular and decaffeinated), raw fish, and shellfish contain thia-
sponsored working group. Am J Clin Nutr 105:249S, 2017. minases, which can destroy the vitamin. Thus, drinking large amounts
of tea or coffee could theoretically lower thiamine body stores.
Deficiency Most dietary deficiency of thiamine worldwide is the
result of poor dietary intake. In Western countries, the primary causes of
thiamine deficiency are alcoholism and chronic illnesses such as cancer.
326 Vitamin
Alcohol interferes directly with the absorption of thiamine and with the
and Trace Mineral synthesis of thiamine pyrophosphate, and it increases urinary excretion.
Thiamine should always be replenished when a patient with alcoholism
Deficiency and Excess is being refed, as carbohydrate repletion without adequate thiamine can
precipitate acute thiamine deficiency with lactic acidosis. Other at-risk
Paolo M. Suter, Robert M. Russell populations are women with prolonged hyperemesis gravidarum and
anorexia, patients with overall poor nutritional status who are receiving
parenteral glucose, patients who have had bariatric/metabolic surgery
Vitamins are required constituents of the human diet since they are (bariatric Wernicke), and patients receiving chronic diuretic therapy (e.g.,
synthesized inadequately or not at all in the human body. Only small in hypertension or heart failure) due to increased urinary thiamine losses.
amounts of these substances are needed to carry out essential biochem- Maternal thiamine deficiency can lead to infantile beriberi in breast-fed
ical reactions (e.g., by acting as coenzymes or prosthetic groups). Overt children. Thiamine deficiency could be an underlying factor in motor
vitamin or trace mineral deficiencies are rare in Western countries vehicle accidents and could be overlooked in the setting of head injury.
because of a plentiful, varied, and inexpensive food supply; food forti- Thiamine deficiency in its early stage induces anorexia and non-
fication; and use of supplements. However, multiple nutrient deficien- specific symptoms (e.g., irritability, decrease in short-term memory).
cies may appear together in persons who are chronically ill or alcoholic. Prolonged thiamine deficiency causes beriberi, which is classically

2310 TABLE 326-1 Principal Clinical Findings of Vitamin Malnutrition
DIETARY LEVEL PER DAY
ASSOCIATED WITH OVERT
NUTRIENT CLINICAL FINDING DEFICIENCY IN ADULTS CONTRIBUTING FACTORS TO DEFICIENCY
Thiamine Beriberi: neuropathy, muscle weakness and wasting, <0.3 mg/1000 kcal Alcoholism, chronic diuretic use, hyperemesis,
cardiomegaly, edema, ophthalmoplegia, confabulation thiaminases in food
Riboflavin Magenta tongue, angular stomatitis, seborrhea, cheilosis, <0.4 mg Alcoholism, individuals with poor diets and low
ocular symptoms, corneal vascularization intake of milk products
Niacin Pellagra: pigmented rash of sun-exposed areas, bright red <9.0 niacin equivalents Alcoholism, vitamin B6 deficiency, riboflavin
tongue, diarrhea, apathy, memory loss, disorientation deficiency, tryptophan deficiency
Vitamin B6 Seborrhea, glossitis, convulsions, neuropathy, depression, <0.2 mg Alcoholism, isoniazid
confusion, microcytic anemia
Folate Megaloblastic anemia, atrophic glossitis, depression, ↑ <100 μg/d Alcoholism, sulfasalazine, pyrimethamine,
homocysteine triamterene
Vitamin B12 Megaloblastic anemia, loss of vibratory and position sense, <1.0 μg/d Gastric atrophy (pernicious anemia), terminal ileal
abnormal gait, dementia, impotence, loss of bladder and disease, strict vegetarianism, acid-reducing drugs
bowel control, ↑ homocysteine, ↑ methylmalonic acid (e.g., H2 blockers), metformin
Vitamin C Scurvy: petechiae, ecchymosis, coiled hairs, inflamed and <10 mg/d Smoking, alcoholism
bleeding gums, joint effusion, poor wound healing, fatigue
Vitamin A Xerophthalmia, night blindness, Bitot’s spots, follicular <300 μg/d Fat malabsorption, infection, measles, alcoholism,
hyperkeratosis, impaired embryonic development, immune protein-energy malnutrition
dysfunction
Vitamin D Rickets: skeletal deformation, rachitic rosary, bowed legs; <2.0 μg/d Aging, lack of sunlight exposure, fat malabsorption,
osteomalacia deeply pigmented skin
Vitamin E Peripheral neuropathy, spinocerebellar ataxia, skeletal Not described unless underlying Occurs only with fat malabsorption or genetic
muscle atrophy, retinopathy contributing factor is present abnormalities of vitamin E metabolism/transport
Vitamin K Elevated prothrombin time, bleeding <10 μg/d Fat malabsorption, liver disease, antibiotic use
PART 10
categorized as wet or dry although there is considerable overlap Toxicity Although anaphylaxis has been reported after high intra-
between the two categories. In either form of beriberi, patients may venous doses of thiamine, no adverse effects have been recorded from
complain of pain and paresthesia. Wet beriberi presents primarily either food or supplements at high doses. Thiamine supplements may
with cardiovascular symptoms that are due to impaired myocardial be bought over the counter in doses of up to 50 mg/d.
energy metabolism and dysautonomia; it can occur after 3 months
of a thiamine-deficient diet. Patients present with an enlarged heart, ■■RIBOFLAVIN (VITAMIN B2)
tachycardia, high-output congestive heart failure, peripheral edema, Riboflavin is important for the metabolism of fat, carbohydrate, and
and peripheral neuritis. Patients with dry beriberi present with a sym- protein, acting as a respiratory coenzyme and an electron donor.
metric peripheral neuropathy of the motor and sensory systems, with Enzymes that contain flavin adenine dinucleotide (FAD) or flavin
diminished reflexes. The neuropathy affects the legs most markedly, mononucleotide (FMN) as prosthetic groups are known as flavoenzymes
and patients have difficulty rising from a squatting position. (e.g., succinic acid dehydrogenase, monoamine oxidase, glutathione
Alcoholic patients with chronic thiamine deficiency also may have reductase). FAD is a cofactor for methyltetrahydrofolate reductase
central nervous system (CNS) manifestations known as Wernicke’s and therefore modulates homocysteine metabolism. The vitamin also
encephalopathy, which consists of horizontal nystagmus, ophthalmople- plays a role in drug and steroid metabolism, including detoxification
gia (due to weakness of one or more extraocular muscles), cerebellar reactions.
ataxia, and mental impairment (Chap. 445). When there is an addi- Although much is known about the chemical and enzymatic
tional loss of memory and a confabulatory psychosis, the syndrome reactions of riboflavin, the clinical manifestations of riboflavin
is known as Wernicke-Korsakoff syndrome. Despite the typical clinical deficiency are nonspecific and are similar to those of other deficien-
picture and history, Wernicke-Korsakoff syndrome is underdiagnosed. cies of B vitamins. Riboflavin deficiency is manifested principally by
The laboratory diagnosis of thiamine deficiency usually is made by lesions of the mucocutaneous surfaces of the mouth and skin. In addi-
a functional enzymatic assay of transketolase activity measured before tion, corneal vascularization, anemia, and personality changes have
and after the addition of thiamine pyrophosphate. A >25% stimulation been described with riboflavin deficiency.
in response to the addition of thiamine pyrophosphate (i.e., an activity Deficiency and Excess Riboflavin deficiency almost always is
coefficient of 1.25) is interpreted as abnormal. Thiamine or the phos- due to dietary deficiency. Milk, other dairy products, and enriched
phorylated esters of thiamine in serum or blood also can be measured breads and cereals are the most important dietary sources of ribo-
by high-performance liquid chromatography to detect deficiency. flavin in the United States, although lean meat, fish, eggs, broccoli,
and legumes are also good sources. Riboflavin is extremely sensitive
TREATMENT to light, and milk should be stored in containers that protect against
Thiamine Deficiency photodegradation. Laboratory diagnosis of riboflavin deficiency can
be made by determination of red blood cell or urinary riboflavin con-
In acute thiamine deficiency with either cardiovascular or neurologic centrations or by measurement of erythrocyte glutathione reductase
signs, 200 mg of thiamine three times daily should be given intra- activity, with and without added FAD. Because the capacity of the
venously until there is no further improvement in acute symptoms; gastrointestinal tract to absorb riboflavin is limited (~20 mg after one
oral thiamine (10 mg/d) should subsequently be given until recov- oral dose), riboflavin toxicity has not been described.
ery is complete. Cardiovascular and ophthalmoplegic improvement
occurs within 24 h. Other manifestations gradually clear, although ■■NIACIN (VITAMIN B3)
psychosis in Wernicke-Korsakoff syndrome may be permanent or The term niacin refers to nicotinic acid and nicotinamide and their
may persist for several months. Other nutrient deficiencies should biologically active derivatives. Nicotinic acid and nicotinamide serve
be corrected concomitantly. as precursors of two coenzymes, nicotinamide adenine dinucleo-
tide (NAD) and NAD phosphate (NADP), which are important in

numerous oxidation and reduction reactions in the body. In addition, “free” niacin (i.e., the non-coenzyme form), bioavailability is excellent. 2311
NAD and NADP are active in adenine diphosphate–ribose transfer Median intakes of niacin in the United States considerably exceed the
reactions involved in DNA repair and calcium mobilization. recommended dietary allowance (RDA).
Metabolism and Requirements Nicotinic acid and nicotin- The amino acid tryptophan can be converted to niacin with an effi-
amide are absorbed well from the stomach and small intestine. The ciency of 60:1 by weight. Thus, the RDA for niacin is expressed in niacin
bioavailability of niacin from beans, milk, meat, and eggs is high; equivalents. A lower-level conversion of tryptophan to niacin occurs
bioavailability from cereal grains is lower. Since flour is enriched with in vitamin B6 and/or riboflavin deficiencies and in the presence of
Active derivative or Principal

Vitamin cofactor form function
Thiamine (B1) Thiamine pyrophosphate Coenzyme for

NH2 cleavage of
CH3 carbon-carbon
N N
bonds; amino
N S CH2CH2OH acid and
carbohydrate
metabolism
Riboflavin (B2) Flavin mononucleotide Cofactor for

O (FMN) and flavin oxidation,
N adenine dinucleotide reduction
NH
(FAD) reactions,
N N O and covalently
Ribityl attached
prosthetic groups
for some
enzymes

Niacin Nicotinamide adenine Coenzymes for
O dinucleotide phosphate oxidation and
C O (NADP) and nicotinamide reduction
+ adenine dinucleotide reactions
N
H (NAD)
Vitamin B6 Pyridoxal phosphate Cofactor for

CH2OH enzymes of amino
HO CH2OH acid metabolism
Folate Polyglutamate forms of Coenzyme for one

n
O COOH (5, 6, 7, 8) carbon transfer in
H
O N C N CH tetrahydrofolate with nucleic acid and
H carbon unit amino acid
N CH2
CH2
attachments metabolism
CH2 COOH
H2N N N
C N CH
H
O CH2
CH2
C OH
Vitamin B12 Methylcobalamine Coenzyme for

CH2CH2CONH2 Adenosylcobalamin methionine
CONH2 HC synthase
CH3 3 CH2CH2CONH2
CH2 and
CH2CH2CONH2 L-methylmalonyl-
H3C N N
CONH2
H3C Co+
CoA mutase
N N CH3
CH2
CH3
NHCOCH2CH2 CH3 CH3 CH2CH2CONH2
CH2 CHCH3 N CH3
O O–
N CH3
P
O O HO
O
HOCH2
OH Cbl
FIGURE 326-1 Structures and principal functions of vitamins associated with human disorders.

2312 Active derivative or Principal
Vitamin cofactor form function
Vitamin C Ascorbic acid and Participation as a

O redox ion in many
O C C C C C CH2OH
dehydroascorbic acid
biologic
OH OH OH oxidation and
hydrogen transfer
reactions
Vitamin A Retinol, retinaldehyde, Formation of

and retinoic acid rhodopsin (vision)
and glycoproteins
(epithelial cell
(β-Carotene) function); also
CH2OH regulates gene
transcription
(Retinol)
Vitamin D 1,25-Dihydroxyvitamin D Maintenance of

blood calcium
OH and phosphorus
levels;
antiproliferative
hormone
CH2
HO OH
Vitamin E Tocopherols and Antioxidants

CH3
PART 10
O tocotrienols
CH2[CH2 CH2 CH CH2]3H
HO
Vitamin K Vitamin K hydroquinone Cofactor for

O
posttranslation
carboxylation of
many proteins
R
including essential
O
clotting factors
isoniazid. The urinary excretion products of niacin include 2-pyridone TREATMENT

and 2-methyl nicotinamide, measurements of which are used in the
diagnosis of niacin deficiency. Pellagra
Deficiency Niacin deficiency causes pellagra, which is Treatment of pellagra consists of oral supplementation with
found mostly among people eating corn-based diets in parts 100–200 mg of nicotinamide or nicotinic acid three times daily for
of China, Africa, and India. Pellagra in North America is 5 days. High doses of nicotinic acid (2 g/d in a time-release form)
found mainly among alcoholics; among patients with congenital are used for the treatment of elevated cholesterol and triglycer-
defects of intestinal and kidney absorption of tryptophan (Hartnup ide levels and/or low high-density lipoprotein cholesterol levels
disease; Chap. 413); and among patients with carcinoid syndrome without, however, a proven benefit on cardiovascular endpoints
(Chap. 80), in which there is increased conversion of tryptophan to (Chap. 400).
serotonin. The antituberculosis drug isoniazid is a structural analog of
niacin and can precipitate pellagra. In the setting of famine or popula- Toxicity Prostaglandin-mediated flushing due to binding of the
tion displacement, pellagra results from the absolute lack of niacin but vitamin to a G protein–coupled receptor has been observed at daily
also from the deficiency of micronutrients required for the conversion nicotinic acid doses as low as 30 mg taken as a supplement or as
of tryptophan to niacin (e.g., iron, riboflavin, and pyridoxine). The therapy for dyslipidemia. There is no evidence of toxicity from niacin
early symptoms of pellagra include loss of appetite, generalized weak- that is derived from food sources. Flushing always starts in the face
ness and irritability, abdominal pain, and vomiting. Bright red glossitis and may be accompanied by skin dryness, itching, paresthesia, and
then ensues and is followed by a characteristic skin rash that is pig- headache. Flushing is subject to tachyphylaxis and often improves
mented and scaling, particularly in skin areas exposed to sunlight. This with time; premedication with aspirin may alleviate these symptoms.
rash is known as Casal’s necklace because it forms a ring around the Nausea, vomiting, and abdominal pain also occur at similar doses of
neck; it is seen in advanced cases. Vaginitis and esophagitis also may niacin. Hepatic toxicity is the most serious toxic reaction caused by sus-
occur. Diarrhea (due in part to proctitis and in part to malabsorption), tained-release niacin and may present as jaundice with elevated aspar-
depression, seizures, and dementia are also part of the pellagra syn- tate aminotransferase (AST) and alanine aminotransferase (ALT) levels.
drome. The primary manifestations of this syndrome are sometimes A few cases of fulminant hepatitis requiring liver transplantation have
referred to as “the four Ds”: dermatitis, diarrhea, and dementia leading been reported at doses of 3–9 g/d. Other toxic reactions include glu-
to death. cose intolerance, hyperuricemia, macular edema, and macular cysts.

The combination of nicotinic acid preparations for dyslipidemia with biosynthesis, conversion of dopamine to norepinephrine, and synthesis 2313
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhib- of many peptide hormones. Vitamin C is also important for connective
itors may increase the risk of rhabdomyolysis. The upper limit for daily tissue metabolism and cross-linking (proline hydroxylation), and it is
niacin intake has been set at 35 mg. However, this upper limit does not a component of many drug-metabolizing enzyme systems, particularly
pertain to the therapeutic use of niacin. the mixed-function oxidase systems.
■■PYRIDOXINE (VITAMIN B6) Absorption and Dietary Sources Vitamin C is almost com-
Vitamin B6 refers to a family of compounds that includes pyridoxine, pletely absorbed if <100 mg is administered in a single dose; however,
pyridoxal, pyridoxamine, and their 5′-phosphate derivatives. 5′-Pyri- only ≤50% is absorbed at doses >1 g. Enhanced degradation and fecal
doxal phosphate (PLP) is a cofactor for >100 enzymes involved in and urinary excretion of vitamin C occur at higher intake levels.
amino acid metabolism. Vitamin B6 also is involved in heme and neu- Good dietary sources of vitamin C include citrus fruits, green veg-
rotransmitter synthesis and in the metabolism of glycogen, lipids, ste- etables (especially broccoli), tomatoes, and potatoes. Consumption
roids, sphingoid bases, and several vitamins, including the conversion of five servings of fruits and vegetables a day provides vitamin C in
of tryptophan to niacin. excess of the RDA of 90 mg/d for men and 75 mg/d for women. In
addition, ~40% of the U.S. population consumes vitamin C as a dietary
Dietary Sources Plants contain vitamin B6 in the form of pyridox- supplement in which “natural forms” of the vitamin are no more
ine, whereas animal tissues contain PLP and pyridoxamine phosphate. bioavailable than synthetic forms. Smoking, hemodialysis, pregnancy,
The vitamin B6 contained in plants is less bioavailable than that in lactation, and stress (e.g., infection, trauma) appear to increase vitamin
animal tissues. Rich food sources of vitamin B6 include legumes, nuts, C requirements.
wheat bran, and meat, although it is present in all food groups.
Deficiency Vitamin C deficiency causes scurvy. In the United
Deficiency Symptoms of vitamin B6 deficiency include epithe- States, this condition is seen primarily among the poor and the elderly,
lial changes, as seen frequently with other B vitamin deficiencies. In
in alcoholics who consume <10 mg/d of vitamin C, and in individu-
addition, severe vitamin B6 deficiency can lead to peripheral neurop-
als consuming macrobiotic diets. Vitamin C deficiency also can occur
athy, abnormal electroencephalograms, and personality changes that in young adults who eat severely unbalanced diets. In addition to
include depression and confusion. In infants, diarrhea, seizures, and generalized fatigue, symptoms of scurvy primarily reflect impaired
anemia have been reported. Microcytic hypochromic anemia is due formation of mature connective tissue and include bleeding into the
to diminished hemoglobin synthesis, since the first enzyme involved skin (petechiae, ecchymoses, perifollicular hemorrhages); inflamed
in heme biosynthesis (aminolevulinate synthase) requires PLP as a and bleeding gums; and manifestations of bleeding into joints, the

cofactor (Chap. 93). In some case reports, platelet dysfunction has been peritoneal cavity, the pericardium, and the adrenal glands. In children,
reported. Since vitamin B6 is necessary for the conversion of homo- vitamin C deficiency may cause impaired bone growth. Laboratory
cysteine to cystathionine, it is possible that chronic low-grade vitamin diagnosis of vitamin C deficiency is based on low plasma or leukocyte
B6 deficiency may result in hyperhomocysteinemia and increased risk levels.
of cardiovascular disease (Chap. 413). Independent of homocysteine, Administration of vitamin C (200 mg/d) improves the symptoms
low levels of circulating vitamin B6 have been associated with inflam- of scurvy within several days. High-dose vitamin C supplementation
mation and elevated levels of C-reactive protein. (e.g., 0.2 up to several grams per day) may slightly decrease the symp-
Certain medications, such as isoniazid, l-dopa, penicillamine, and toms and duration of upper respiratory tract infections. Vitamin C sup-
cycloserine, interact with PLP due to a reaction with carbonyl groups. plementation has also been reported to be useful in Chédiak-Higashi
Pyridoxine should be given concurrently with isoniazid to avoid syndrome (Chap. 60) and osteogenesis imperfecta (Chap. 406). Diets
neuropathy. The increased ratio of AST to ALT seen in alcoholic liver high in vitamin C have been claimed to lower the incidence of certain
disease reflects the relative vitamin B6 dependence of ALT. Vitamin B6 cancers, particularly esophageal and gastric cancers. If proved, this
dependency syndromes that require pharmacologic doses of vitamin B6 effect may be because vitamin C can prevent the conversion of nitrites
are rare; they include cystathionine β-synthase deficiency, pyridoxine- and secondary amines to carcinogenic nitrosamines. Evidence for a
responsive (primarily sideroblastic) anemias, and gyrate atrophy with potential role of pro-oxidative effects of parenteral ascorbic acid in the
chorioretinal degeneration due to decreased activity of the mitochon- treatment of advanced cancers is emerging in laboratory studies.
drial enzyme ornithine aminotransferase. In these situations, 100–200
mg/d of oral vitamin B6 is required for treatment. Toxicity Taking >2 g of vitamin C in a single dose may result
Severe nausea and vomiting in pregnancy might respond to pyrin abdominal pain, diarrhea, and nausea. Since vitamin C may be
idoxine combined with doxylamine. High doses of vitamin B6 have metabolized to oxalate, it is feared that chronic high-dose vitamin C
been used to treat carpal tunnel syndrome, premenstrual syndrome, supplementation could result in an increased prevalence of kidney
schizophrenia, autism, and diabetic neuropathy but have not been stones. However, except in patients with preexisting renal disease,
found to be effective. this association has not been borne out in several trials. Nevertheless,
The laboratory diagnosis of vitamin B6 deficiency is generally based it is reasonable to advise patients with a history of kidney stones and
on low plasma PLP values (<20 nmol/L). Vitamin B6 deficiency is renal insufficiency not to take large doses of vitamin C. There is also an
treated with 50 mg/d; higher doses of 100–200 mg/d are given if the unproven but possible risk that chronic high doses of vitamin C could
deficiency is related to medication use. Vitamin B6 should not be given promote iron overload and iron toxicity. High doses of vitamin C can
with l-dopa, since the vitamin interferes with the action of this drug. induce hemolysis in patients with glucose-6-phosphate dehydrogenase
deficiency, and doses >1 g/d can cause false-negative guaiac reactions
Toxicity The safe upper limit for vitamin B6 has been set at 100 mg/d, and interfere with tests for urinary glucose. High doses may inter-
although no adverse effects have been associated with high intakes fere with the activity of certain drugs (e.g., bortezomib in myeloma
of vitamin B6 from food sources only. When toxicity occurs, it causes patients).
severe sensory neuropathy, leaving patients unable to walk. Some cases
of photosensitivity and dermatitis have been reported. ■■BIOTIN
■■FOLATE (VITAMIN B12) Biotin is a water-soluble vitamin that plays a role in gene expression,
See Chap. 95. gluconeogenesis, and fatty acid synthesis and serves as a CO2 carrier on
the surface of both cytosolic and mitochondrial carboxylase enzymes.
■■VITAMIN C The vitamin also functions in the catabolism of specific amino acids
Both ascorbic acid (only the l-isomer) and its oxidized product dehy- (e.g., leucine) and in gene regulation by histone biotinylation. Excellent
droascorbic acid are biologically active. Actions of vitamin C include food sources of biotin include organ meat such as liver or kidney, soy
antioxidant activity, promotion of nonheme iron absorption, carnitine and other beans, yeast, and egg yolks; however, egg white contains

2314 the protein avidin, which strongly binds the vitamin and reduces its of dietary flavonoids include anthocyanidins in berries; catechins in
bioavailability. green tea and chocolate; flavonols (e.g., quercetin) in broccoli, kale,
Biotin deficiency due to low dietary intake is rare; rather, deficiency leeks, onions, and the skins of grapes and apples; and isoflavones
is due to inborn errors of metabolism. Biotin deficiency has been (e.g., genistein) in legumes. Isoflavones have a low bioavailability and
induced by experimental feeding of egg white diets and by biotin-free are partially metabolized by the intestinal flora. The dietary intake of
parenteral nutrition in patients with short bowels. In adults, biotin defi- flavonoids is estimated at 10–100 mg/d; this figure is almost certainly
ciency results in mental changes (depression, hallucinations), paresthe- an underestimate attributable to a lack of information on their concen-
sia, anorexia, and nausea. A scaling, seborrheic, and erythematous rash trations in many foods. Several flavonoids have antioxidant activity
may occur around the eyes, nose, and mouth as well as on the extrem- and affect cell signaling. From observational epidemiologic studies
ities. In infants, biotin deficiency presents as hypotonia, lethargy, and and limited clinical (human and animal) studies, flavonoids have been
apathy. In addition, infants may develop alopecia and a characteristic postulated to play a role in the prevention of several chronic diseases,
rash that includes the ears. The laboratory diagnosis of biotin defi- including neurodegenerative disease, diabetes, and osteoporosis. The
ciency can be established on the basis of a decreased concentration of ultimate importance and usefulness of these compounds against
urinary biotin (or its major metabolites), increased urinary excretion of human disease have not been consistently demonstrated.
3-hydroxyisovaleric acid after a leucine challenge, or decreased activ-
ity of biotin-dependent enzymes in lymphocytes (e.g., propionyl-CoA ■■VITAMIN A
carboxylase). Treatment requires pharmacologic doses of biotin, that is, Vitamin A, in the strictest sense, refers to retinol. However, the
up to 10 mg/d. No toxicity is known. oxidized metabolites retinaldehyde and retinoic acid are also biolog-
ically active compounds. The term retinoids includes all molecules
■■PANTOTHENIC ACID (VITAMIN B5) (including synthetic molecules) that are chemically related to retinol.
Pantothenic acid is a component of coenzyme A and phosphopanteth- Retinaldehyde (11-cis) is the form of vitamin A that is required for
eine, which are involved in fatty acid metabolism and the synthesis of normal vision, whereas retinoic acid is necessary for normal mor-
cholesterol, steroid hormones, and all compounds formed from isopre- phogenesis, growth, and cell differentiation. Retinoic acid does not
noid units. In addition, pantothenic acid is involved in the acetylation function directly in vision and, in contrast to retinol, is not involved in
of proteins. The vitamin is excreted in the urine, and the laboratory reproduction. Vitamin A also plays a role in iron utilization, humoral
diagnosis of deficiency is based on low urinary vitamin levels. immunity, T cell–mediated immunity, natural killer cell activity, and
The vitamin is ubiquitous in the food supply. Liver, yeast, egg yolks, phagocytosis.
whole grains, and vegetables are particularly good sources. Human Vitamin A is found in the human food supply in two forms: pre-
pantothenic acid deficiency has been demonstrated only by experimen- formed as esters and provitamin A in carotenoids. There are >600
tal feeding of diets low in pantothenic acid or by administration of a carotenoids in nature, ~50 of which can be metabolized to vitamin A.
PART 10
specific pantothenic acid antagonist. The symptoms of pantothenic acid β-Carotene is the most prevalent carotenoid with provitamin A activ-
deficiency are nonspecific and include gastrointestinal disturbance, ity in the food supply. In humans, significant fractions of carotenoids
depression, muscle cramps, paresthesia, ataxia, and hypoglycemia. are absorbed intact and are stored in liver and fat. It is estimated that
Pantothenic acid deficiency is believed to have caused the “burning ≥12 μg (range, 4–27 μg) of dietary all-trans β-carotene is equivalent to
feet syndrome” seen in prisoners of war during World War II. No tox- 1 μg of retinol activity, whereas the figure is ≥24 μg for other dietary
icity of this vitamin has been reported. provitamin A carotenoids (e.g., cryptoxanthin, α-carotene). The vita-
min A equivalency for a β-carotene supplement in an oily solution
■■CHOLINE is 2:1.
Choline is a precursor for acetylcholine, phospholipids, and betaine.
Choline is necessary for the structural integrity of cell membranes, cholin- Metabolism The liver contains ~90% of the vitamin A reserves
ergic neurotransmission, lipid and cholesterol metabolism, methyl-group and secretes vitamin A in the form of retinol, which is bound in the
metabolism, and transmembrane signaling. Recently, a recommended circulation to retinol-binding protein. Once binding has occurred,
adequate intake was set at 550 mg/d for men and 425 mg/d for women, the retinol-binding protein complex interacts with a second protein,
although certain genetic polymorphisms can increase an individual’s transthyretin. This trimolecular complex functions to prevent vitamin
requirement. Choline is thought to be a “conditionally essential” nutrient A from being filtered by the kidney glomerulus, thus protecting the
in that its de novo synthesis occurs in the liver and results in lesser-than- body against the toxicity of retinol and allowing retinol to be taken up
used amounts only under certain stress conditions (e.g., alcoholic liver by specific cell-surface receptors that recognize retinol-binding protein.
disease). The dietary requirement for choline depends on the status of A certain amount of vitamin A enters peripheral cells even if it is not
other nutrients involved in methyl-group metabolism (folate, vitamin B12, bound to retinol-binding protein. After retinol is internalized by the
vitamin B6, and methionine) and thus varies widely. Choline is widely cell, it becomes bound to a series of cellular retinol-binding proteins,
distributed in food (e.g., egg yolks, wheat germ, organ meat, milk) in the which function as sequestering and transporting agents as well as
form of lecithin (phosphatidylcholine). Choline deficiency has occurred co-ligands for enzymatic reactions. Certain cells also contain retinoic
in patients receiving parenteral nutrition devoid of choline. Deficiency acid–binding proteins, which have sequestering functions but also
results in fatty liver, elevated aminotransferase levels, and skeletal mus- shuttle retinoic acid to the nucleus and enable its metabolism.
cle damage with high creatine phosphokinase values. The diagnosis of Retinoic acid is a ligand for certain nuclear receptors that act as
choline deficiency is currently based on low plasma levels, although non- transcription factors. Two families of receptors (retinoic acid receptors
specific conditions (e.g., heavy exercise) may also suppress plasma levels. [RARs] and retinoid X receptors [RXRs]) are active in retinoid-mediated
Toxicity from choline results in hypotension, cholinergic sweating, gene transcription. Retinoid receptors regulate transcription by binding
diarrhea, salivation, and a fishy body odor. The upper limit for choline as dimeric complexes to specific DNA sites—the retinoic acid response
intake has been set at 3.5 g/d. Because of its ability to lower choles- elements—in target genes (Chap. 370). The receptors can either stimu-
terol and homocysteine levels, choline treatment has been suggested late or repress gene expression in response to their ligands. RARs bind
for patients with dementia and patients at high risk of cardiovascular all-trans retinoic acid and 9-cis-retinoic acid, whereas RXRs bind only
disease. However, the benefits of such treatment have not been firmly 9-cis-retinoic acid.
documented. Choline- and betaine-restricted diets are of therapeutic The retinoid receptors play an important role in controlling cell
value in trimethylaminuria (“fish odor syndrome”). proliferation and differentiation. RXRs dimerize with other nuclear
receptors to function as coregulators of genes responsive to retinoids,
■■FLAVONOIDS but also to thyroid hormone and calcitriol. RXR agonists induce insulin
Flavonoids constitute a large family of polyphenols that contribute sensitivity experimentally, perhaps because RXRs are cofactors for the
to the aroma, taste, and color of fruits and vegetables. Major groups peroxisome proliferator-activated receptors, which mediate also fatty

acid and carbohydrate metabolism and are targets for different drugs 2315
TREATMENT
including thiazolidinedione drugs (e.g., rosiglitazone and pioglitazone)
(Chap. 397). Vitamin A Deficiency
Dietary Sources The retinol activity equivalent (RAE) is used to Vitamin A is commercially available for treatment and prevention in
express the vitamin A value of food: 1 RAE is defined as 1 μg of retinol esterified forms (e.g., acetate, palmitate), which are more stable than
(0.003491 mmol), 12 μg of β-carotene, and 24 μg of other provitamin other forms. Any stage of xerophthalmia should be treated with 60 mg
A carotenoids. In older literature, vitamin A often was expressed in (or RAE) or 200,000 IU of vitamin A in oily solution, usually con-
international units (IUs), with 1 μg of retinol equal to 3.33 IU of retinol tained in a soft-gel capsule. The same dose is repeated 1 and 14 days
and 20 IU of β-carotene. Although these IUs are no longer in scientific later. Doses should be reduced by half for patients 6–11 months of
use, they can still be found in reports of the food industry and in public age. Mothers with night blindness or Bitot’s spots should be given
health interventions in low-income countries. vitamin A orally 3 mg daily for at least 3 months. These regimens are
Liver, fish, and eggs are excellent food sources for preformed efficacious, and they are far less expensive and more widely avail-
vitamin A; vegetable sources of provitamin A carotenoids include dark able than injectable water-miscible vitamin A. A common approach
green and deeply colored fruits and vegetables. Moderate cooking of to prevention is to provide vitamin A supplementation every
vegetables enhances carotenoid release for uptake in the gut. Carote- 4–6 months to young children 6 months to 5 years of age (both
noid absorption is also aided by some fat in a meal. Exclusive breast- HIV-positive and HIV-negative) in high-risk areas. For prevention,
feeding can cover the vitamin A needs of infants if the mother has an infants 6–11 months of age should receive 30 mg vitamin A; children
adequate vitamin A status and a large enough volume of milk. If the 12–59 months of age, 60 mg. For reasons that are not clear, while
nursing mother has inadequate vitamin A intake, concomitant diseases, early neonatal vitamin A may reduce infant mortality, vitamin A
or her infant was a preterm delivery, breast milk probably will not sup- given between 1 and 5 months of age has not proven effective in
ply enough vitamin A to prevent deficiency. In developing countries, improving survival in high-risk settings.
chronic dietary deficiency is the main cause of vitamin A deficiency Uncomplicated vitamin A deficiency is rare in industrialized
and is exacerbated by infection. In early childhood, low vitamin A sta- countries. One high-risk group—extremely low-birth-weight
tus results from inadequate intakes of animal food sources and edible (<1000-g) infants—is likely to be vitamin A–deficient and should
oils, both of which are expensive, coupled with seasonal unavailability receive a supplement of 1500 μg (or RAE) three times a week for
of vegetables and fruits and lack of marketed fortified food products. 4 weeks. Severe measles in any society can lead to secondary vita-
Factors that interfere with vitamin A metabolism may also affect status min A deficiency. Children hospitalized with measles should receive
or function. For example, concurrent zinc deficiency can interfere with two 60-mg doses of vitamin A on two consecutive days. Vitamin A

the mobilization of vitamin A from liver stores. Alcohol interferes with deficiency most often occurs in patients with malabsorptive diseases
the conversion of retinol to retinaldehyde in the eye by competing for (e.g., celiac sprue, short-bowel syndrome) who have abnormal dark
alcohol (retinol) dehydrogenase. Drugs that interfere with the absorp- adaptation or symptoms of night blindness without other ocular
tion of vitamin A include mineral oil, neomycin, and cholestyramine. changes. Typically, such patients are diagnosed in advanced care
Deficiency Vitamin A deficiency is endemic in areas settings where they are treated for 1 month with 15 mg/d of a
where diets are chronically poor, especially in southern Asia, water-miscible preparation of vitamin A. This treatment is followed
sub-Saharan Africa, some parts of Latin America, and the by a lower maintenance dose, with the exact amount determined
western Pacific, including parts of China. Vitamin A status is usually by monitoring serum retinol. Finding application elsewhere in
assessed by measuring serum retinol (normal range, 1.05–3.50 μmol/L medicine, retinoic acid is useful in the treatment of promyelocytic
[30–100 μg/dL]) or blood-spot retinol or by tests of dark adaptation. leukemia (Chap. 100) and also is used in the treatment of cystic acne
Stable isotopic or invasive liver biopsy methods are available to esti- because it inhibits keratinization, decreases sebum secretion, and
mate total body stores of vitamin A. As judged by deficient serum possibly alters the inflammatory reaction (Chap. 53).
retinol (<0.70 μmol/L [20 μg/dL]), vitamin A deficiency worldwide is No specific signs or symptoms result from carotenoid deficiency.
present in 190 million preschool-age children, among whom >5 million It was postulated that β-carotene would be an effective chemopre-
have an ocular manifestation of deficiency termed xerophthalmia. This ventive agent for cancer because numerous epidemiologic studies
condition includes milder stages of night blindness and conjunctival had shown that diets high in β-carotene were associated with lower
xerosis (dryness) with Bitot’s spots (white patches of keratinized epithe- incidences of cancers of the respiratory and digestive systems.
lium appearing on the sclera) that may affect 1–5% of children in defi- However, intervention studies in smokers found that treatment
cient populations as well as rare, potentially blinding corneal ulceration with high doses of β-carotene actually resulted in more lung cancers
and necrosis. Keratomalacia (softening of the cornea) leads to corneal than did treatment with placebo. Non–provitamin A carotenoids
scarring that blinds an estimated quarter of a million children each year such as lutein and zeaxanthin have been suggested to confer protec-
and is associated with fatality rates of 4–25%. However, vitamin A defi- tion against macular degeneration, and one large-scale intervention
ciency severe enough to cause any clinical stage poses an increased risk study did not show a beneficial effect except in those with a low
of death from diarrhea, dysentery, measles, malaria, or respiratory lutein status. The use of the non–provitamin A carotenoid lycopene
disease. This is because vitamin A deficiency can compromise barrier, to protect against prostate cancer has been proposed. Again, how-
innate, and acquired immune defenses to infection. In areas where ever, the effectiveness of these agents has not been proved by inter-
deficiency is widely prevalent, vitamin A supplementation can mark- vention studies, and the mechanisms underlying these purported
edly reduce the risk of childhood mortality (by 23–34%, on average). biologic actions are unknown.
About 10% of pregnant women in undernourished settings also Selective plant-breeding techniques that lead to a higher provi-
develop night blindness (assessed by history) during the latter half of tamin A carotenoid content in staple foods may decrease vitamin A
pregnancy; this level of moderate to severe vitamin A deficiency is malnutrition in low-income countries. Moreover, a recently devel-
associated with an increased risk of maternal infection and death. oped genetically modified food (Golden Rice) has an improved
Maternal vitamin A deficiency may also exacerbate already low vita- β-carotene–to–vitamin A conversion ratio of ~3:1.
min A nutrition and associated risks for the newborn. In South Asia,
where maternal deficiency is prominent, giving infants a single oral Toxicity The acute toxicity of vitamin A was first noted in Arctic
dose (50,000 IU) of vitamin A shortly after birth has reduced infant explorers who ate polar bear liver and has also been seen after admin-
mortality by ≥10%, whereas in African settings less affected by mater- istration of 150 mg to adults or 100 mg to children. Acute toxicity
nal vitamin A deficiency, no effect has been noted, revealing differences is manifested by increased intracranial pressure, vertigo, diplopia,
in risk of deficiency and benefit of supplementation across regions. bulging fontanels (in children), seizures, and exfoliative dermatitis; it

2316 may result in death. Among children being treated for vitamin A defi- prevention) for reduction of the incidence of fractures in healthy men
ciency according to the protocols outlined above, transient bulging of and premenopausal women.
fontanels occurs in 2% of infants, and transient nausea, vomiting, and Risk factors for vitamin D deficiency are old age, lack of sun expo-
headache occur in 5% of preschoolers. Chronic vitamin A intoxication sure, dark skin (especially among residents of northern latitudes), fat
is largely a concern in industrialized countries and has been seen in malabsorption, and obesity. Rickets represents the classic disease of
otherwise healthy adults who ingest 15 mg/d and children who ingest vitamin D deficiency. Signs of deficiency are muscle soreness, weak-
6 mg/d over a period of several months. Manifestations include dry ness, and bone pain. Some of these effects are independent of calcium
skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization and intake.
pain, hypercalcemia, lymph node enlargement, hyperlipidemia, amen- The U.S. National Academy of Sciences recently advised that the
orrhea, and features of pseudotumor cerebri with increased intracranial majority of adult North Americans should receive 600 IU/d of vitamin
pressure and papilledema. Liver fibrosis with portal hypertension may D (RDA = 15 μg/d or 600 IU/d; Chap. 325). However, for people aged
also result from chronic vitamin A intoxication. Provision of vitamin >70 years, the RDA is set at 20 μg/d (800 IU/d). The consumption
A in excess to pregnant women has resulted in spontaneous abortion of fortified or enriched foods as well as suberythemal sun exposure
and in congenital malformations, including craniofacial abnormalities should be encouraged for people at risk for vitamin D deficiency.
and valvular heart disease. In pregnancy, the daily dose of vitamin A If adequate intake is impossible, vitamin D supplements should be
should not exceed 3 mg. Commercially available retinoid derivatives taken, especially during the winter months. Vitamin D deficiency can
are also toxic, including 13-cis-retinoic acid, which has been associated be treated by the oral administration of 50,000 IU/week for 6–8 weeks
with birth defects. Thus contraception should be continued for at least followed by a maintenance dose of 800 IU/d (20 μg/d) from food and
1 year and possibly longer in women who have taken 13-cis-retinoic acid. supplements once normal plasma levels have been attained. There is
In malnourished children, vitamin A supplements (30–60 mg), in uncertainty regarding the optimal therapeutic dosage (high vs low) for
amounts calculated as a function of age and given in several rounds elderly at risk of falls. The physiologic effects of vitamin D2 and vitamin
over 2 years, are considered to amplify nonspecific effects of vaccines. D3 are similar when these vitamins are ingested over long periods.
However, for unclear reasons, in one African setting there has been a
negative effect on mortality rates in incompletely vaccinated girls. Toxicity The upper limit of intake has been set at 4000 IU/d.
High doses of carotenoids do not result in toxic symptoms but should Contrary to earlier beliefs, acute vitamin D intoxication is rare and
be avoided in smokers due to an increased risk of lung cancer. Very high usually is caused by the uncontrolled and excessive ingestion of sup-
doses of β-carotene (~200 mg/d) have been used to treat or prevent plements or by faulty food fortification practices. High plasma levels
the skin rashes of erythropoietic protoporphyria. Carotenemia, which of 1,25(OH)2 vitamin D and calcium are central features of toxicity and
is characterized by a yellowing of the skin (increases of the palms and mandate discontinuation of vitamin D and calcium supplements; in
soles) but not the sclerae, may follow ingestion of >30 mg of β-carotene addition, treatment of hypercalcemia may be required.
PART 10
daily. Hypothyroid patients are particularly susceptible to the develop-

ment of carotenemia due to impaired breakdown of carotene to vitamin ■■VITAMIN E
A. Reduction of carotenes in the diet results in the disappearance of skin Vitamin E is the collective designation for all stereoisomers of toco-
yellowing and carotenemia over a period of 30–60 days. pherols and tocotrienols, although only the RR tocopherols meet
human requirements. Vitamin E acts as a chain-breaking antioxidant

■■VITAMIN D and is an efficient peroxyl radical scavenger that protects low-density
The metabolism of the fat-soluble vitamin D is described in detail in lipoproteins and polyunsaturated fats in membranes from oxidation.
Chap. 402. The biologic effects of this vitamin are mediated by vitamin D A network of other antioxidants (e.g., vitamin C, glutathione) and
receptors, which are found in most tissues; binding with these recep- enzymes maintains vitamin E in a reduced state. Vitamin E also inhib-
tors potentially expands vitamin D actions to many different cell sys- its prostaglandin synthesis and the activities of protein kinase C and
tems and organs (e.g., immune cells, brain, breast, colon, and prostate) phospholipase A2.
in addition to the classic endocrine effects on calcium and phosphate
metabolism and bone health. Vitamin D is thought to be important Absorption and Metabolism After absorption, vitamin E is
for maintaining normal function of many nonskeletal tissues such as taken up from chylomicrons by the liver, and a hepatic α-tocopherol
muscle (including heart muscle), for immune function, and for inflam- transport protein mediates intracellular vitamin E transport and incor-
mation as well as for cell proliferation and differentiation. Studies have poration into very low density lipoprotein. The transport protein has a
shown that vitamin D may be useful as adjunctive treatment for tuber- particular affinity for the RRR isomeric form of α-tocopherol; thus, this
culosis, psoriasis, and multiple sclerosis or for the prevention of certain natural isomer has the most biologic activity.
cancers. Vitamin D insufficiency may increase the risk of type 1 diabe-
Requirement Vitamin E is widely distributed in the food supply,
tes mellitus, cardiovascular disease (insulin resistance, hypertension,
with particularly high levels in sunflower oil, safflower oil, and wheat
or low-grade inflammation), or brain dysfunction (e.g., depression).
germ oil; γ-tocotrienols are notably present in soybean and corn oils. Vita-
However, the exact physiologic roles of vitamin D in these nonskeletal
min E is also found in meats, nuts, and cereal grains, and small amounts
diseases and the importance of these roles have not been clarified.
are present in fruits and vegetables. Vitamin E pills containing doses of
The skin is a major source of vitamin D, which is synthesized upon
50–1000 mg are ingested by ~10% of the U.S. population. The RDA for
skin exposure to ultraviolet B radiation (UV-B; wavelength, 290–320 nm).
vitamin E is 15 mg/d (34.9 μmol or 22.5 IU) for all adults. Diets high in
Except for fish, food (unless fortified) contains only limited amounts of
polyunsaturated fats may necessitate a slightly higher intake of vitamin E.
vitamin D. Vitamin D2 (ergocalciferol) is obtained from plant sources
Dietary deficiency of vitamin E does not exist. Vitamin E deficiency
and is the chemical form found in some supplements.
is seen only in severe and prolonged malabsorptive diseases, such as
Deficiency Vitamin D status has been assessed by measuring celiac disease, or after small-intestinal resection or bariatric surgery.
serum levels of 25-dihydroxyvitamin D (25[OH] vitamin D); however, Children with cystic fibrosis or prolonged cholestasis may develop
there is no consensus on a uniform assay or on optimal serum levels. vitamin E deficiency characterized by areflexia and hemolytic anemia.
The optimal level might, in fact, differ according to the targeted disease Children with abetalipoproteinemia cannot absorb or transport vita-
entity. Epidemiologic and experimental data indicate that a 25(OH) min E and become deficient quite rapidly. A familial form of isolated
vitamin D level of >20 ng/mL (≥50 nmol/L; to convert ng/mL to vitamin E deficiency also exists; it is due to a defect in the α-tocopherol
nmol/L, multiply by 2.496) is sufficient for good bone health. Some transport protein. Vitamin E deficiency causes axonal degeneration of
experts, however, advocate higher serum levels (e.g., >30 ng/mL) for the large myelinated axons and results in posterior column and spinoc-
other desirable endpoints of vitamin D action. There is insufficient erebellar symptoms. Peripheral neuropathy is initially characterized by
evidence to recommend combined vitamin D and calcium supple- areflexia, with progression to an ataxic gait, and by decreased vibration
mentation as a primary preventive strategy (as opposed to secondary and position sensations. Ophthalmoplegia, skeletal myopathy, and

pigmented retinopathy may also be features of vitamin E deficiency. A resection. Broad-spectrum antibiotic treatment can precipitate vitamin 2317
deficiency of either vitamin E or selenium in the host has been shown K deficiency by reducing numbers of gut bacteria, which synthesize
to increase certain viral mutations and, therefore, virulence. The labo- menaquinones, and by inhibiting the metabolism of vitamin K. In
ratory diagnosis of vitamin E deficiency is based on low blood levels patients with warfarin therapy, the antiobesity drug orlistat can lead
of α-tocopherol (<5 μg/mL, or <0.8 mg of α-tocopherol per gram of to changes in international normalized ratio due to vitamin K mal-
total lipids). absorption. Vitamin K deficiency usually is diagnosed on the basis of
an elevated prothrombin time or reduced clotting factors, although
vitamin K may also be measured directly by high-pressure liquid chro-
TREATMENT matography. Vitamin K deficiency is treated with a parenteral dose of
Vitamin E Deficiency 10 mg. For patients with chronic malabsorption, 1–2 mg/d should be
given orally or 1–2 mg per week can be taken parenterally. Patients
Symptomatic vitamin E deficiency should be treated with 800– with liver disease may have an elevated prothrombin time because
1200 mg of α-tocopherol per day. Patients with abetalipoproteinemia of liver cell destruction as well as vitamin K deficiency. If an elevated
may need as much as 5000–7000 mg/d. Children with symptomatic prothrombin time does not improve during vitamin K therapy, it can be
vitamin E deficiency should be treated orally with water-miscible deduced that this abnormality is not the result of vitamin K deficiency.
esters (400 mg/d); alternatively, 2 mg/kg/d may be administered
intramuscularly. Vitamin E in high doses may protect against Toxicity Toxicity from dietary phylloquinones and menaquinones
oxygen-induced retrolental fibroplasia and bronchopulmonary has not been described. High doses of vitamin K can impair the actions
dysplasia as well as intraventricular hemorrhage of prematurity. of oral vitamin K antagonist anticoagulants.
Vitamin E has been suggested to increase sexual performance, treat
intermittent claudication, and slow the aging process, but convinc- MINERALS
ing evidence for these properties is lacking. When given in combi- See also Table 326-2.
nation with other antioxidants, vitamin E may help prevent macular
■■CALCIUM
degeneration. Vitamin E may have favorable therapeutic effects in
See Chap. 402.
noncirrhotic nondiabetic patients with NASH (nonalcoholic steato-
hepatitis). High doses (60–800 mg/d) of vitamin E have been shown ■■ZINC
in controlled trials to improve parameters of immune function and Zinc is an integral component of many metalloenzymes in the body;
reduce colds in nursing home residents, but intervention studies it is involved in the synthesis and stabilization of proteins, DNA, and

using vitamin E to prevent cardiovascular disease or cancer have RNA, and plays a structural role in ribosomes and membranes. Zinc
not shown efficacy, and, at doses >400 mg/d, vitamin E may even is necessary for the binding of steroid hormone receptors and several
increase all-cause mortality rates and prostate cancer risk. other transcription factors to DNA. Zinc is absolutely required for
normal spermatogenesis, fetal growth, and embryonic development.
Toxicity All forms of vitamin E are absorbed and could contribute
to toxicity; however, the toxicity risk seems to be rather low as long as Absorption The absorption of zinc from the diet is inhibited by
liver function is normal. High doses of vitamin E (>800 mg/d) may dietary phytate, fiber, oxalate, iron, and copper as well as by certain
reduce platelet aggregation and interfere with vitamin K metabolism drugs, including penicillamine, sodium valproate, and ethambutol.
and are therefore contraindicated in patients taking warfarin and anti- Meat, shellfish, nuts, and legumes are good sources of bioavailable zinc,
platelet agents (such as aspirin or clopidogrel). Nausea, flatulence, and whereas zinc in grains and legumes is less available for absorption.
diarrhea have been reported at doses >1 g/d. Deficiency Mild zinc deficiency has been described in
many diseases, including diabetes mellitus, HIV/AIDS, cir-
■■VITAMIN K rhosis, alcoholism, inflammatory bowel disease, malabsorp-
There are two natural forms of vitamin K: vitamin K1, also known as tion syndromes, and sickle cell disease. In these diseases, mild chronic
phylloquinone, from vegetable sources, and vitamin K2, or menaquinones, zinc deficiency can cause stunted growth in children, decreased taste
which are synthesized by bacterial flora and found in hepatic tissue. sensation (hypogeusia), and impaired immune function. Severe chronic
Phylloquinone can be converted to menaquinone in some organs. zinc deficiency has been described as a cause of hypogonadism and
Vitamin K is required for the posttranslational carboxylation of glu- dwarfism in several Middle Eastern countries. In these children,
tamic acid, which is necessary for calcium binding to γ-carboxylated hypopigmented hair is also part of the syndrome. Acrodermatitis
proteins such as prothrombin (factor II); factors VII, IX, and X; protein C; enteropathica is a rare autosomal recessive disorder characterized by
protein S; and proteins found in bone (osteocalcin) and vascular abnormalities in zinc absorption. Clinical manifestations include diar-
smooth muscle (e.g., matrix Gla protein). However, the importance of rhea, alopecia, muscle wasting, depression, irritability, and a rash
vitamin K for bone mineralization and prevention of vascular calcifica- involving the extremities, face, and perineum. The rash is characterized
tion is not known. Warfarin-type drugs inhibit γ-carboxylation by pre- by vesicular and pustular crusting with scaling and erythema. Occa-
venting the conversion of vitamin K to its active hydroquinone form. sional patients with Wilson’s disease have developed zinc deficiency as
Dietary Sources Vitamin K is found in green leafy vegetables a consequence of penicillamine therapy (Chap. 408).
such as kale and spinach, and appreciable amounts are also present Zinc deficiency is prevalent in many developing countries and usu-
in margarine and liver. Vitamin K is present in vegetable oils; olive, ally coexists with other micronutrient deficiencies (especially iron defi-
canola, and soybean oils are particularly rich sources. The average ciency). Zinc (20 mg/d until recovery) may be an effective adjunctive
daily intake by Americans is estimated to be ~100 μg/d. therapeutic strategy for diarrheal disease and pneumonia in children
≥6 months of age.
Deficiency The symptoms of vitamin K deficiency are due to hem- The diagnosis of zinc deficiency is usually based on a serum zinc
orrhage; newborns are particularly susceptible because of low fat stores, level <12 μmol/L (<70 μg/dL). Pregnancy and birth control pills may
low breast milk levels of vitamin K, relative sterility of the infantile cause a slight depression in serum zinc levels, and hypoalbuminemia
intestinal tract, liver immaturity, and poor placental transport. Intra- from any cause can result in hypozincemia. In acute stress situations
cranial bleeding as well as gastrointestinal and skin bleeding can occur (illness but also post-exercise recovery), zinc may be redistributed
in vitamin K–deficient infants 1–7 days after birth. Thus, vitamin K from serum into tissues. Zinc deficiency may be treated with 60 mg of
(0.5–1 mg IM) is given prophylactically at delivery. elemental zinc taken by mouth twice a day. Zinc gluconate lozenges
Vitamin K deficiency in adults may be seen in patients with (13 mg of elemental zinc every 2 h while awake) have been reported to
chronic small-intestinal disease (e.g., celiac disease, Crohn’s dis- reduce the duration and symptoms of the common cold in adults, but
ease), in those with obstructed biliary tracts, or after small-bowel study results are conflicting.

2318 Toxicity Acute zinc toxicity after oral ingestion causes nausea, X-linked metabolic disturbance of copper metabolism characterized
vomiting, and fever. Zinc fumes from welding may also be toxic and by mental retardation, hypocupremia, and decreased circulating
cause fever, respiratory distress, excessive salivation, sweating, and ceruloplasmin (Chap. 406). This syndrome is caused by mutations in
headache. Chronic large doses of zinc may depress immune function the copper-transporting ATP7A gene. Children with this disease often
and cause hypochromic anemia as a result of copper deficiency. Intra- die within 5 years because of dissecting aneurysms or cardiac rupture.
nasal zinc preparations should be avoided because they may lead to Aceruloplasminemia is a rare autosomal recessive disease character-
irreversible damage of the nasal mucosa and anosmia. ized by tissue iron overload, mental deterioration, microcytic anemia,
and low serum iron and copper concentrations.
■■COPPER The diagnosis of copper deficiency is usually based on low serum levels
Copper is an integral part of numerous enzyme systems, including of copper (<65 μg/dL) and low ceruloplasmin levels (<20 mg/dL). Serum
amine oxidases, ferroxidase (ceruloplasmin), cytochrome c oxidase, levels of copper may be elevated in pregnancy or stress conditions
superoxide dismutase, and dopamine hydroxylase. Copper is also a since ceruloplasmin is an acute-phase reactant and 90% of circulating
component of ferroprotein, a transport protein involved in the baso- copper is bound to ceruloplasmin.
lateral transfer of iron during absorption from the enterocyte. As such,
copper plays a role in iron metabolism, melanin synthesis, energy Toxicity Copper toxicity is usually accidental (Table 326-2). In severe
production, neurotransmitter synthesis, and CNS function; the syn- cases, kidney failure, liver failure, and coma may ensue. In Wilson’s
thesis and cross-linking of elastin and collagen; and the scavenging of disease, mutations in the copper-transporting ATP7B gene lead to accu-
superoxide radicals. Dietary sources of copper include shellfish, liver, mulation of copper in the liver and brain, with low blood levels due to
nuts, legumes, bran, and organ meats. decreased ceruloplasmin (Chap. 408).
Deficiency Dietary copper deficiency is relatively rare, although ■■SELENIUM

it has been described in premature infants who are fed milk diets Selenium, in the form of selenocysteine, is a component of the
and in infants with malabsorption (Table 326-2). Copper-deficiency enzyme glutathione peroxidase, which serves to protect pro-
anemia (refractory to therapeutic iron) has been reported in patients teins, cell membranes, lipids, and nucleic acids from oxidant
with malabsorptive diseases and nephrotic syndrome and in patients molecules. As such, selenium is being actively studied as a chemopre-
treated for Wilson’s disease with chronic high doses of oral zinc, which ventive agent against certain cancers, such as prostate cancer. However,
can interfere with copper absorption. Menkes kinky hair syndrome is an it remains unclear whether selenium is effective as a chemopreventive
PART 10
TABLE 326-2 Deficiencies and Toxicities of Metals

TOLERABLE UPPER (DIETARY)
ELEMENT DEFICIENCY TOXICITY INTAKE LEVEL
Boron No biologic function determined Developmental defects, male sterility, testicular 20 mg/d (extrapolated from animal
atrophy data)
Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syndrome), 2500 mg/d (milk-alkali)
nephrolithiasis, impaired iron absorption, thiazide
diuretics
Copper Anemia, growth retardation, defective Nausea, vomiting, diarrhea, hepatic failure, 10 mg/d (liver toxicity)
keratinization and pigmentation of hair, tremor, mental deterioration, hemolytic anemia,
hypothermia, degenerative changes in aortic renal dysfunction
elastin, osteopenia, mental deterioration
Chromium Impaired glucose tolerance Occupational: Renal failure, dermatitis, pulmonary Not determined
cancer
Fluoride ↑ Dental caries Dental and skeletal fluorosis, osteosclerosis 10 mg/d (fluorosis)
Iodine Thyroid enlargement, ↓ T4, cretinism Thyroid dysfunction, acne-like eruptions 1100 μg/d (thyroid dysfunction)
Iron Muscle abnormalities, koilonychia, pica, Gastrointestinal effects (nausea, vomiting, 45 mg/d of elemental iron
anemia, ↓ work performance, impaired cognitive diarrhea, constipation), iron overload with organ (gastrointestinal side effects)
development, premature labor, ↑ perinatal damage, acute and chronic systemic toxicity,
maternal death increased susceptibility to malaria, increased risk
association with certain chronic diseases (e.g.,
diabetes)
Manganese Impaired growth and skeletal development, General: Neurotoxicity, Parkinson-like symptoms 11 mg/d (neurotoxicity)
reproduction, lipid and carbohydrate metabolism; Occupational: Encephalitis-like syndrome,
upper body rash Parkinson-like syndrome, psychosis,
pneumoconiosis
Molybdenum Severe neurologic abnormalities Reproductive and fetal abnormalities 2 mg/d (extrapolated from animal
data)
Selenium Cardiomyopathy, heart failure, striated muscle General: Alopecia, nausea, vomiting, abnormal 400 μg/d (hair, nail changes)
degeneration nails, emotional lability, peripheral neuropathy,
lassitude, garlic odor to breath, dermatitis
Occupational: Lung and nasal carcinomas, liver
necrosis, pulmonary inflammation
Phosphorus Rickets (osteomalacia), proximal muscle Hyperphosphatemia 4000 mg/d
weakness, rhabdomyolysis, paresthesia, ataxia,
seizure, confusion, heart failure, hemolysis,
acidosis
Zinc Growth retardation, ↓ taste and smell, alopecia, General: Reduced copper absorption, gastritis, 40 mg/d (impaired copper
dermatitis, diarrhea, immune dysfunction, sweating, fever, nausea, vomiting metabolism)
failure to thrive, gonadal atrophy, congenital Occupational: Respiratory distress, pulmonary
malformations fibrosis

agent or whether it increases cancer risk (e.g., prostate cancer). Seleno- 2319
cysteine is also found in the deiodinase enzymes, which mediate the
deiodination of thyroxine to triiodothyronine (Chap. 375). Rich dietary
sources of selenium include seafood, muscle meat, and cereals,
327 Malnutrition and
Nutritional Assessment
although the selenium content of cereal is determined by the soil con-
centration. Countries with low soil concentrations include parts of Gordon L. Jensen
Scandinavia, China, and New Zealand. Keshan disease is an endemic
cardiomyopathy found in children and young women residing in
regions of China where dietary intake of selenium is low (<20 μg/d). Malnutrition occurs in 30–50% of hospitalized patients depending upon
Concomitant deficiencies of iodine and selenium may worsen the clin- the setting and criteria that are used. Poor wound healing, compromised
ical manifestations of cretinism. Chronic ingestion of large amounts of immune status, impaired organ function, increased length of hospital
selenium leads to selenosis, characterized by hair and nail brittleness stay, and increased mortality are among the notable adverse outcomes
and loss, garlic breath odor, skin rash, myopathy, irritability, and other associated with malnutrition. It is now widely appreciated that acute
abnormalities of the nervous system. or chronic inflammation contribute to the pathophysiology of disease-
related or injury-related malnutrition. The presence of inflammation
■■CHROMIUM can also render historic nutrition assessment indicators, like albumin
Chromium potentiates the action of insulin in patients with impaired and prealbumin, unreliable and inflammation diminishes favorable
glucose tolerance, presumably by increasing insulin receptor–mediated responses to nutrition therapies. In order to guide appropriate care, it
signaling, although its usefulness in treating type 2 diabetes is uncer- is necessary to properly assess and diagnose malnutrition. Nutrition
tain. In addition, improvement in blood lipid profiles has been reported assessment is a comprehensive evaluation to diagnose a malnutrition
in some patients. The usefulness of chromium supplements in muscle syndrome and to guide intervention and expected outcomes. Patients
building has not been substantiated. Rich food sources of chromium are often targeted for assessment after being identified at nutritional risk
include yeast, meat, and grain products. Chromium in the trivalent based upon screening procedures conducted by nursing or nutrition
state is found in supplements and is largely nontoxic; however, chro- personnel within 24 h of hospital admission. Screening tends to focus
mium-6 is a product of stainless steel welding and is a known pulmo- explicitly on a few risk variables like weight loss, compromised dietary
nary carcinogen as well as a cause of liver, kidney, and CNS damage. intake, and high risk medical/surgical diagnoses. Preferably, health pro-
■■MAGNESIUM fessionals complement this screening with a systematic approach to com-
See Chap. 402. prehensive nutrition assessment that incorporates an appreciation for the
CHAPTER 327 Malnutrition and Nutritional Assessment

contributions of inflammation that serve as the basis for new approaches
■■FLUORIDE, MANGANESE, AND ULTRATRACE to the diagnosis and management of malnutrition syndromes.
ELEMENTS
An essential function for fluoride in humans has not been described, ■■MALNUTRITION SYNDROMES
although it is useful for the maintenance of structure in teeth and Famine and starvation have long been leading causes of mal-
bones. Adult fluorosis results in mottled and pitted defects in tooth nutrition and remain so in developing countries. However,
enamel as well as brittle bone (skeletal fluorosis). with improvements in agriculture, education, public health,
Manganese and molybdenum deficiencies have been reported in healthcare, and living standards, malnutrition in the settings of disease,
patients with rare genetic abnormalities and in a few patients receiv- surgery, and injury has become a prevalent concern throughout the
ing prolonged total parenteral nutrition. Several manganese-specific world. Malnutrition now encompasses the full continuum of undernu-
enzymes have been identified (e.g., manganese superoxide dismutase). trition and over-nutrition (obesity). For the objectives of this chapter,
Deficiencies of manganese have been reported to result in bone demin- we will focus upon the former. Historic definitions for malnutrition
eralization, poor growth, ataxia, disturbances in carbohydrate and lipid syndromes are problematic in their use of diagnostic criteria that suffer
metabolism, and convulsions. poor sensitivity, sensitivity, and inter-observer reliability. Definitions
Ultratrace elements are defined as those needed in amounts <1 overlap and confusion and misdiagnosis are frequent. In addition,
mg/d. Essentiality has not been established for most ultratrace ele- some approaches do not recognize undernutrition in obese persons.
ments, although selenium, chromium, and iodine are clearly essential While the historic syndromes of marasmus, kwashiorkor, and pro-
(Chap. 375). Molybdenum is necessary for the activity of sulfite and tein-calorie malnutrition remain in use, this chapter will instead high-
xanthine oxidase, and molybdenum deficiency may result in skeletal light new insights to the diagnosis of malnutrition syndromes.
and brain lesions. The Subjective Global Assessment, a comprehensive nutrition assess-
ment that included a metabolic stress of disease component, was
■■FURTHER READING described and validated in the 1980s. In 2010, an International Consensus
Boyce SG et al: Can composite nutritional supplement based on the Guideline Committee incorporated a new appreciation for the role of
current guidelines prevent vitamin and mineral deficiency after inflammatory response into their proposed nomenclature for nutrition
weight loss surgery? Obes Surg 26:966, 2016. diagnosis in adults in the clinical practice setting. Starvation-associated
Colleen R et al: Revisiting vitamin C and cancer. Science 350:1317, malnutrition, when there is chronic starvation without inflammation
2015. (anorexia nervosa or major depression with lack of interest in eating),
Day E et al: Thiamine for prevention and treatment of Wernicke- chronic disease-associated malnutrition, when inflammation is chronic and
Korsakoff syndrome in people who abuse alcohol. Cochrane Data- of mild to moderate degree (e.g., organ failure, pancreatic cancer, or sar-
base Syst Rev 7:CD004033, 2013. copenic obesity), and acute disease or injury-associated malnutrition, when
Imdad A et al: Vitamin A supplementation for preventing morbid- inflammation is acute and of severe degree (e.g., major infection, burns,
ity and mortality in children from six months to five years of age. trauma, or closed head injury). In 2012, the Academy of Nutrition and
Cochrane Database Syst Rev 3:CD008524, 2017. Dietetics and the American Society for Parenteral and Enteral Nutrition
Stevens GA et al: Trends and mortality effects of vitamin A deficiency (ASPEN) extended this approach with corresponding nomenclature
in children in 138 low-income and middle-income countries between that included malnutrition in the setting of social and environmental
1991 and 2013: A pooled analysis of population-based surveys. Lancet circumstances, malnutrition in the setting of chronic illness, and mal-
Glob Health 3:e528, 2015. nutrition in the setting of acute illness or injury. Clinical characteristics
Vinceti M, Rothman KJ: More results but no clear conclusion on sele- were proposed to support a diagnosis that encompasses the presence of
nium and cancer. Am J Clin Nutr 104:245, 2016. illness or injury, poor food intake, weight loss, and physical findings of
WHO: Guideline: Vitamin A supplementation in pregnant women. fat loss, muscle loss, edema, or reduced grip strength. In 2016, the Euro-
Geneva, World Health Organization, 2011. pean Society for Parenteral and Enteral Nutrition (ESPEN) formally

2320 adopted an inflammation-based construct similar to these earlier of patients can be facilitated using the indicators of malnutrition and
approaches. Also in 2016, the Global Leadership Initiative on Malnutri- inflammation described below.
tion, a collaborative effort of ASPEN, ESPEN, the Latin American Fed-
eration of Parenteral and Enteral Nutrition, the Parenteral and Enteral ■■NUTRITION ASSESSMENT
Society of Asia, and other nutrition societies embarked on an effort to There is unfortunately no single clinical or laboratory indicator of com-
identify evidence-based criteria that will be disseminated throughout prehensive nutritional status. Assessment therefore requires systematic
the world for use as dictated by regional preference. integration of data from a variety of sources. Micronutrient deficiencies
Recent studies suggest that these newer approaches to diagnosis of of clinical relevance may be detected in association with any of the
malnutrition have similar utility in predicting adverse outcomes. This malnutrition syndromes, but a detailed discussion of their assessment
is not surprising since they share a number of common criteria includ- is beyond the scope of this chapter (see Chap. 326). Physical findings
ing a metabolic stress of disease component that is a proxy indicator of characteristic of micronutrient deficiencies are however summarized
inflammation. Irrespective of the approach that is selected, assessment in Table 327-1.
TABLE 327-1 History and Physical Examination Elements

ELEMENT NOTES
Historical Data
Body weight Ask about usual weight, peak weight, and deliberate weight loss. A 4.5 kg (10-lb) weight loss over 6 months is noteworthy and a weight loss
of >10% of usual body weight is prognostic of clinical outcomes. Use medical records, family, and caregivers as information resources.
Medical and surgical Look for medical or surgical conditions or chronic disease that can place one at nutritional risk secondary to increased requirements, or
conditions; chronic compromised intake or assimilation like: critical illness, severe burns, major abdominal surgery, multi-trauma, closed head injury, previous
disease gastrointestinal surgery, severe gastrointestinal hemorrhage, enterocutaneous fistula, gastrointestinal obstruction, mesenteric ischemia,
severe acute pancreatitis, chronic pancreatitis, inflammatory bowel disease, celiac disease, bacterial overgrowth, solid or hematologic
malignancy, bone marrow transplant, acquired immune deficiency syndrome, and organ failure/transplant—kidney, liver, heart, lung, or gut.
A number of conditions or diseases are characterized by severe acute inflammatory response including critical illness, major infection/
sepsis, adult respiratory distress syndrome, systemic inflammatory response syndrome, severe burns, major abdominal surgery, multi-
trauma, and closed head injury.
Many conditions or diseases are more typically associated with mild to moderate chronic inflammatory response. Examples include
cardiovascular disease, congestive heart failure, cystic fibrosis, inflammatory bowel disease, celiac disease, chronic pancreatitis,
rheumatoid arthritis, solid tumors, hematologic malignancies, sarcopenic obesity, diabetes mellitus, metabolic syndrome, cerebrovascular
PART 10
accident, neuromuscular disease, dementia, organ failure/transplant—kidney, liver, heart, lung, or gut, periodontal disease, pressure
wounds, and chronic obstructive pulmonary disease. Note that acute exacerbations, infections, or other complications may superimpose
acute inflammatory response on such conditions or diseases.
Examples of starvation-associated conditions that generally have little or no inflammatory component include anorexia nervosa or
compromised intake in the setting of major depression.
Constitutional signs/ Fever or hypothermia can indicate active inflammatory response. Tachycardia is also common. Anorexia is another manifestation of
symptoms inflammatory response and is also often a side effect of treatments and medications.
Eating difficulties/ Poor dentition or problems swallowing can compromise oral intake. Vomiting, nausea, abdominal pain, abdominal distension, diarrhea,
gastrointestinal constipation, and gastrointestinal bleeding can be signs of gastrointestinal pathology that may place one at nutritional risk.
complaints
Eating disorders Look for distorted body image, compulsive exercise, amenorrhea, vomiting, tooth loss, dental caries, and use of laxatives, diuretics or
Ipecac.
Medication use Many medications can adversely affect nutrient intake or assimilation. Review potential drug–drug and drug–nutrient interactions. A
pharmacist consultant can be helpful.
Dietary practices and Look for dietary practices including therapeutic, weight reduction, vegetarian, macrobiotic, and fad diets. Also record use of dietary
supplement use supplements, including vitamins, minerals, and herbals. Ask about dietary intake. Recall, record, and food frequency tools are available.
It is estimated that 50% or more of adults take dietary supplements.
Influences on Ask about factors such as living environment, functional status (activities of daily living and instrumental activities of daily living),
nutritional status dependency, caregiver status, resources, dentition, alcohol or substance abuse, mental health (depression or dementia), and lifestyle.
Physical Examination Data
Body mass index (BMI) BMI = weight in kg/(height in meters)2
BMI <18.5 kg/m2 proposed screen for malnutrition per National Institutes of Health guidelines. BMI ≤15 kg/m2 or less is associated with
increased mortality. Comparison with ideal body weight for stature can also be determined from reference tables. Note hydration status
and edema at the time body weight is determined.
Weight loss Look for loss of muscle mass and subcutaneous fat.
Temporal and neck muscle wasting may be readily observed. Anthropometrics including skin-folds and circumferences can be useful but
require training to achieve reliability.
Weakness/loss of Decreased hand-grip and leg extensor strength have been related to loss of muscle mass in malnourished states. Lower extremity
strength weakness may be observed in thiamine deficiency.
Peripheral edema Peripheral edema may confound weight measurements and is often observed with reduced visceral proteins as well as inflammatory
states. Edema may also be observed with thiamine deficiency.
Hair examination Hair findings are indicative of certain nutrient deficiencies.
Loss: protein, B12, folate
Brittle: biotin
Color change: zinc
Dry: vitamins A and E
Easy pluckability: protein, biotin, zinc
Coiled, corkscrew: vitamins A and C
Alopecia is common in severely malnourished persons.
Ask about excessive hair loss on pillow or when combing hair.
(Continued)

2321
TABLE 327-1 History and Physical Examination Elements (Continued)
ELEMENT NOTES
Skin examination Skin findings are indicative of certain nutrient deficiencies.
Desquammation: riboflavin
Petechiae: vitamins A and C
Perifollicular hemorrhage: vitamin C
Ecchymosis: vitamins C and K
Xerosis, bran-like desquamation: essential fatty acid
Pigmentation, cracking, crusting: niacin
Acneiform lesions, follicular keratosis, xerosis: vitamin A
Acro-orificial dermatitis, erythematous, vesiculbullous, and pustular: zinc
Characteristic nutritional dermatitis and skin findings may be observed with a number of nutrient deficiencies. Wounds and pressure
sores should also be noted as indicators of compromised nutritional status.
Eye examination Ocular findings are indicative of certain nutrient deficiencies.
Bitot’s spots: vitamin A
Xerosis: vitamin A
Angular palpebritis: riboflavin
Also ask about difficulties with night vision/night blindness; indicates vitamin A deficiency.
Perioral examination Perioral findings are indicative of certain nutrient deficiencies.
Angular stomatitis and cheilosis: B complex, iron, and protein
Glossitis: niacin, folate, and vitamin B12
Magenta tongue: riboflavin
Bleeding gums, gingivitis, tooth loss: vitamin C
Angular stomatitis, cheilosis, and glossitis are associated with vitamin and mineral deficiencies. Note poor dentition, caries, and tooth
loss. Difficulty swallowing and impairment of gag should also be recognized.
Extremity examination Extremity findings indicate certain nutrient deficiencies

Arthralgia: vitamin C
Calf pain: thiamine
Extremities may also exhibit loss of muscle mass and/or peripheral edema. Neurological findings in the extremities may also result from
deficiencies described below.
Mental status/ Mental and nervous system findings indicate certain nutrient deficiencies.
nervous system Ophthalmoplegia and foot drop: thiamine
examination
Paresthesia: thiamine, vitamin B12, and biotin
Depressed vibratory and position senses: vitamin B12
Anxiety, depression, and hallucinations: niacin
Memory disturbance: vitamin B12
Hyporeflexia, loss of lower extremity deep tendon reflexes: thiamine and vitamin B12
Conduct formal cognitive and depression assessments as appropriate. Dementia and depression are common causes of malnutrition
among older persons. Wernicke-Korsakoff syndrome may be observed with severe thiamine deficiency.
Functional assessment Observe and test physical performance as indicated: gait, chair stands, stair steps, and balance. These provide complex measures of
integrated neurological status, coordination, and strength.
Source: Adapted with permission from G Jensen: Nutritional Syndromes. Smart Medicine/PIER. Philadelphia, American College of Physicians, 2013.
Medical/Surgical History and Clinical Diagnosis Knowl- nitrogen losses. Inflammation also promotes anorexia, decreasing food
edge of a patient’s medical/surgical history and associated clinical intake and further compromising nutritional status. A deteriorating
diagnoses is especially helpful in discerning the likelihood of mal- course may result because the presence of inflammation may reduce
nutrition and inflammation. Non-volitional weight loss is a well the benefit of nutritional interventions and the associated malnutrition
validated nutrition assessment indicator and is often also associated may in turn diminish the effectiveness of medical therapies. It is also
with underlying disease or inflammatory condition. The degree and imperative to recognize medical/surgical conditions or diseases that
duration of weight loss determine its clinical significance. A 10% loss place the patient at increased risk to become malnourished because
of body weight over 6-months is of clinical relevance, while a 30% loss they have increased nutritional requirements, or compromised intake
of body weight over the same duration is severe and life-threatening. or assimilation (Table 327-1).
Since weight loss history is often unavailable or unreliable, one should Nutrition assessment should also include a review of medications
query the patient as well as the medical records, family, and caregivers with attention to undesirable side effects including anorexia, xeros-
as appropriate to secure a valid weight trajectory. tomia, nausea, diarrhea, and constipation. Potential drug/nutrient
A number of conditions or diseases are characterized by severe interactions should also be identified.
acute inflammatory response whereas others are more typically asso-
ciated with a chronic inflammatory response that is mild to moderate Clinical Signs and Physical Examination Nonspecific clini-
in severity and may be relapsing and remitting (Table 327-1). It is also cal indicators of inflammation include fever, hypothermia, and tachy-
common for acute inflammatory events to be superimposed on those cardia. The nutrition-focused physical examination should identify
with chronic conditions; for example, a patient with chronic renal dis- edema as well as signs of weight gain/loss and specific nutrient
ease is admitted to the hospital with sepsis. The inflammatory milieu, deficiencies. Thorough examination should be particularly directed to
especially when severe, may modify nutrient requirements by elevat- those parts of the body where high cell turnover occurs (e.g., hair, skin,
ing resting energy expenditure and promoting muscle catabolism and mouth, tongue) as they are most likely to exhibit observable signs of

2322 nutritional deficiencies (Table 327-1). Physical findings of weight loss National Institutes of Health BMI categories for adults are: BMI <18.5 =
associated with decreased muscle and subcutaneous fat mass should underweight, BMI 18.5–24.9 = desirable, BMI 25.0–29.9 = overweight,
not be overlooked, but when appreciable edema is present, these and BMI ≥30 = obese. A higher desirable BMI range for persons 65 years
changes may not be readily appreciated. of age and older has been proposed by the Centers for Medicare and
Medicaid Services in its quality indicators system: BMI ≥23 and <30.
Anthropometric Data Body weight measurements are recom- While classical anthropometric measurements including skin-folds
mended with each clinic visit or hospitalization so that a reliable weight and circumferences can be helpful, their utility in routine patient
change trajectory may be monitored. Patients should be weighed in a care has been limited because practitioner training is required to
consistent manner without over-garments or shoes. In order to secure achieve suitable reliability. Body composition assessment methodolo-
valid measurements, calibration of scales and appropriate staff training gies include bioelectrical impedance analysis (BIA), dual-energy x-ray
are essential. Chair or bed scales may be used for those who cannot absorptiometry (DEXA), computed tomography (CT), and magnetic
stand. For those who are able, height should be measured in a standing resonance imaging (MRI). The imaging modalities have become the
position without shoes using a stadiometer. If an adult cannot safely state of the art for precise measurements of muscle mass. It is possible
stand, height can be estimated by doubling the arm span measurement to take advantage of CT or MRI studies that are being done for other
(from the patient’s sternal notch to the end of the longest finger). Stat- clinical purposes to evaluate musculature.
ure of frail older persons can also be estimated from measurement of
knee height using a caliper device. Laboratory Indicators Laboratory findings (Table 327-2) are but
Body weight is often standardized for height to obtain an ideal one part of the comprehensive nutrition assessment and must be used
weight for comparison, but available reference tables require subjective in combination with other domains of assessment to appropriately diag-
assessment of frame size and offer limited reference data for many nose a malnutrition syndrome. Although serum albumin or prealbumin
relevant population groups, including older persons. A simple mea- are often measured in patients with suspected malnutrition, their utility
sure of body size and an indirect measure of body fatness is provided is limited due to their poor sensitivity and specificity as indicators of
by body mass index (BMI), defined as weight (kg) / height (m2). The nutritional status. Patients with low albumin or prealbumin may or
TABLE 327-2 Body Composition, Laboratories, and Other Studies

TEST NOTES
Body Composition Studies
PART 10
Anthropometrics Skin folds and circumferences require training for reliability. Typical coefficient of variation is ≥10%.
Bioelectrical impedance Based upon differential resistance of body tissues. Equipment easily portable. Good measure of body water. Requires
population specific validation of regression equations.
Water displacement Impractical for most clinical settings. Weighed in water tank. Historic reference measure.
Whole body counting and isotope Research methodologies. Naturally occurring 40K isotope to measure body cell mass by whole body counting. Total body
dilution techniques water measurement by dilution volume of tritium, deuterium, or 18O-labeled water.
Air plethysmography Research methodology. Subject sits inside moderately sized BodPod chamber. Validated against water displacement and
impedance.
Dual energy x-ray absorptiometry Often used for bone density but can be used for soft tissue measurements with appropriate software. Can compare
(DEXA) truncal and appendicular components. Modest x-ray exposure.
Imaging with computed tomography State of the art research methods for visualizing body tissue compartments. Can quantify visceral fat. Costly and CT
(CT) or magnetic resonance imaging entails X-ray exposure.
(MRI)
Laboratories and Other Studies
Albumin Lacks sensitivity and specificity for malnutrition. Potent risk indicator for morbidity and mortality. Proxy measure for
underlying injury, disease or inflammation. Half-life is 14–20 days. Also consider liver disease, nephrotic syndrome, and
protein-wasting enteropathy.
Prealbumin Sensitive to short-term changes in inflammation and protein nutrition with half-life of 2–3 days. Otherwise suffers the
same limitations of albumin with limited sensitivity and specificity for malnutrition. Levels may be decreased in liver failure
and increased in renal failure.
Transferrin Acute phase reactant also altered by perturbation in iron status. Half-life is 8–10 days. Lacks sensitivity and specificity for
malnutrition.
Retinol-binding protein Responds to very short-term changes in nutritional status but utility is also limited by response to stress and
inflammation. Half-life is 12 h. Also affected by vitamin A deficiency and renal disease.
C-reactive protein C-reactive protein is a positive acute phase reactant. It is generally elevated if an active inflammatory process is
manifest.
Cholesterol Low cholesterol (<160 mg/dL) is often observed in malnourished persons with serious underlying disease. It is unrelated
to dietary intake in many clinical settings. Increased complications and mortality are observed. It appears that low
cholesterol is again a nonspecific feature of poor health status that reflects cytokine-mediated inflammatory condition.
Vegans and patients with hyperthyroidism may also exhibit low cholesterol.
Carotene Nonspecific indicator of malabsorption and poor nutritional intake.
Cytokines Research is exploring prognostic use of cytokine measurements as indicators of inflammatory status.
Electrolytes, blood urea nitrogen, Monitor for abnormalities consistent with under- or over-hydration status and purging (contraction alkalosis). BUN
creatinine, and glucose may also be low in the setting of markedly reduced body cell mass. Blood urea nitrogen and creatinine are elevated in
renal failure. Hyperglycemia may be nonspecific indicator of inflammatory response.
Complete blood count with differential Screen for nutritional anemias (iron, B12, and folate), lymphopenia (malnutrition) and thrombocytopenia (vitamin C and
folate). Leukocytosis may be observed with inflammatory response.
Total lymphocyte count Relative lymphopenia (total lymphocyte count <1200/mm3) is a nonspecific marker for malnutrition.
Helper/suppressor T cell ratio Ratio may be reduced in severely undernourished patients. Not specific for nutritional status.
(Continued)

TABLE 327-2 Body Composition, Laboratories, and Other Studies (Continued) 2323
TEST NOTES
Nitrogen balance 24-h urine can be analyzed for urine urea nitrogen (UUN) to determine nitrogen balance and give indication of degree of
catabolism and adequacy of protein replacement. Requires accurate urine collection and normal renal function. Nitrogen
balance = (protein/6.25) - (UUN+4). Generally negative in the setting of acute severe inflammatory response.
Urine 3-methylhistidine Indicator of muscle catabolism and protein sufficiency. Released upon breakdown of myofibrillar protein and excreted
without reutilization. Urine measurement requires a meat-free diet for 3 days prior to collection.
Creatinine height index (CHI) CHI = (24-h urinary creatinine excretion/ideal urinary creatinine for gender and height) × 100. Indicator of muscle
depletion. Requires accurate urine collection and normal renal function.
Prothrombin time/international Nonspecific indicator of vitamin K status. Prolonged in liver failure.
normalized ratio (INR)
Specific micronutrients When suspected a variety of specific micronutrient levels may be measured: thiamine, riboflavin, niacin, folate,
pryridoxine, vitamins A, C, D, E, B12, zinc, iron, selenium, carnitine, and homocysteine—indicator of B12, folate, and
pyridoxine status.
Skin testing—recall antigens Delayed hypersensitivity testing. While malnourished patients are often anergic, this is not specific for nutritional
status.
Electrocardiogram Severely malnourished patients with reduced body cell mass may exhibit low voltage and prolonged QT interval. These
findings are not specific for malnutrition.
Video fluoroscopy Helpful to evaluate suspected swallowing disorders.
Endoscopic and x-ray studies of Useful to evaluate impaired function, motility, and obstruction.
gastrointestinal tract
Fat absorption 72-h fecal fat can be used to quantitate degree of malabsorption.
Schilling test Identify the cause for impaired vitamin B12 absorption.
Indirect calorimetry Metabolic cart can be used to determine resting energy expenditure (REE) for accurate estimation of energy needs.
Elevated REE is a sign of systemic inflammatory response.
Source: Adapted with permission from G Jensen: Nutritional Syndromes. Smart Medicine/PIER. Philadelphia, American College of Physicians, 2013.

may not prove to be malnourished when evaluated by comprehensive imperative to monitor quantities of food and/or supplements that are
nutrition assessment because these proteins are readily reduced by actually consumed as well as patient tolerance to feeding. Meals are
the systemic response to injury, disease or inflammation. C-reactive often delayed or missed for tests or procedures. If possible, the patient
protein is a positive acute phase reactant that may be measured to help should be queried about intake since tray inspection is notoriously
discern whether active inflammation is manifest. If C-reactive protein is unreliable as an indicator of consumption.
increased, and albumin or prealbumin decreased, then inflammation is
likely to be a contributing factor. Since it is recognized that C-reactive Functional Outcomes Advanced malnutrition is accompanied
protein suffers limitations as a point in time measure, trends in levels by declines in muscle mass and function that can be detected by
over the clinical course may be helpful. Research suggests that interleu- strength and physical performance measures. Hand-grip strength
kin 6, and perhaps other cytokines, may also offer promise as indica- measured with a simple handgrip dynamometer is the most practical
tors of inflammatory status. Nonspecific laboratory indicators that are routine clinical assessment. Physical performance tests like timed gait,
often associated with inflammatory response include leukocytosis and chair stands, and stair steps are used in the comprehensive assessment
hyperglycemia. Additional tests that may be obtained to help confirm of integrated functions in frail older persons.
the presence of inflammatory response include 24-h urine urea nitro- The decline in overall functional status observed in advanced mal-
gen and indirect calorimetry. In the setting of severe acute systemic nutrition is associated with nutrient deficiencies and impairment of
inflammatory response, negative nitrogen balance and elevated resting organ system functions. Poor wound healing and immune compromise
energy expenditure are anticipated. are examples of such impairments. Improved wound healing parame-
ters and restored responsiveness to recall antigens by delayed hyper-
Dietary Assessment Dietary assessment can be used to detect sensitivity testing may be measured to demonstrate improvements
inadequate or imbalanced food or nutrient intakes. While dietary with nutritional repletion, though it must be appreciated that these are
assessment in patient care settings can be quite challenging, 24-h recall multivariable outcomes for which improved nutritional status is but
and modified diet history approaches are sometimes used. A modified one variable.
diet history is targeted to query types and frequencies of intake of spe-
cific foods of interest. It is often necessary to access diverse resources ■■FURTHER READING
for diet history information including the patient, medical records, Cederholm T et al: ESPEN guidelines on definitions and terminology
family, and caregivers. Consultation of a registered dietitian nutrition- of clinical nutrition. Clin Nutr 36:49, 2017.
ist is highly recommended. Dietary practices and supplements should Cederholm T, Jensen GL: To create a consensus on malnutrition diag-
be carefully reviewed for potential inadequacies and toxicities. Since nostic criteria. JPEN J Parenter Enteral Nutr 41:311, 2017.
patients will often present to healthcare practitioners with acute medi- Detsky AS et al: What is Subjective Global Assessment of nutritional
cal events superimposed upon chronic health conditions, it is common status? J Parenter Enteral Nutr 11:8, 1987.
for patients to have had decreased food intakes and malnutrition for Guerra RS et al: Usefulness of six diagnostic and screening measures
extended periods prior to assessment. It is therefore imperative that for undernutrition in predicting length of hospital stay: A compara-
compromised dietary intake should not be overlooked so that appro- tive analysis. J Acad Nutr Diet 115:927, 2015.
priate intervention may be undertaken. Jensen GL: Inflammation as the key interface of the medical and nutri-
Ongoing assessment is indicated when parenteral or enteral feed- tion universes: A provocative examination of the future of clinical
ings are initiated, because it is necessary to discern what amount of nutrition and medicine. J Parenter Enteral Nutr 30:453, 2006.
formula is actually being administered to and received by the patient. Jensen GL: Malnutrition and inflammation—“Burning down the
Enteral feedings, in particular, often interrupted or held for procedures, house”: Inflammation as an adaptive physiologic response versus
tolerance issues, and feeding tube displacements. It is therefore not self-destruction? J Parenter Enteral Nutr 39:56, 2015.
unusual for such patients to be appreciably underfed for extended Jensen GL: Global leadership conversation: Addressing malnutrition. J
periods. When a patient is beginning to transition to oral feedings, it is Parenter Enteral Nutr 40:455, 2016.

2324 Jensen GL, Hsiao PY, Wheeler D: Adult nutrition assessment tutorial. Protein and Amino Acids Protein is an essential nutrient because
J Parenter Enteral Nutr 36:267, 2012. whole body protein turnover—a continuous process of protein synthe-
Jensen GL et al: Adult starvation and disease-related malnutrition: A sis and breakdown to its constituent amino acids—is associated with
proposal for etiology-based diagnosis in the clinical practice setting obligatory amino acid catabolism to carbon dioxide, water, carbohy-
from the International Consensus Guideline Committee. J Parenter drates, ammonium, urea, and sulfuric acid. Amino acid catabolism can
Enteral Nutr 34:156, 2010. be adaptively reduced when protein intake decreases, but not below a
White JV et al: Consensus statement: Academy of Nutrition and certain lowest rate known as the protein minimum. After adjustment
Dietetics and American Society for Parenteral and Enteral Nutrition. for the inefficiency of exogenous protein retention, this rate defines the
Characteristics recommended for the identification and documenta- minimum dietary protein intake necessary to maintain whole body
tion of adult malnutrition (under-nutrition). J Parenter Enteral Nutr protein homeostasis and zero nitrogen (N) balance. Proteins of nutri-
36:275, 2012. tional interest, including the ones that form the metabolically active tis-
sues of the body known as the body cell mass (BCM), are 16% nitrogen
(N) by weight. Skeletal muscle makes up ~80% of the BCM and 40–50%
of the body weight of normal-weight young adults. The excretion of 1 g
N from the body—mostly as urinary urea N—implies the loss of 6.25 g
formed protein and (since the BCM is ~80% tissue water) ~31 g of BCM,
328 Enteral and Parenteral

Nutrition
almost of all it as muscle tissue.
The lowest daily protein intake compatible with zero N balance—
approximately 0.65 g/kg body weight—is the average minimum
protein requirement of a healthy adult. To account for inter-individual
L. John Hoffer, Bruce R. Bistrian, variability, two standard deviations are added to calculate the “safe”
David F. Driscoll or “recommended” daily minimum protein intake of 0.80 g/kg normal
body weight. Protein intakes greater than the minimum requirement
are usually inconsequential, as surfeit amino acids are normally easily
catabolized. The average protein consumption in wealthy societies is
There are three kinds of specialized nutritional support (SNS): (1) opti- approximately twice the average minimum requirement.
mized voluntary nutritional support, which is used when a patient’s Many diseases (or their treatment) increase the dietary protein
barriers to adequate nutrition can be overcome by special attention to requirement, by (1) increasing amino acid loss from the body (as in
the details of how their food is constituted, prepared, served, and its malabsorption and protein loss via wound exudates, fistulas or inflam-
consumption monitored, (2) forced enteral nutrition (EN), in which
PART 10
matory diarrhea), removing amino acids from the circulation (renal

a liquid nutrient formula is delivered through a tube placed in the replacement therapy), or (2) increasing muscle protein catabolism (as
stomach or small intestine, and (3) parenteral nutrition (PN), in which with high-dose glucocorticoid therapy). Protein-catabolic critically ill
a nutritionally complete mixture of crystalline amino acids, dextrose, patients often excrete 15 g N/day or more in their urine in the absence
triglyceride emulsions, minerals, electrolytes, and micronutrients is of dietary protein provision. This rate of N loss implies a loss of 15 ×
infused directly into the bloodstream. 6.25 = 94 g muscle protein—equivalent to one pound of muscle lost
When does a hospitalized patient need SNS? When SNS is indicated, from the body every day. Sufficiently generous protein provision can
how should it be provided? This chapter reviews the physiological minimize this kind of muscle atrophy, and there is widespread agree-
principles that underlie the correct use of SNS, and provides practical ment that protein-catabolic patients require much more dietary protein
information about the diagnosis and management of nutritional disor- requirement than healthy people. The exact magnitude of the increase
ders in adult hospitalized patients. has not yet been determined, but the most frequent recommendation
The management of in-hospital nutritional disorders follows 3 for patients with protein-catabolic diseases is 1.5 g protein/kg normal
steps: (1) screening and diagnosis; (2) determination of the severity body weight/day, close to the habitual protein intake of healthy people
and urgency of treating a diagnosed nutritional disorder in its overall in wealthy societies.
clinical context; and (3) selection of the modality of SNS, its composi-
tion, and the details of providing it. To follow these steps effectively, Protein-Energy Interaction Energy deficiency—whether delib-
physicians require a general understanding of nutritional physiology, erate, as in weight reduction therapy, or inadvertent, as frequently
nutrient requirements, the pathophysiology and diagnosis of the occurs in hospitalized patients—increases amino acid loss from muscle
nutritional disorders, and familiarity with the indications, advantages, and increases the dietary protein requirement. The mechanism respon-
risks, and administration of the different kinds of SNS. Because most sible for energy deficiency’s protein-wasting effect differs from the one
physicians are incompletely trained in clinical nutrition, they must that mediates inflammation-induced muscle atrophy, and the inter-
collaborate with clinical dietitians and specialized pharmacists when action between these different processes is imperfectly understood.
ordering EN and PN. It does appear, however, that systemic inflammation diminishes, but
doesn’t prevent the protein-sparing effect of generous protein provi-
■■NUTRITIONAL PHYSIOLOGY sion as long as the protein is combined with some exogenous energy
(See Chaps. 325–327) (e.g., 50% of TEE). Energy provision more generous than ~50–70% of
TEE exerts little further protein-sparing effect in this situation, and the
Energy Total energy expenditure (TEE) is comprised of resting energy
additional amounts of glucose and fluid volume required to provide it
expenditure (REE, ~24 kcal/kg normal adult body weight/day), activity
often have adverse effects.
energy expenditure (~12 kcal/kg in healthy sedentary individuals) and
the thermic effect of food (10% of TEE). The TEE of a healthy adult is ~36 Micronutrients Minimum amounts of nine water-soluble vitamins
kcal/kg. REE can be measured by indirect calorimetry or estimated using (the B vitamins and vitamin C) and four fat-soluble vitamins (A, D,
a variety of predictive equations that input weight, height, age, sex, and E, and K), eight minerals (calcium, phosphate, potassium, sodium,
sometimes disease-related factors. Fever and some forms of critical illness chloride, magnesium, zinc, and iron), essential fatty acids, and several
increase REE. Prolonged semi-starvation normally triggers an adaptive essential trace elements (notably including selenium, copper, and
reduction in REE, voluntary physical activity, and the thermic effect of iodine) are required throughout life to avoid deficiency diseases and
food. Broadly speaking, a patient’s TEE identifies the amount of dietary death. Patients who have been hospitalized for more than a few days
energy they have to consume and metabolize to maintain their existing commonly consume inadequate amounts of food and the micronutri-
store of body fat (and protein). The amount of energy they actually ents it provides.
require may be less than TEE (as in obesity therapy) or greater than TEE Overt deficiencies of potassium, sodium, magnesium, phosphate,
(when rehabilitating nutritionally depleted patients). and iron occur so often in hospitalized patients that it is standard

practice to monitor for and correct them. Many drugs used in acute- young adults at the cusp of survival; older patients with co-morbidities 2325
care medicine induce renal potassium, magnesium, or zinc wasting are at even greater risk. People with SM feel unwell, lack strength, are
that necessitate appropriate increases in their provision. Gastrointes- frail, and are at risk of hypothermia. The severity of SM is revealed by
tinal losses from nasogastric drainage tubes or intestinal losses from physical examination and an evaluation of the patient’s strength and
fistulas or diarrhea incur losses of potassium, sodium, calcium, magne- physical function.
sium, and zinc which add to their normal daily requirement. The main cause of SM worldwide is involuntary food deprivation.
Less studied, but nonetheless common, are subclinical or unrecog- The causes of SM in hospitalized patients are many. They include inad-
nized deficiencies of calcium, zinc, vitamin D, vitamin C, and possibly vertent or physician-ordered food deprivation, psychologic depression
other micronutrients. Physicians often assume that consumption of or distress, poorly controlled pain or nausea, badly presented unap-
the regular hospital diet will protect patients from these deficiencies. pealing food, communication barriers, anorexia nervosa, physical or
This assumption is not warranted when the patient’s nutritional status sensory disability (including dysgeusia), thrush, dysphagia and other
was borderline or deficient when they were admitted to hospital and mechanical difficulties ingesting food, partial obstruction of the esoph-
remains inadequate throughout their hospital stay. These patients are at agus, stomach or intestinal tract, intestinal angina, and very commonly,
risk of a variety of micronutrient deficiency diseases in addition to the combinations of these causes.
symptoms and disability created by continuing in-hospital starvation.
Chronic Disease-Related Malnutrition and Cachexia
■■PROTEIN-ENERGY MALNUTRITION AND ITS These two terms refer to starvation-induced PEM that is complicated
VARIANTS by chronic systemic inflammation. Chronic disease-related malnutri-
The decision to embark on SNS should be justified by a well- tion (CDM) is highly prevalent among patients with chronic infections,
formulated nutritional diagnosis and explicitly defined therapeutic inflammatory autoimmune diseases, chronic severe hepatic, renal, car-
goal. This chapter focuses on the diagnosis, treatment, and prevention diac and pulmonary disease, and certain inflammatory cancers. CDM
of in-hospital protein-energy malnutrition (PEM). PEM is the disease both causes and is worsened by anorexia: a strong disinclination to eat
caused by prolonged inadequate energy and protein consumption— much food even when there is no physical barrier to eating. CDM is
starvation—with consequent depletion of the BCM and body fat. The characterized by a moderately increased rate of muscle protein cata-
pathologic features that differentiate PEM—which is a disease—from bolism, muscle atrophy and weakness, fatigue and reduced voluntary
the physiological process of starvation that leads to it, emerge when activity, and a subverted adaption to starvation, all of which contribute
the BCM has become depleted seriously enough to impair specific to a vicious cycle of worsening CDM. Fortunately, the nutrient deficit
physiological functions. There are many synonyms for simple, starva- on the input side (anorexia-driven inadequate food consumption) is
CHAPTER 328 Enteral and Parenteral Nutrition

tion-induced PEM: starvation disease, hunger disease, inanition and, often a stronger driver of the patient’s CDM than increased nutrient
most recently, starvation-related malnutrition (SM). loss on the output side (increased amino acid catabolism and REE),
The body normally adapts to starvation by reducing energy expendi- thus making CDM amenable to nutritional intervention while effective
ture and curtailing protein catabolism, partly by hormone- and nervous treatment of the primary disease is underway. The anorexia of CDM
system-regulated alterations in cellular metabolism, and partly by is less inhibiting to people who have a hearty pre-morbid appetite
reducing its muscle mass. These adaptations enable prolonged survival and obesity-prone phenotype than it is to previously thin, habitual
during sub-lethal starvation, but survival comes at a cost that includes under-eaters.
lethargy, a tendency to hypothermia, muscle atrophy (including of the
cardiac and respiratory muscles), skin thinning, and functional dis- Acute Disease-Related Malnutrition The term acute disease-
ability. The cardinal diagnostic features of PEM—generalized muscle related malnutrition (ADM) refers to a specific metabolic-nutritional
atrophy and subcutaneous adipose tissue depletion—are easy to detect environment that creates a very high risk of severe PEM, rather than
by simple physical examination. Too often, however, in-hospital PEM an existing disease entity. A synonym for ADM is “catabolic critical
remains undiagnosed, partly because of health care worker unaware- illness.” The intense systemic inflammation that accompanies severe
ness and inattention, and partly because PEM overlaps and is often con- tissue injury and sepsis causes extremely rapid and severe muscle atro-
fused with other common conditions that also cause muscle atrophy. phy (and increases REE to a variable extent) in a setting in which vol-
untary food intake is impossible. People with ADM are usually treated
Terminology The terms used to describe nutritional disorders are in intensive care units. They may or may not have PEM at the onset of
often ambiguous and confusing. “Malnutrition” is a blanket term that ADM, but it will surely develop within days to a few weeks unless their
indiscriminately refers to the sum total of the nutritional environments medical or surgical disease is rapidly and effectively treated and SNS is
that give rise to starvation, the physiological process of starvation, appropriately provided.
and the PEM that may result from it. Until this terminology is better
standardized, we suggest that health care workers explicitly distin- ■■NUTRITIONAL DIAGNOSIS
guish among (1) situations that create a risk of inadequate nutrient The cardinal anatomic features of PEM—generalized muscle atrophy
intake, (2) situations in which inadequate intake of specific nutrients and diminished body fat—are revealed by a discerning physical exami-
actually occurs and creates a discernable risk of developing a specific nation, but what ought to be an easy diagnosis is commonly missed.
nutritional disease, and (3) the specific diseases themselves, as enu- This section explains the details and pitfalls of diagnosing PEM and
merated below. judging its severity.
Starvation-Related Malnutrition (Uncomplicated Protein- Muscle Mass Once the examiner’s attention has been drawn
Energy Malnutrition) PEM is diagnosed when the physical to it, generalized muscle atrophy is easy to identify and its severity
examination reveals generalized muscle atrophy and diminished (but determinable almost at a glance. The problem with diagnosing PEM
not necessarily depleted) subcutaneous adipose tissue due to pro- in the hospital setting, apart from simple inattention, is that general-
longed inadequate food consumption or malabsorption. PEM is always ized muscle atrophy has many causes: old age-related muscle atrophy
associated with weight loss, but weight loss alone may not reveal its (sarcopenia), disuse muscle atrophy due to reduced mobility and bed
full severity, because extracellular fluid (ECF) volume and hence body rest, high-dose glucocorticoid therapy, certain endocrine diseases, and
weight increase, sometimes seriously enough to cause edema. SM is primary muscle or neuromuscular diseases. Indeed, muscle atrophy
“uncomplicated” PEM due solely to prolonged starvation. Adaptation is so common among hospitalized patients that health care workers
is an important feature of SM that increases the likelihood of survival often mistakenly regard it is a usual, even defining, characteristic of the
by reducing energy expenditure and slowing body protein turnover, patient’s primary disease. In reality, muscle atrophy is very commonly
thus reducing or halting the loss of body protein and fat. The risk at least partly due to SM or CDM. As such, it represents a poten-
of complications, including death, increases as the depletion of BCM tially remediable complication of the patient’s primary disease rather
worsens. A 50% depletion of BCM puts otherwise uncompromised than a necessary feature of it. Whenever a health care worker detects

2326 generalized muscle atrophy, they should review the patient’s overall concentration and an increased serum C-reactive protein concentra-
situation and identify which of its potential causes are pertinent, and in tion. Systemic inflammation increases the permeability of capillary
particular, which of them are treatable and reversible. The combination walls to large molecules; the resulting osmotic shift increases the ECF
of old age, disuse muscle atrophy, and starvation is very common. Old volume. Intravascular albumin pool redistributes into this large vol-
age is irreversible, but adequate protein and energy provision com- ume, decreasing the serum albumin concentration. Increased albumin
bined with physical rehabilitation can be lifesaving. catabolism likely also contributes. Muscle atrophy and dietary pro-
Muscle atrophy, no matter what its cause, is especially dangerous tein deficiency perpetuate inflammation-induced hypoalbuminemia,
in ADM, because patients in this situation are closer to the cliff-edge because muscle protein and the diet provide the amino acids required
of lethal BCM depletion. As well, their reduced muscle protein mass is for hepatic albumin synthesis.
unable to release amino acids into the circulation at a rate sufficient to Hypoalbuminemia is often claimed to indicate or diagnose “mal-
meet the need for protein synthesis at sites of injury and healing, and nutrition.” This is incorrect. Hypoalbuminemia indicates the presence
within the central protein pool to regulate the immuno-inflammatory of systemic inflammation, which, by inducing anorexia and increasing
process. muscle catabolism, creates a high risk that PEM could develop; but
PEM may or may not exist at the present moment. Hypoalbuminemia
Subcutaneous Adipose Tissue Severe adipose tissue depletion will not improve as long as systemic inflammation persists, even with
is sufficient to diagnose PEM, but it is not a necessary criterion. The prolonged optimal nutritional therapy. After systemic inflammation
modern obesity epidemic has created a population of obese patients has subsided, several weeks of optimal nutrition may be required for
with chronic inflammation and starvation whose muscle atrophy serum albumin concentrations to renormalize.
outpaces their fat loss. A targeted physical examination easily differen-
tiates these patients’ muscle groups from their subcutaneous fat, and PROTEIN-CATABOLIC INTENSITY The defining feature of protein-
reveals their moderate and sometimes severe PEM. catabolic disease (as occurs most intensely in ADM, but also in CDM)
is increased muscle amino acid catabolism. Conditions that increase
ECF Volume The ECF volume normally represents ~20% of body body protein loss can be identified by measuring the rate of body
weight. Chronic starvation increases the ECF volume, occasionally N loss. Most N leaves the body in the urine (almost all of it in urea,
enough to cause dependent edema (“starvation edema”). Hospitalized ammonium, and creatinine), the feces, skin, and by other minor routes.
patients with CDM commonly have other edema-causing conditions, Total N is not usually measured in hospital laboratories, but urinary
including hypoalbuminemia with its associated reduction in plasma urea concentrations are routinely available. Urea normally accounts
oncotic pressure. Unless recognized and accounted for, increased ECF for ~85% of urinary N. Formulas are available that estimate that total
volume can mask the true extent of muscle and adipose tissue deple- N loss solely from 24-h urinary urea excretion. A recent, validated
tion in patients with PEM. formula estimates daily total N loss (g) = g N in urinary urea/0.85 + 2.
PART 10
Body Mass Index Body mass index (BMI) is defined as body Net muscle protein catabolism follows approximately first-order
weight (kg) divided by the square of height (m2). Normal BMI ranges (“decay”) kinetics, such that the rate of N loss from muscle is propor-
from 20 to 25 kg/m2. BMI >25 usually indicates increased body fat; BMI tional to the existing total amount of N available to be lost. Muscle
<20 indicates decreased muscle mass and body fat. Survival during atrophic, protein-catabolic patients lose less body N/day in absolute
prolonged, severe starvation depends both on fat and protein stores. terms than an equivalently catabolic patients with normal muscle
A BMI of 11–13 is usually incompatible with life. Some guidelines and mass, but they are at nevertheless at greater risk of succumbing to their
clinical trial enrollment criteria define “malnutrition”—in this context critical illness. The interpretation of a patient’s rate of N loss should be
a synonym for PEM—as a BMI <16 or 17. This oversimplification can tempered by a consideration of their existing muscle mass.
lead to serious error. A BMI of 17 certainly is consistent with PEM, Instrumental Nutritional Assessment Many nutritional
because the body architecture of such a BMI can only be created by assessment instruments claim to identify “malnutrition” by enu-
jettisoning a large amount of BCM and adipose tissue. But a BMI >17 merating and summing a list of risk factors, laboratory results, and
does not rule out PEM. Many patients with PEM have normal or above- physical findings. These tools are often hindered by ambiguity about
normal BMIs due to residual obesity or an expanded ECF volume. the intended meaning of “malnutrition” and failure to distinguish
Visual BMI After some practice, health care workers can accu- between screening and diagnosis. Diagnosis is the process of identify-
rately predict the BMI of non-obese, non-edematous patients by exam- ing a known pathological entity in a particular patient—SM or CDM,
ining their muscular architecture. Visual BMI is useful for quantifying for example—by considering the patient’s medical history, pertinent
and communicating the severity of a patient’s PEM. Once acquired, this findings on physical examination, and laboratory or imaging reports.
skill can be used to estimate the severity of PEM in obese or edematous Diagnosis also involves an estimation of the probability that the diag-
patients—in whom measured BMI is unreliable—by focusing attention nosis is correct and a judgment about its severity. By contrast, screening
on their muscular architecture while simultaneously discounting their is the application of a test that identifies people at sufficiently high
subcutaneous fat and edema. Visual BMI may also be used to estimate risk of a certain disease to warrant carrying out definitive procedures
a patient’s “normalized dry body weight.” The normalized dry body to establish the diagnosis or rule it out, or which identifies people at
weight of a 1.75 m tall patient with visual BMI 17 = 1.752 × 17 = 52 kg. sufficient risk of developing the disease to warrant specific preventive
Since protein and energy targets are based on normal body weight, interventions. Screening tools and risk predictors are useful, but it’s a
this calculation is useful in situations in which actual body weight is mistake to confuse them with clinical diagnosis.
unreliable or difficult to measure. Subjective Global Assessment The best-validated and most
Laboratory and Technical Assessment Laboratory measure- useful formal bedside instrument for diagnosing SM and CDM (and
ments have three main purposes in the evaluation and management judging their severity) is subjective global assessment. With this
of PEM. method the examiner reflects on the totality of (1) the patient’s history
(for evidence of inadequate food intake, weight loss, and the presence
MUSCLE MASS Bedside ultrasound is a potentially valuable technique
of factors, such as gastrointestinal disease, and systemic inflamma-
for quantifying muscle mass at specific body sites, but it need not, nor tion, that strongly predict diminished ability consume enough food),
should it, replace the immediate and comprehensive evaluation pro- (2) the patient’s current body composition (muscle mass, subcutane-
vided by the eyes, hands and mind of the discerning bedside examiner. ous fat, and ECF volume), and (3) their functional status (strength
SYSTEMIC INFLAMMATION The presence or absence of systemic inflam- and mobility), then takes a moment to form an intuitive judgment as
mation distinguishes SM from CDM/cachexia. The most useful labora- to whether the patient has (A) no SM or CDM, (B) is in the gray zone
tory indicators of systemic inflammation are a reduced serum albumin of possible or mild SM or CDM, or (C) definitely has SM or CDM.

A judgment is also reached as to how urgently nutritional interven- increasingly used to provide protein-catabolic patients an appropriately 2327
tion is required. generous amount of protein without calorie-overfeeding.
OTHER FORMULAS A wide variety of disease-specific EN products are
■■SPECIALIZED NUTRITION SUPPORT available for patients with diabetes, hepatic, and renal or pulmonary
Optimized Voluntary Nutritional Support When feasible, disease. The details and evidence related to these products go beyond
this is the approach of choice because it engages and empowers the the scope of this chapter.
patient, encourages mobilization and reconditioning, is consistent Parenteral Nutrition PN delivers a complete nutritional regimen
with the objectives of patient-centered medicine, and is risk free. Its directly into the bloodstream in the form of crystalline amino acids,
disadvantage is that it is time-consuming and labor-intensive, and dextrose, triglyceride emulsions, minerals (calcium, phosphate, mag-
demands interest in and attention to the specific needs of individual nesium, and zinc), electrolytes, and micronutrients. Because of its high
patients. osmolarity (>1200 mOsm/L) and often large volume, PN is infused
Enteral Nutrition This is nutrition provided through a feeding into a central vein in adults. Ready-to-use PN admixtures typically
tube placed through the nose into the stomach or beyond it into the containing 4–7% hydrous amino acids and 20–25% dextrose (with
duodenum, via a mini-surgical procedure in which a feeding tube is or without electrolytes) are available in 2-chamber (amino acids and
inserted through the abdominal wall into the stomach or beyond it dextrose) or 3-chamber (amino acids, dextrose, and lipid) bags that are
into the jejunum using an endoscope, or by an open surgical approach intermixed and vitamins, trace minerals and additional electrolytes
to access the stomach or small intestine. EN is the treatment of choice added just prior to infusion. Although convenient and cost-effective,
when optimized voluntary nutritional support is impossible or has these products have fixed nutrient composition and thus are dosed
failed. It is relatively simple, safe, inexpensive, and maintains the according to the volume required to meet calorie requirements. In some
digestive, absorptive, and immunologic barrier functions of the gastro- situations—especially ADM—a costlier approach is justified that uses
intestinal tract. EN allows the delivery of accurately known amounts of a computer-controlled sterile compounder to generate combinations
nutrients. Pliable, small-bore feeding tubes make placement relatively of amino acid and dextrose that meet the precise protein and energy
easy and acceptable to most patients. Constant-rate infusion pumps requirements of individual patients.
increase the reliability of nutrient delivery. Patients are candidates for For example, 1 L of a standard ready-to-use admixture of 5% amino
EN when optimized voluntary nutrition is not feasible or has failed, acids and 25% dextrose provides 50 g of amino acids (equivalent to
and their GI tract is adequately functional and can be accessed. 41.5 g protein substrate) and 1000 kcal; the use of this solution to meet
the 1.5–2.0-g/kg protein requirement of an acutely ill 70-kg patient
EN Products The commonest forms of EN used are commercially

requires the infusion of 2.5–3.4 L of fluid and a potentially excessive
manufactured formulas with defined compositions. amount of energy (2500–3300 kcal). When the patient has an adequate
STANDARD POLYMERIC FORMULAS These are the most widely used fat store, clinical evidence increasingly supports the safety and efficacy
sources of EN. They are available in a wide variety of formats that gen- of high-protein, moderately hypocaloric nutrition in ADM. A sterile
erally meet the nutritional requirements of a normal, healthy person. compounder can accurately generate an appropriate recipe for such
Carbohydrates provide most of the energy. The proteins (from casein, a patient. For example, 1 L of an admixture of 600 mL of 15% amino
whey, or soy) are intact and require normal pancreatic enzyme function acids, 300 mL of 70% dextrose, and 100 mL of electrolyte/micronutrient
for digestion and absorption. These products are isotonic or nearly so, mix contains 90 g amino acids (equivalent to 75 g of protein substrate)
and provide from 1000 to 2000 kcal and 50–70 g protein/L. and 1020 kcal. (1 g mixed hydrated amino acids provides 3.3 kcal; 1 g
dextrose provides 3.4 kcal; 1 g lipid emulsion provides ~10 kcal.) When
POLYMERIC FORMULAS WITH FIBER The addition of dietary fiber to a compounder is used, this patient’s increased protein requirement can
formulas sometimes improves bowel function and feeding tolerance. be met with less volume and avoid excessive calorie provision.
Fermentable (soluble) fibers such as pectin and guar are metabolized
by colonic bacteria, yielding short-chain fatty acids that fuel colono- Amino Acids Protein synthesis requires 21 alpha-amino acids,
cytes. Nonfermentable (insoluble) fibers increase fecal bulk, improve 9 of which are essential and 11 are non-essential because they are
peristalsis, and may improve diarrhea. readily synthesized from an essential amino acid (methionine or phe-
nylalanine) or from widely available carbohydrate precursors and the
ELEMENTAL AND SEMI-ELEMENTAL FORMULAS The macronutrients in
amine groups provided by the body’s large and rapidly interconverting
these formulas are partially or completely hydrolyzed. They are pri- pool of non-essential amino acids. One amino acid—arginine—is con-
marily designed for patients with known maldigestion and malabsorp- ditionally essential. PN amino acid admixtures vary somewhat but all
tion, but they are sometimes used empirically for patients who have of them provide appropriate amounts of the essential amino acids and
had prolonged bowel rest or are critically ill without strong evidence arginine while compensating for their lack of glutamine (and some-
of their superiority, or when a patient is intolerant of a standard poly- times glutamate or aspartate) by including large amounts of glycine
meric formula. or other non-essential amino acids. The specific contribution of each
IMMUNE-ENHANCING FORMULAS In addition to providing macronu- non-essential amino acid to a nutritional admixture is less important
trients and conventional amounts of micronutrients, these products than the total amount of non-essential N it provides. The hydrated
(IEFs) contain large amounts of certain nutrients designed to favorably status of the free amino acids in PN reduces their calorie density from
modulate the immune response: arginine and n-3 fatty acids especially, 4.0 to 3.3 kcal/g, and reduces the amount of protein substrate they
but also various combinations of glutamine, nucleotides, and antioxi- provide by 17%. For example, 100 g of free mixed amino acids provide
dants. It is difficult to evaluate the IEFs because there are many differ- 83 g protein substrate and 340 kcal.
ent formulations on the market, and considerable heterogeneity in the Carbohydrate and Lipids The carbohydrate in PN is dextrose
patient populations studied. Good evidence of benefit has emerged monohydrate (3.4 kcal/g). Lipid emulsions provide calories and the
from clinical trials of perioperative IEFs in patients undergoing elective essential n-6 and n-3 fatty acids. Traditional lipid emulsions are based
gastrointestinal surgery and patients with traumatic brain injury. EIFs solely on soy bean oil, but they are giving way to mixed emulsions that
have not yet demonstrated benefit in other kinds of critical illness. include medium-chain triglycerides, n-9 monounsaturated fatty acids,
PROTEIN-ENRICHED FORMULAS Most EN formulas provide calories and n-3 fatty acids. Emulsions of pure soybean oil, a mixture of 80%
and protein in a ratio appropriate for a healthy person, whereas olive oil and 20% soybean oil, and a mixture of 30% soybean oil, 30%
protein-enriched formulas provide ~90 g protein and 1000 kcal/L. medium chain triglycerides, 25% olive oil and 15% fish oil are avail-
Originally marketed to meet increased protein requirement associ- able. The more complex lipid emulsions are more highly enriched in
ated with hypocaloric nutrition in obese patients, these products are n-3 fatty acids and fewer n-6 polyunsaturated fatty acids than soybean

2328 lipid, which is more prone to lipid peroxidation and could promote the
formation of the pro-inflammatory n-6 derivatives. As a general rule, Intestinal ischemia, mechanical obstruction, peritonitis, and gas-
lipid infusion rates should not exceed 8 g/h (for a 70 kg patient) or trointestinal hemorrhage are contraindications to EN. Severe coagul-
175 g (1925 kcal)/day. opathy, esophageal varices, absent gag reflex, hypotension, adynamic
ileus, pancreatitis, diarrhea, and nausea and vomiting are not absolute
Minerals, Micronutrients, and Trace Elements The contraindications, but they increase the risk of complications and
default concentrations of electrolytes, minerals, and micronutrients in make it less likely that EN will succeed in achieving its nutritional
PN solutions are designed to meet normal requirements, and adjusted goal.
to meet the frequently abnormal and often-changing requirements of
Initiation, Progression, and Monitoring Feeding tube insertion
individual patients. Because they are unstable, multivitamin mixtures
and EN delivery are medical procedures that require voluntary
are injected into PN bags just prior to their delivery to the floor. Parent-
informed consent. Nasogastric tube feeding may proceed when
eral water-soluble vitamin requirements are greater than standard oral
gastrointestinal function is adequate with regard to gastric con-
requirements because hospitalized patients often have vitamin defi-
tractility (e.g., nasogastric tube output <1200 mL/d), intestinal
ciencies or increased requirements, and because intravenous adminis-
contractility (absence of a known or suspected intraabdominal
tration of vitamins increases urinary losses. Vitamin C spontaneously
pathologic process, non-distended abdomen and detectable bowel
degrades in PN solutions even when light-protected. The amount of
sounds, although the absence of bowel sounds is not, in itself, a
vitamin D in currently used intravenous vitamin products is inade-
contraindication), and adequate colonic function (passage of stools
quate. Iron salts are incompatible with most PN solutions.
and flatus). After consent has been obtained and the appropriate
feeding tube (usually a nasogastric tube for short-term feeding) has
APPROACH TO THE PATIENT been placed and its position verified, the head of the patient’s bed
is raised to at least 30° and kept raised to reduce the risk of regurgi-
Indications, Selection, and Provision of Specialized tation. A standard polymeric formula is infused, usually at a starting
Nutritional Support rate of 50 mL/h and advanced by 25 mL/h every 4–8 h until the
goal rate is met. Elemental formulas commence at a slower rate and
SNS is complicated, and the quantity and quality of the formal clini- progress more slowly. Intragastric feeding allows a higher formula
cal evidence supporting its different uses is limited. Yet malnutrition- osmolarity. Intragastric bolus feeding is an option (200–400 mL
caused diseases are highly prevalent; they worsen clinical outcomes; feeding solution infused over 15–60 min at regular intervals with
and they are preventable and treatable. Physicians are charged with verification of residual gastric contents every 4 h). Bolus feeding is
preventing, diagnosing, and treating these diseases, and they carry not possible with jejunal feeding, which requires the patient to be
out their duty properly when guided by a sound understanding of
PART 10
monitored for abdominal pain and abdominal distention and bowel

nutritional principles, astute observation, rigorous clinical reasoning, sounds every 4 h.
and collaboration with dietitians and specialized clinical pharmacists.
Most hospitalized patients should not require SNS. Many of them Complications and Their Management The most common compli-
will improve with appropriate management of their primary disease. cations of EN are aspiration of regurgitated or vomited formula,
Others have a terminal disease whose downward course will not be diarrhea, fluid volume and electrolyte derangements, hyperglyce-
halted by SNS. Patients who can’t eat enough hospital food and who mia, nausea, abdominal pain, constipation, and failure to achieve
have, or are at high risk of SM or CDM, are candidates for optimized the nutritional goal.
voluntary nutrition support. When this approach is inappropriate Aspiration Debilitated patients with delayed gastric emptying,
or has failed, the pros and cons of invasive SNS are considered. The impaired gag reflex, and ineffective cough are at high risk of aspi-
decision to provide or withhold EN or PN is based on a synthesis of ration pneumonia. Aspiration is particularly common in mechani-
four factors: (1) the determination that nutrient ingestion will likely cally ventilated patients. Ventilator-associated pneumonia is mostly
continue to be inadequate for many days; (2) the patient has impor- caused by aspiration of microbial pathogens in the mouth and throat
tant muscle atrophy (of any cause) or fat depletion; (3) the patient’s past the cuffs of endotracheal or tracheostomy tubes, but tracheal
nutrient requirements are increased (as from inflammatory diarrhea, suctioning induces coughing and gastric regurgitation. Measures
enterocutaneous fistulas or exudates, or a pronounced inflammatory to prevent ventilator-associated pneumonia include elevation of
protein-catabolic state); and (4) the reasoned judgment that SNS has the head of the bed, mouth hygiene and gastrointestinal decontam-
a reasonable prospect of improving the patient’s clinical outcome or ination, nurse-directed algorithms for formula advancement and,
quality of life. When the patient already has PEM (and treating it is sometimes, post–pyloric feeding. EN does not have to be held for
likely to improve their well-being and clinical outcome), the decision gastric residual volumes less than 300 to 400 mL in the absence of
tips more steeply in favor of intervention. It is important to formally other signs of gastrointestinal intolerance (nausea, vomiting, severe
diagnose and document PEM and its variants. Formal diagnosis abdominal pain, abdominal distention). Continuous EN is often
focuses attention on the urgency of the situation and guides the tolerated better than bolus feeding, and it is the only option with
selection, composition, and urgency of nutritional therapy. jejunal feeding.
EN THERAPY Diarrhea Diarrhea is common when bowel function is compro-
EN is indicated when patients cannot eat enough food and unlikely mised by disease or drugs (most often, broad-spectrum antibiotics).
to do so for a long time, their gastrointestinal tract is functional and Once infectious and inflammatory causes have been ruled out,
accessible, and optimized voluntary nutrition is impossible or inad- EN-associated diarrhea may be controlled by the use of a fiber-
equate to meet the patient’s nutritional needs. EN is most commonly containing formula or the addition of an antidiarrheal agent to it. H2
used in settings of impaired consciousness, severe dysphagia, severe blockers or proton pump inhibitors may help reduce the net volume
upper gastrointestinal tract dysfunction or obstruction, the require- of fluid presented to the colon. Diarrhea does not usually impair
ment for mechanical ventilation, and critical illness in general. As macronutrient absorption, since amino acids, lipids, and glucose are
well, situations frequently arise in which a patient’s voluntary food mostly absorbed in the proximal-to-middle small intestine. Since
intake is seriously curtailed by combinations of anorexia, nausea, luminal nutrients have trophic effects on the intestinal mucosa, it
vomiting, pain, delirium, depression, distress, chewing difficulties, is often appropriate to persist with tube feeding despite moderate,
undiagnosed thrush, unappealing food, and physical and sensory tolerable diarrhea, even it necessitates supplemental parenteral
disability (including dysgeusia). In these complicated, difficult, and fluid support. Except for patients with markedly impaired small-
evolving situations, the diagnosis of SM or CDM should tip the intestinal absorptive function, there are no well-established indi-
decision towards EN. cations for elemental formulas, but they may be used empirically

2329
when diarrhea persists despite the use of fiber-enriched formulas and maintaining a central venous catheter (traumatic injury from
and antidiarrheal agents. the insertion, serious infection, and venous thrombosis), allergy
Gastrointestinal Intolerance Abnormally high gastric residual vol- to some of its components, glucose, electrolyte, magnesium, phos-
umes, abdominal distention, pain, and nausea are distressing for phate, and acid-base balance abnormalities, the adverse effects of the
patients, increase the nursing workload, and delay the progression of large intravenous fluid volumes. Prolonged PN—especially when it
EN. These problems can be avoided or minimized by ensuring normal delivers excess calories—can lead to hepatic dysfunction.
fluid and electrolyte balance, preventing severe hyperglycemia, and, INITIATION, PROGRESSION, MONITORING,
when a patient experiences nausea, vomiting or abdominal distention, AND DISCONTINUATION
by the judicious use of antiemetic and prokinetic drugs (and some- PN may commence after the patient has been hemodynamically
times proton pump inhibitors) on a regular—rather than as needed— resuscitated, glucose, electrolyte, and acid-base homeostasis are
basis. Patients with gastroparesis require post-pyloric feeding. established, and the patient is able to tolerate the fluid volumes
Fluid Volume, Electrolyte, and Blood Glucose Abnormalities The involved. In adults, the high osmolarity of PN solutions, fluid
essential purpose of EN is to provide macronutrients at an appro- demands, and need for strict sterility require their infusion through
priate rate. EN formulas provide standard amounts of fluid, a dedicated port in a central venous catheter. Peripherally inserted
electrolytes, minerals, and micronutrients. They are not designed central catheters (PICCs) are increasingly favored, although they
to manage abnormal fluid volume, electrolyte, and mineral require- limit monitoring for catheter infection by wire exchange. Jugular or
ments, which vary considerably among different patients and can femoral vein catheters are discouraged because it is very difficult
change rapidly. Altered fluid volume requirements can, to a certain to maintain a dry, sterile dressing over the insertion site. The initial
extent, be accommodated by selecting EN formulas with appropri- dose of dextrose should not exceed 200 g/day to avoid hypergly-
ate osmolarities, but medically active patients have widely vary- cemia (or, in susceptible patients, the refeeding syndrome). On the
ing and rapidly changing requirements for fluid, electrolyte, and other hand, the full requirement dose of amino acids can be admin-
glucose control. Blood glucose status must be monitored regularly istered from the first day onwards (this option is unavailable when
and measures—including intravenous fluid, electrolyte, and insulin premixed PN solutions are used). The glucose dose increases on
therapy—taken to maintain homeostasis. a daily basis until it approaches the patient’s energy requirement.
Failure to Reach the Nutritional Goal EN is frequently delayed or Lipid emulsions are added after the first week.
interrupted in medically active patients. The reasons are many: Capillary blood glucose is monitored several times daily and
diagnostic tests and procedures (including dialysis), physical or subcutaneous regular insulin is added to the PN admixture as

occupational therapy, a clogged or pulled out tube, and intolerance required to maintain average serum glucose concentrations
to EN. When the flow rate is low, formula at the tip of the feeding <140 mg/dL and >80 mg/dL. The dose of regular insulin required
tube may be precipitated by gastric acid and cause an occlusion. to do this on a given day can be added to the following day’s
Inadequate tube flushing, dense formulas, and the introduction PN solution. The insulin dose increases roughly proportionately
of inadequately homogenized solid medications also cause tube to the increasing glucose dose. Certain benchmarks are useful.
clogging. The end result is prolonged delay in the progression of Basal endogenous insulin secretion is ~30 units/day in normal
EN and failure to meet the patient’s nutrient requirements. Brief people. When insulin is required for non-diabetic, non-catabolic
periods of inadequate calorie provision are usually inconsequential patients, 10 units of regular insulin will roughly cover 100 g infused
in patients who have adequate fat reserves, but deficient provision dextrose. Patients with non-insulin dependent diabetes require
of protein is a serious but, unfortunately, under-investigated prob- ~20 units/100 g dextrose. Non-catabolic patients with insulin-
lem. The protein-to-calorie ratio of most EN formulas is appropriate dependent diabetes usually require approximately twice the
for healthy people and hence too low for patients whose protein at-home insulin dose, because parenteral glucose is a more potent
requirement is increased. High-protein formulas are appropriate insulin secretagogue than oral carbohydrate and because some insu-
when EN is progressing too slowly or the patient has an increased lin adheres to the infusion bag. As a general rule (for a patient with
protein requirement, existing PEM, or is obese and will directly dry body weight 70 kg) the glucose infusion rate should not exceed
benefit from hypocaloric nutrition. ~500 g (1700 kcal)/day in non-critically ill patients, and should not
exceed ~350 g (1200 kcal)/day in critically ill patients. Even lower
EN in the Intensive Care Unit Most critically ill patients cannot glucose infusion rates (e.g., 200 g/day) are advisable if they prevent
eat anything—they depend entirely on SNS. EN has two pur- or minimize hyperglycemia in insulin-resistant patients.
poses in the intensive care unit. The first purpose is to meet the In general, the benefits of constraining glucose, lipid, and fluid
patient’s macronutrient requirements—especially their often dra- volume provision in ADM justify hypocaloric nutrition for the first
matically increased protein requirement. The second purpose is to 2 weeks of SNS as long as the calorie deficit is counterbalanced by
infuse nutrients into the intestines at a rate that sustains normal generous amino acid provision. Lipids are commonly introduced
intestinal barrier and immunological functions in the face of a after the first week of PN and can make up calorie shortfalls. Serum
systemic inflammatory response that threatens intestinal integrity triglyceride concentrations are measured before commencing lipid
and immune function. Current guidelines recommend that EN infusions in order to detect preexisting hypertriglyceridemia (usually
commence as soon as possible after a critically ill patient has been defined as >400 mg/dL), which is a relative contraindication. They
fluid resuscitated and stabilized. The initial rate is 10–20 kcal/h. may be infused daily or 2–3 times weekly. As appreciation or the
This rate of EN delivery provides ~25 g protein and ~500 kcal/d to adverse effects of excessive glucose administration has increased,
patients who may require >100 g protein and >1800 kcal/d. Once interest has grown in the use of lipid emulsions as an energy source.
EN is underway, the rate of delivery is increased as tolerated toward Lipid infusion rates should not usually exceed ~50 g (500 kcal)/day
the patient’s nutritional goal. Too often, however, EN falls far short in critical illness.
of the protein provision target, even after a week or longer in the
Biochemical Monitoring Serum biochemistry (urea, creatinine, elec-
intensive care unit. Newer, high-protein EN products may reduce
trolytes, glucose, magnesium, phosphate, calcium, and albumin)
the severity of this protein shortfall.
are measured prior to starting PN and followed daily for the first
PN THERAPY few days, then twice weekly or as required. Serum triglycerides
PN is costlier, more resource-intensive, potentially riskier, and and liver function tests (and often ferritin) are measured at baseline
requires more expertise than EN. It is used when invasive SNS is and again after PN is underway to confirm that the lipid infusions
indicated and EN is impossible, inappropriate, or unable to meet are well tolerated. N balance (calculated from 24-h urinary urea
the patient’s nutritional needs. The risks of PN are those of inserting N excretion) is useful at the outset for evaluating the severity

2330
of protein catabolism in patients with CDM or ADM to identify antinatriuretic and antidiuretic hormone, insulin potentiates sodium
patients who require more generous amino acid provision, and dur- and water retention. In this setting net fluid retention is likely when
ing PN to determine whether the patient’s N balance is improving total fluid provision exceeds 2 L/day in patients not experiencing
with therapy. Serum ferritin should be measured every 2 months, large gastrointestinal losses. The problem of volume overload can
although the duration of most in-hospital PN is shorter than this. be reduced by preparing PN solutions with a compounder, infusing
Discontinuation PN is tapered and discontinued as soon as the glucose at a rate that minimizes the need for exogenous insulin
patient can be adequately nourished by the enteral route. The dose therapy, and avoiding overfeeding in general. Sodium intake plays
of PN is reduced as food intake increases. As a general rule, once a an important role in fluid retention. Net fluid retention can be
patient is tolerating one-half to two-thirds of their food requirement minimized by limiting sodium delivery to 20–30 mmol/day (with
by the enteral route and there is no mechanical or other barrier an adjustment for gastric or intestinal sodium losses) since, when
to further improvements in intake, PN can be discontinued. The renal function is normal and antidiuretic hormone secretion is not
transition to oral nutrition is slow for many patients with CDM. increased, urinary sodium concentrations are usually <10 mmol/L.
Optimized voluntary nutrition is much preferred to invasive EN Hypertriglyceridemia This complication occurs when the rate of
for these patients because it is safe, effective, fosters well-being, lipid infusion exceeds plasma triglyceride clearance capacity. Renal
and prepares them for discharge. It is tempting to stop PN as a failure, sepsis, excessive glucose (which stimulates lipogenesis),
way to stimulate more food consumption; the temptation should diabetes mellitus, high-dose glucocorticoid therapy, and mul-
be resisted. PN does not create anorexia, nor does discontinuing tiple-organ failure reduce triglyceride clearance. An impaired
it stimulate appetite. Too-early discontinuation of PN may delay immune response, increased risk of acute pancreatitis, and altered
a patient’s progression to full voluntary food consumption by pulmonary hemodynamics are potential but not well documented
inducing anxiety and recreating starvation conditions. PN is most complications of PN-induced severe hypertriglyceridemia.
successfully weaned by encouraging physical activity, optimizing Hepatic Dsyfunction Mild elevations of serum liver enzyme con-
voluntary nutrition (including food from home), emotional sup- centrations can occur within 2–4 weeks of initiating PN, but in most
port, and having patience. On the other hand, patients who are at cases they return to normal even when PN is continued. Clinically
the cusp of adequate oral nutrition commonly benefit from hospital important hepatic dysfunction, although common in children, is
discharge, where the security and pleasure of being at home and uncommon in adults as long as energy overfeeding and resultant
eating home-made food are potent stimuli. fatty liver are avoided. Intrahepatic cholestasis occasionally occurs
Drawbacks, Side Effects, and Complications • Complications after many weeks of continuous PN and is most often multifactorial
of Central Catheters Patients receiving PN are at greater risk in origin. Cyclic PN—in which PN is infused for only 12 h/day—
PART 10
of bloodstream infections than other patients with central venous may prevent or reduce the severity of this complication.
catheters. Proper aseptic insertion technique, meticulous dress- PN IN THE INTENSIVE CARE UNIT
ing care, and one port dedicated solely to PN reduce this risk.
Current guidelines recommend starting EN as soon as a critically ill
Catheter-induced upper arm venous thrombosis is an uncommon
patient has been resuscitated, stabilized, and enteral access estab-
but important complication.
lished. EN is then advanced over the following days to toward the

Hyperglycemia The most frequent metabolic complication of PN patient’s nutritional goal. If the goal has not been achieved after
is hyperglycemia in patients with insulin resistance due to non- 7–10 days, amino acid-rich PN is recommended, especially when the
insulin dependent diabetes mellitus, high-dose glucocorticoid ther- patient remains protein catabolic. PN that is generous in amino acids
apy, or severe systemic inflammation; the problem is exacerbated by (85–140 g protein substrate/day for a 70 kg patient) and hypocaloric
excessively high rates of glucose provision. Glucose concentrations (1200–1400 kcal/day) limits the risk and severity of hyperglycemia
are most easily kept at <140 mg/dL with the least risk of hypogly- and volume overload and may improve clinical outcomes in this set-
cemia by infusing hypocaloric amounts of glucose and, if necessary, ting. Soy-based lipid emulsions should be avoided during the first
meeting the patient’s energy requirement with intravenous lipid. week of PN in the intensive care unit; alternative lipid emulsions
In ADM, the benefits of using the lowest insulin dose—minimal may prove to be safe and beneficial.
hyperinsulinemia and a reduced risk of hypoglycemia—almost
always outweigh the doubtful goal of rapidly matching calorie SPECIAL CLINICAL CONDITIONS
provision to the patient’s energy expenditure rate. Old Age In addition to their other physiological frailties, elderly
Hypoglycemia Reactive hypoglycemia is uncommon but may people commonly suffer from age-related muscle atrophy that is
occur when high-dextrose, non-insulin containing PN is abruptly compounded by disuse muscle atrophy. These factors place them at
discontinued. It is prevented by slowing the PN infusion rate to high risk of PEM and make them plausible candidates for early SNS.
50 mL/h for 1 or 2 h prior to discontinuing it (or replacing it with Inactivity Physical activity and adequate nutrition are closely
10% dextrose), or, when the oral route is available, providing a interdependent. Reduced physical activity reduces appetite, and
snack. More often, hypoglycemia occurs when the intensity of the physical rehabilitation and its associated emotional benefits restore
patient’s metabolic stress (or their glucocorticoid dose) decreases optimism and appetite. Full nutrient provision will maintain or
without an appropriate downward adjustment of the insulin dose. normalize many physiological functions in bedridden patients, but
This problem is avoided by frequent capillary glucose determina- they will not increase muscle mass.
tions and careful attention to medication doses and the patient’s Renal Failure Protein provision should not be reduced in the pres-
general condition. ence of renal injury unless renal replacement therapy is unavail-
Artefactual Hyperglycemia and Hyperkalemia Blood samples must able. Protein and vitamin C provision should increase when renal
be carefully and appropriately drawn from dual-port PICC. Inter- replacement therapy is used, for it removes large amounts of amino
mixing of the sample with even a tiny volume of PN solution will acids and vitamin C from the circulation.
falsely indicate hyperglycemia and hyperkalemia, and may trigger a Liver Failure Patients with severe hepatic disease are plausible
treatment error. The problem is identified when the patient’s appar- candidates for SNS because they are relatively intolerant of starva-
ent serum glucose (and potassium) concentrations abruptly increase tion and commonly already have CDM when they are admitted to
without reason and the apparently very high glucose concentration hospital. SNS should be generous in calories and especially protein,
is out of keeping with concurrent capillary glucose readings. which should be provided despite an increased risk of hepatic
Volume Overload Hypertonic intravenous dextrose stimulates a encephalopathy. The risk of encephalopathy can be mitigated by
much more intense insulin response than oral glucose. A potent meticulous attention to fluid balance and electrolyte status and by

2331
spreading protein provision over the day to accommodate the liv- therapy because the side effects and complications of invasive SNS
er’s reduced capacity to clear amino acid-derived ammonia. are not counterbalanced by an improved disease trajectory. In some
Perioperative SNS Patients awaiting elective major surgery benefit cases, a disease may be inexorably progressing but so slowly that the
from 7 to 10 days of preoperative SNS if SM (or especially CDM) patient will die of starvation long before they would from the cancer.
is present. When feasible and properly implemented, optimized EN or PN is usually appropriate in these cases.
voluntary nutrition is greatly preferred, but when a patient has been Advanced Dementia Optimized voluntary nutrition is the key
admitted to hospital their condition is by definition semi-urgent, approach in this situation, and it can be used to deal with problems
and EN or PN will meet the patient’s nutritional goal more quickly. such as disability and dysphagia in patients who show discernable
Preoperative SNS improves immunity and reduces postoperative pleasure from eating. There is no evidence that EN or PN improve
complications, but it will not increase serum albumin concentrations quality or length of life in patients who have advanced dementia
and it should not be provided for >7–10 days with that goal in mind. and show little or no interest in eating food, and their side effects
More prolonged preoperative EN or PN may confer slight addi- and complications are unpleasant and sometimes dangerous.
tional nutritional benefits, but they are counterbalanced by its risks
REFEEDING SYNDROME
and the consequences of prolonged hospitalization and delayed
surgery. Surgery should not be delayed for starving patients whose The refeeding syndrome can occur in starving patients during the
muscle mass is normal or only mildly depleted and who are not first week of nutritional repletion if carbohydrates are introduced too
experiencing systemic inflammation, since they tolerate even major rapidly. Carbohydrate provision stimulates insulin secretion, which,
uncomplicated surgery well without preoperative SNS. The urgency owing to its antinatriuretic effect, expands the ECF volume when
of surgery often precludes otherwise indicated preoperative SNS. excessive sodium is provided. Refeeding edema can be minimized
Early postoperative PN is usually indicated for these patients, for by severely limiting sodium provision and increasing carbohydrate
they are at increased risk of postoperative complications and are provision slowly. Carbohydrate refeeding may stimulate enough
highly unlikely to consume an adequate amount of food voluntarily intracellular glucose-6-phosphate and glycogen synthesis to seri-
over the next many days. Patients with only mild muscle atrophy, ously lower serum phosphate concentrations. Refeeding increases
no systemic inflammation, and no postoperative complications do the adaptively down-regulated REE of patients with SM and stimu-
not require postoperative PN unless (1) adequate feeding by mouth lates N retention, new cell synthesis, and cellular rehydration. Phos-
has not been achieved by day 5–7 after surgery or (2) there are phate, potassium, magnesium, and zinc are common and dangerous
indications that voluntary feeding will be further delayed. Warning during refeeding. Their status must be monitored and appropriate
supplements provided. Acute thiamine deficiency is a devastating

indicators include inadequately controlled nausea or pain, impaired
gastric, small intestinal or colonic function, serum electrolyte imbal- but preventable complication of refeeding, even with simple dex-
ance, altered mental status, inability to mobilize from the bed, or a trose infusions. Left heart failure may occur in predisposed patients.
suspected surgical-site infection or anastomotic leak. Perioperative The precipitants of left heart failure are an abrupt increase of intra-
immune-enhancing EN appears to reduce morbidity in patients vascular volume due to the administration of fluids and of glucose,
undergoing major elective gastrointestinal surgery. which stimulates insulin secretion with associated renal sodium
retention; increased cardiac demand because of increased REE in a
Iron and PN Iron deficiency is common in acutely ill hospitalized patient with an atrophic left ventricle and low stroke volume; and
patients. Risk factors for in-hospital iron deficiency include inad- myocardial deficiencies of potassium, phosphorus, or magnesium.
equate nutritional intake, gastrointestinal disease, and frequent Cardiac arrhythmias may occur. Refeeding may precipitate acute
blood withdrawals. In-hospital iron deficiency is often missed wet beriberi in malnourished, poverty-stricken populations.
because inflammation-associated anemia is much commoner and
increases serum concentrations of ferritin, a positive acute-phase
protein. The parenteral iron requirement is normally only ~1 mg/day, ■■GLOBAL CONSIDERATIONS
but since iron is a highly reactive catalyst of oxidative reactions it is The macro-nutritional diseases are the same worldwide, but
not included in PN mixtures. Serum ferritin concentrations should their prevalence varies in accordance with regional variations
usually be measured when PN commences and re-measured at in the prevalence of the primary medical and surgical diseases
~8 week intervals. A falling mean red cell volume (even within that induce them and the two most important causes of starvation:
the low-normal range) or an intermediate serum ferritin concen- poverty and social iniquity. Longstanding borderline SM is so preva-
tration in the presence of systemic inflammation strongly suggest lent in some parts of the world that the World Health Organization has
iron deficiency. Intravenous iron should be ordered according to coined the term chronic energy deficiency (CED) to describe it. CED is
standard guidelines. A termination order should also be written classified into three grades of severity: Grade I: BMI 17.0–18.4, Grade II:
to avoid the risk of inadvertent iron overdosing. Iron replacement BMI 16.0–16.9, and Grade III: BMI <16. In otherwise healthy adults,
should be avoided during the acute phase of critical illness because CED of Grades II and III are associated with an increasing probability
a substantial rise in the serum iron concentration could increase of days of illness, reduced work capacity, poorer reproductive function,
susceptibility to some bacterial infections, but it is indicated in SM and poorer lactation performance. Voluntary physical activity is
and CDM both to improve iron-deficiency anemia and provide the decreased in Grade III CED, which is equivalent to the diagnosis of SM.
non-hematologic benefits of adequate iron nutrition.
Zinc It is insufficiently appreciated that 1 L of secretory diarrhea ■■FURTHER READING
contains ~12 mg of zinc. Patients with intestinal fistulas or high vol- Derenski K et al: Parenteral nutrition basics for the clinician caring for
ume chronic diarrhea require this amount of zinc in addition to their the Adult Patient. Nutr Clin Pract 31:578, 2016.
daily requirement of 15 mg to avoid zinc deficiency. Zinc may be Esuro AA, Hummell AC: Enteral formulas in nutrition support prac-
provided parenterally or enterally (because of its low bioavailabil- tice: Is there a better choice for your patient? Nutr Clin Pract 31:709,
ity, 12 mg parenteral zinc is equivalent to 30 mg oral elemental zinc). 2016.
Lembeck ME et al: The role of intravenous fluids and enteral or paren-
Cancer SNS plays a crucial role in cancer therapy. Many cancers teral nutrition in patients with life-limiting illness. Med Clin North
(especially those that involve the gastrointestinal tract or induce sys- Am 100:1131, 2016.
temic inflammation) and most cancer therapies create the conditions McClave SA et al: Guidelines for the provision and assessment of
for starvation and commonly lead to SM or CDM. The prevention or nutrition support therapy in the adult critically ill patient: Society of
treatment of these diseases may improve patients’ quality of life and Critical Care Medicine (SCCM) and American Society for Paren-
tolerance to anti-cancer therapy. As a general rule, EN and PN are teral and Enteral Nutrition (ASPEN). J Parenter Enteral Nutr 40:
not prescribed to patients who are not undergoing active anti-cancer 159, 2016.

2332 White JV et al: Consensus statement: Academy of Nutrition and from zone 3 to zone 1. The sinusoids are lined by unique endothelial
Dietetics and American Society for Parenteral and Enteral Nutrition: cells that have prominent fenestrae of variable sizes, allowing the free
Characteristics recommended for the identification and documenta- flow of plasma but not of cellular elements. The plasma is thus in direct
tion of adult malnutrition (undernutrition). J Parenter Enteral Nutr contact with hepatocytes in the subendothelial space of Disse.
36:275, 2012. Hepatocytes have distinct polarity. The basolateral side of the hepa-
tocyte lines the space of Disse and is richly lined with microvilli; it
exhibits endocytotic and pinocytotic activity, with passive and active
uptake of nutrients, proteins, and other molecules. The apical pole of
the hepatocyte forms the canalicular membranes through which bile
components are secreted. The canaliculi of hepatocytes form a fine
network, which fuses into the bile ductular elements near the portal
areas. Kupffer cells usually lie within the sinusoidal vascular space and
Section 3 Liver and Biliary Tract Disease represent the largest group of fixed macrophages in the body. The stel-
late cells are located in the space of Disse but are not usually prominent
unless activated, when they produce collagen and matrix. Red blood
329 Approach to the Patient

with Liver Disease
cells stay in the sinusoidal space as blood flows through the lobules,
but white blood cells can migrate through or around endothelial cells
into the space of Disse and from there to portal areas, where they can
return to the circulation through lymphatics.
Marc G. Ghany, Jay H. Hoofnagle Hepatocytes perform numerous and vital roles in maintaining
homeostasis and health. These functions include the synthesis of most
essential serum proteins (albumin, carrier proteins, coagulation factors,
A diagnosis of liver disease usually can be made accurately by careful many hormonal and growth factors), the production of bile and its
elicitation of the patient’s history, physical examination, and applica- carriers (bile acids, cholesterol, lecithin, phospholipids), the regulation
tion of a few laboratory tests. In some circumstances, radiologic exami- of nutrients (glucose, glycogen, lipids, cholesterol, amino acids), and
nations are helpful or, indeed, diagnostic. Liver biopsy is considered the metabolism and conjugation of lipophilic compounds (bilirubin,
the criterion standard in evaluation of liver disease, but is now needed anions, cations, drugs) for excretion in the bile or urine. Measurement
less for diagnosis than for grading (activity) and staging (fibrosis) of of these activities to assess liver function is complicated by the mul-
disease. Non-invasive means of assessing fibrosis stage have become tiplicity and variability of these functions. The most commonly used
PART 10
increasingly helpful and may allow for avoidance of biopsy in a pro- liver “function” tests are measurements of serum bilirubin, serum
portion of patients. This chapter provides an introduction to diagnosis albumin, and prothrombin time. The serum bilirubin level is a measure
and management of liver disease, briefly reviewing the structure and of hepatic conjugation and excretion; the serum albumin level and
function of the liver; the major clinical manifestations of liver disease; prothrombin time are measures of protein synthesis. Abnormalities of
and the use of clinical history, physical examination, laboratory tests, bilirubin, albumin, and prothrombin time are typical of hepatic dys-
imaging studies, and liver biopsy. function. Frank liver failure is incompatible with life, and the functions
of the liver are too complex and diverse to be subserved by a mechan-
LIVER STRUCTURE AND FUNCTION ical pump; a dialysis membrane; or a concoction of infused hormones,
The liver is the largest organ of the body, weighing 1–1.5 kg and rep- proteins, and growth factors.
resenting 1.5–2.5% of the lean body mass. The size and shape of the
liver vary and generally match the general body shape—long and lean LIVER DISEASES
or squat and square. This organ is located in the right upper quadrant While there are many causes of liver disease (Table 329-1), these dis-
of the abdomen under the right lower rib cage against the diaphragm orders generally present clinically in a few distinct patterns and are
and projects for a variable extent into the left upper quadrant. It is held usually classified as hepatocellular, cholestatic (obstructive), or mixed.
in place by ligamentous attachments to the diaphragm, peritoneum, In hepatocellular diseases (such as viral hepatitis and alcoholic liver
great vessels, and upper gastrointestinal organs. The liver receives a disease), features of liver injury, inflammation, and necrosis predomi-
dual blood supply; ~20% of the blood flow is oxygen-rich blood from nate. In cholestatic diseases, such as gallstone or malignant obstruction,
the hepatic artery, and 80% is nutrient-rich blood from the portal vein primary biliary cholangitis (previously referred to as primary biliary
arising from the stomach, intestines, pancreas, and spleen. cirrhosis), and some drug-induced liver diseases, features of inhibition
The majority of cells in the liver are hepatocytes, which constitute of bile flow predominate. In a mixed pattern, features of both hepato-
two-thirds of the organ’s mass. The remaining cell types are Kupffer cellular and cholestatic injury are present (such as in cholestatic forms
cells (members of the reticuloendothelial system), stellate (Ito or of viral hepatitis and many drug-induced liver diseases). The pattern
fat-storing) cells, endothelial and blood vessel cells, bile ductular of onset and prominence of symptoms can rapidly suggest a diagnosis,
cells, and cells of supporting structures. Viewed by light microscopy, particularly if major risk factors are considered, such as the age and sex
the liver appears to be organized in lobules, with portal areas at the of the patient and a history of exposure or risk behaviors.
periphery and central veins in the center of each lobule. However, Typical presenting symptoms of liver disease include jaundice,
from a functional point of view, the liver is organized into acini, with fatigue, itching, right-upper-quadrant pain, nausea, poor appetite,
both hepatic arterial and portal venous blood entering the acinus from abdominal distention, and intestinal bleeding. At present, however,
the portal areas (zone 1) and then flowing through the sinusoids to the many patients are diagnosed with liver disease who have no symp-
terminal hepatic veins (zone 3); the intervening hepatocytes constitute toms and who have been found to have abnormalities in biochemical
zone 2. The advantage of viewing the acinus as the physiologic unit of liver tests as a part of a routine physical examination or screening for
the liver is that this perspective helps to explain the morphologic pat- blood donation or for insurance or employment. The wide availability
terns and zonality of many vascular and biliary diseases not explained of batteries of liver tests makes it relatively simple to demonstrate the
by the lobular arrangement. presence of liver injury as well as to rule it out in someone in whom
Portal areas of the liver consist of small veins, arteries, bile ducts, and liver disease is suspected.
lymphatics organized in a loose stroma of supporting matrix and small Evaluation of patients with liver disease should be directed at (1)
amounts of collagen. Blood flowing into the portal areas is distributed establishing the etiologic diagnosis, (2) estimating disease severity
through the sinusoids, passing from zone 1 to zone 3 of the acinus and (grading), and (3) establishing the disease stage (staging). Diagnosis
draining into the terminal hepatic veins (“central veins”). Secreted bile should focus on the category of disease (hepatocellular, cholestatic, or
flows in the opposite direction—that is, in a counter-current pattern mixed injury) as well as on the specific etiologic diagnosis. Grading refers

TABLE 329-1 Liver Diseases Fatigue is the most common and most characteristic symptom of 2333
Inherited hyperbilirubinemia Liver involvement in systemic liver disease. It is variously described as lethargy, weakness, listless-
Gilbert syndrome diseases ness, malaise, increased need for sleep, lack of stamina, and poor
Sarcoidosis energy. The fatigue of liver disease typically arises after activity or
Crigler-Najjar syndrome, types I
and II Amyloidosis exercise and is rarely present or severe after adequate rest; that is, it is
“afternoon” rather than “morning” fatigue. Fatigue in liver disease is
Dubin-Johnson syndrome Glycogen storage diseases
often intermittent and variable in severity from hour to hour and day
Rotor syndrome Celiac disease
to day. In some patients, it may not be clear whether fatigue is due to
Viral hepatitis Tuberculosis the liver disease or due to other problems such as stress, anxiety, sleep
Hepatitis A Mycobacterium avium-intracellulare disturbance, or a concurrent illness.
Hepatitis B infection
Nausea occurs with more severe liver disease and may accompany
Hepatitis C Cholestatic syndromes fatigue or be provoked by smelling food odors or eating fatty foods.
Hepatitis D Benign postoperative cholestasis Vomiting can occur but is rarely persistent or prominent. Poor appetite
Hepatitis E Jaundice of sepsis with weight loss occurs frequently in acute liver disease, but is rare
Others (Epstein-Barr virus Total parenteral-nutrition–induced in chronic disease except when cirrhosis is present and advanced.
[mononucleosis] herpesvirus, jaundice Diarrhea is uncommon in liver disease except with severe jaundice, in
cytomegalovirus, adenovirus Cholestasis of pregnancy which a lack of bile acids reaching the intestine can lead to steatorrhea.
hepatitis) Cholangitis and cholecystitis Right-upper-quadrant discomfort or ache (“liver pain”) occurs in
Cryptogenic hepatitis Extrahepatic biliary obstruction many liver diseases and is usually marked by tenderness over the liver
Immune and autoimmune liver (stone, stricture, cancer) area. The pain arises from stretching or irritation of Glisson’s capsule,
diseases Biliary atresia which surrounds the liver and is rich in nerve endings. Severe pain is
Primary biliary cholangitis Caroli disease most typical of gallbladder disease, liver abscess, and severe sinusoidal
Autoimmune hepatitis Cryptosporidiosis obstruction syndrome (previously known as veno-occlusive disease)
Sclerosing cholangitis Drug-induced liver disease but is also an occasional accompaniment of acute hepatitis.
Overlap syndromes Hepatocellular patterns (isoniazid, Itching occurs with acute liver disease, appearing early in obstruc-
Graft-versus-host disease acetaminophen) tive jaundice (from biliary obstruction or drug-induced cholestasis) and
Allograft rejection Cholestatic patterns somewhat later in hepatocellular disease (acute hepatitis). Itching also
Genetic liver diseases (methyltestosterone) occurs in chronic liver diseases—typically the cholestatic forms such
CHAPTER 329 Approach to the Patient with Liver Disease

α1 antitrypsin deficiency Mixed patterns (sulfonamides, as primary biliary cholangitis and sclerosing cholangitis, in which it is
phenytoin) often the presenting symptom, preceding the onset of jaundice. How-
Hemochromatosis
Micro- and macrovesicular steatosis ever, itching can occur in any liver disease, particularly once cirrhosis
Wilson disease
(methotrexate, fialuridine) develops.
Benign recurrent intrahepatic Jaundice is the hallmark symptom of liver disease and perhaps the
Vascular injury
cholestasis
Sinusoidal obstruction syndrome most reliable marker of severity. Patients usually report darkening of
Progressive familial intrahepatic
Budd-Chiari syndrome the urine before they notice scleral icterus. Jaundice is rarely detectable
cholestasis, types I–III
Ischemic hepatitis with a bilirubin level <43 μmol/L (2.5 mg/dL). With severe cholestasis,
Others (galactosemia, tyrosinemia,
cystic fibrosis, Niemann-Pick-disease, Passive congestion
there will also be lightening of the color of the stools and steatorrhea.
Gaucher’s disease) Jaundice without dark urine usually indicates indirect (unconjugated)
Portal vein thrombosis
Alcoholic liver disease hyperbilirubinemia and is typical of hemolytic anemia and the genetic
Nodular regenerative hyperplasia
disorders of bilirubin conjugation, the common and benign form being
Acute fatty liver Mass lesions Gilbert syndrome and the rare and severe form being Crigler-Najjar
Acute alcoholic hepatitis Hepatocellular carcinoma syndrome. Gilbert syndrome affects up to 5% of the general popula-
Laënnec cirrhosis Cholangiocarcinoma tion; the jaundice in this condition is more noticeable after fasting and
Nonalcoholic fatty liver Adenoma with stress.
Steatosis Focal nodular hyperplasia Major risk factors for liver disease that should be sought in the clin-
Steatohepatitis Metastatic tumors ical history include details of alcohol use, medication use (including
Acute fatty liver of pregnancy Abscess herbal compounds, birth control pills, and over-the-counter medica-
Cysts tions), personal habits, sexual activity, travel, exposure to jaundiced or
Hemangioma other high-risk persons, injection drug use, recent surgery, remote or
recent transfusion of blood or blood products, occupation, accidental
exposure to blood or needlestick, and familial history of liver disease.
to assessment of the severity or activity of disease—active or inactive For assessing the risk of viral hepatitis, a careful history of sexual
as well as mild, moderate, or severe. Staging refers to estimation of the activity is of particular importance and should include the number
point in the course of the natural history of the disease, whether early of lifetime sexual partners and, for men, a history of having sex with
or late; or precirrhotic, cirrhotic, or end-stage. This chapter introduces men. Sexual exposure is a common mode of spread of hepatitis B but is
general, salient concepts in the evaluation of patients with liver disease uncommon for hepatitis C. A family history of hepatitis, liver disease,
that help lead to the diagnoses discussed in subsequent chapters. and liver cancer is also important. Maternal-infant transmission occurs
with both hepatitis B and C. Vertical spread of hepatitis B can now be
■■CLINICAL HISTORY prevented by passive and active immunization of the infant at birth,
The clinical history should focus on the symptoms of liver disease— although addition of antiviral therapy during the third trimester of
their nature, patterns of onset, and progression—and on potential risk pregnancy is now recommended for mothers with levels of HBV DNA
factors for liver disease. The manifestations of liver disease include >200,000 IU/mL. Vertical spread of hepatitis C is uncommon, but there
constitutional symptoms such as fatigue, weakness, nausea, poor appe- are no reliable means of prevention. Transmission is more common
tite, and malaise and the more liver-specific symptoms of jaundice, among HIV-co-infected mothers and is also linked to prolonged and
dark urine, light stools, itching, abdominal pain, and bloating. Symp- difficult labor and delivery, early rupture of membranes, internal fetal
toms can also suggest the presence of cirrhosis, end-stage liver disease, monitoring, and a high viral load. A history of injection drug use,
or complications of cirrhosis such as portal hypertension. Generally, even in the remote past, is of great importance in assessing the risk for
the constellation of symptoms and their patterns of onset rather than a hepatitis B and C. Injection drug use is now the single most common
specific symptom points to an etiology. risk factor for hepatitis C. Transfusion with blood or blood products

2334 is no longer an important risk factor for acute viral hepatitis. How- adulthood suggests hemochromatosis and should prompt investiga-
ever, blood transfusions received before the introduction of sensitive tion of iron status. Abnormal iron studies in adult patients warrant
enzyme immunoassays for antibody to hepatitis C virus in 1992 is an genotyping of the HFE gene for the C282Y and H63D mutations typical
important risk factor for chronic hepatitis C. Blood transfusion before of genetic hemochromatosis. In children and adolescents with iron
1986, when screening for antibody to hepatitis B core antigen was intro- overload, other non-HFE causes of hemochromatosis should be sought.
duced, is also a risk factor for hepatitis B. Travel to a developing area of A family history of emphysema should lead to investigation of α1 antit-
the world, exposure to persons with jaundice, and exposure to young rypsin levels and, if levels are low, for protease inhibitor (Pi) genotype.
children in day-care centers are risk factors for hepatitis A. Tattooing
and body piercing (for hepatitis B and C) and eating shellfish (for hep- ■■PHYSICAL EXAMINATION
atitis A) are frequently mentioned but are actually types of exposure The physical examination rarely uncovers evidence of liver dysfunc-
that quite rarely lead to the acquisition of hepatitis. tion in a patient without symptoms or laboratory findings, nor are
Hepatitis E is one of the more common causes of jaundice in most signs of liver disease specific to one diagnosis. Thus, the phys-
Asia and Africa but is uncommon in developed nations. In ical examination complements rather than replaces the need for other
endemic areas transmission is usually through exposure to diagnostic approaches. In many patients, the physical examination is
fecally contaminated water. Recently, non-travel-related (autochthonous) normal unless the disease is acute or severe and advanced. Neverthe-
cases of hepatitis E have been described in developed countries, includ- less, the physical examination is important in that it can yield the first
ing the United States. These cases appear to be due to strains of hepa- evidence of hepatic failure, portal hypertension, and liver decompen-
titis E virus that are endemic in swine and some wild animals sation. In addition, the physical examination can reveal signs—related
(genotypes 3 and 4). While occasional cases are associated with eating either to risk factors or to associated diseases or findings—that point
raw or undercooked pork or game (deer and wild boars), most cases of to a specific diagnosis.
hepatitis E occur without known exposure, predominantly in elderly Typical physical findings in liver disease are icterus, hepatomegaly,
men without typical risk factors for viral hepatitis. Hepatitis E infection hepatic tenderness, splenomegaly, spider angiomata, palmar erythema,
can become chronic in immunosuppressed individuals (such as trans- and skin excoriations. Signs of advanced disease include muscle wast-
plant recipients, patients receiving chemotherapy, or patients with HIV ing, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis,
infection), in whom it presents with abnormal serum enzymes in the mental confusion, stupor, and coma. In male patients with cirrhosis,
absence of markers of hepatitis B or C. particularly that related to alcohol use, signs of hyperestrogenemia
A history of alcohol intake is important in assessing the cause of such as gynecomastia, testicular atrophy, and loss of male-pattern hair
liver disease and also in planning management and recommendations. distribution may be found.
In the United States, for example, at least 70% of adults drink alcohol Icterus is best appreciated when the sclera is inspected under nat-
PART 10
to some degree, but significant alcohol intake is less common; in pop- ural light. In fair-skinned individuals, a yellow tinge to the skin may
ulation-based surveys, only 5% of individuals have more than two be obvious. In dark-skinned individuals, examination of the mucous
drinks per day, the average drink representing 11–15 g of alcohol. Alco- membranes below the tongue can demonstrate jaundice. Jaundice
hol consumption associated with an increased rate of alcoholic liver is rarely detectable if the serum bilirubin level is <43 μmol/L
disease is probably more than two drinks (22–30 g) per day in women (2.5 mg/dL) but may remain detectable below this level during recov-
and three drinks (33–45 g) in men. Most patients with alcoholic cirrho- ery from jaundice (because of protein and tissue binding of conjugated
sis have a much higher daily intake and have drunk excessively for bilirubin).
≥10 years before onset of liver disease. In assessing alcohol intake, the Spider angiomata and palmar erythema occur in both acute and
history should also focus on whether alcohol abuse or dependence is chronic liver disease; these manifestations may be especially prominent
present. Alcoholism is usually defined by the behavioral patterns and in persons with cirrhosis but can develop in normal individuals and are
consequences of alcohol intake, not by the amount. Abuse is defined frequently found during pregnancy. Spider angiomata are superficial,
by a repetitive pattern of drinking alcohol that has adverse effects on tortuous arterioles, and—unlike simple telangiectases—typically fill
social, family, occupational, or health status. Dependence is defined by from the center outward. Spider angiomata occur only on the arms,
alcohol-seeking behavior, despite its adverse effects. Many alcoholics face, and upper torso; they can be pulsatile and may be difficult to
demonstrate both dependence and abuse, and dependence is consid- detect in dark-skinned individuals.
ered the more serious and advanced form of alcoholism. A clinically Hepatomegaly is not a highly reliable sign of liver disease because
helpful approach to diagnosis of alcohol dependence and abuse is the of variability in the liver’s size and shape and the physical impedi-
use of the CAGE questionnaire (Table 329-2), which is recommended ments to assessment of liver size by percussion and palpation. Marked
for all medical history-taking. hepatomegaly is typical of cirrhosis, sinusoidal obstruction syndrome,
Family history can be helpful in assessing liver disease. Familial infiltrative disorders such as amyloidosis, metastatic, or primary can-
causes of liver disease include Wilson disease; hemochromatosis and cers of the liver, and alcoholic hepatitis. Careful assessment of the liver
α1 antitrypsin deficiency; and the more uncommon inherited pedi- edge may also reveal unusual firmness, irregularity of the surface,
atric liver diseases—that is, familial intrahepatic cholestasis, benign or frank nodules. Perhaps the most reliable physical finding in the
recurrent intrahepatic cholestasis, and Alagille syndrome. Onset of liver examination is hepatic tenderness. Discomfort when the liver is
severe liver disease in childhood or adolescence in conjunction with a touched or pressed upon should be carefully sought with percussive
family history of liver disease or neuropsychiatric disturbance should comparison of the right and left upper quadrants.
lead to investigation for Wilson’s disease. A family history of cirrhosis, Splenomegaly, which occurs in many medical conditions, can be a
diabetes, or endocrine failure and the appearance of liver disease in subtle but significant physical finding in liver disease. The availability
of ultrasound (US) methods for assessment of the spleen allows confir-
mation of the physical finding.
Signs of advanced liver disease include muscle wasting and weight
TABLE 329-2 CAGE Questionsa
loss as well as hepatomegaly, bruising, ascites, and edema. Ascites is
ACRONYM QUESTION best appreciated by attempts to detect shifting dullness by careful per-
C Have you ever felt you ought to cut down on your drinking? cussion. US examination will confirm the finding of ascites in equivocal
A Have people annoyed you by criticizing your drinking? cases. Peripheral edema can occur with or without ascites. In patients
G Have you ever felt guilty or bad about your drinking? with advanced liver disease, other factors frequently contribute to
E Have you ever had a drink first thing in the morning to edema formation, including hypoalbuminemia, venous insufficiency,
steady your nerves or get rid of a hangover (eye-opener)? heart failure, and medications.
a
One “yes” response should raise suspicion of an alcohol use problem, and more Hepatic failure is defined as the occurrence of signs or symptoms of
than one is a strong indication of abuse or dependence. hepatic encephalopathy in a person with severe acute or chronic liver

disease. The first signs of hepatic encephalopathy can be subtle and TABLE 329-3 Important Diagnostic Tests in Common Liver Diseases 2335
nonspecific—change in sleep patterns, change in personality, irritabil-
DISEASE DIAGNOSTIC TEST
ity, and mental dullness. Thereafter, confusion, disorientation, stupor,
Hepatitis A Anti-HAV IgM
and eventually coma supervene. In acute liver failure, excitability and
mania may be present. Physical findings include asterixis and flapping Hepatitis B
tremors of the body and tongue. Fetor hepaticus refers to the slightly Acute HBsAg and anti-HBc IgM
sweet, ammoniacal odor that can develop in patients with liver failure, Chronic HBsAg and HBeAg and/or HBV DNA
particularly if there is portal-venous shunting of blood around the liver. Hepatitis C Anti-HCV and HCV RNA
Other causes of coma and disorientation should be excluded, mainly Hepatitis D (delta) HBsAg and anti-HDV
electrolyte imbalances, sedative use, and renal or respiratory failure. Hepatitis E Anti-HEV IgM and HEV RNA
The appearance of hepatic encephalopathy during acute hepatitis is Autoimmune hepatitis ANA or SMA, elevated IgG levels, and
the major criterion for diagnosis of fulminant hepatitis and indicates compatible histology
a poor prognosis. In chronic liver disease, encephalopathy is usually Primary biliary cholangitis Mitochondrial antibody, elevated IgM levels,
triggered by a medical complication such as gastrointestinal bleeding, and compatible histology
over-diuresis, uremia, dehydration, electrolyte imbalance, infection, Primary sclerosing P-ANCA, cholangiography
constipation, or use of narcotic analgesics. cholangitis
A helpful measure of hepatic encephalopathy is a careful mental- Drug-induced liver disease History of drug ingestion
status examination and use of the trail-making test, which consists of Alcoholic liver disease History of excessive alcohol intake and
a series of 25 numbered circles that the patient is asked to connect as compatible histology
rapidly as possible using a pencil. The normal range for the connect- Nonalcoholic steatohepatitis Ultrasound or CT evidence of fatty liver and
the-dot test is 15–30 sec; it is considerably longer in patients with early compatible histology
hepatic encephalopathy. Other tests include drawing of abstract objects α1 antitrypsin disease Reduced α1 antitrypsin levels, phenotype PiZZ
or comparison of a signature to previous examples. More sophisticated or PiSZ
testing—for example, with electroencephalography and visual evoked Wilson disease Decreased serum ceruloplasmin and
potentials—can detect mild forms of encephalopathy but are rarely increased urinary copper; increased hepatic
clinically useful. copper level
Other signs of advanced liver disease include umbilical hernia from Hemochromatosis Elevated iron saturation and serum ferritin;
ascites, hydrothorax, prominent veins over the abdomen, and caput genetic testing for HFE gene mutations

medusa, a condition that consists of collateral veins radiating from the Hepatocellular cancer Elevated α-fetoprotein level (to >500 ng/mL);
umbilicus and results from recanulation of the umbilical vein. Widened ultrasound or CT image of mass
pulse pressure and signs of a hyperdynamic circulation can occur Abbreviations: ANA, antinuclear antibody; anti-HBc, antibody to hepatitis B core
in patients with cirrhosis as a result of fluid and sodium retention, (antigen); HAV, HBV, HCV, HDV, HEV: hepatitis A, B, C, D, E virus; HBeAg, hepatitis
B e antigen; HBsAg, hepatitis B surface antigen; P-ANCA, peripheral antineutrophil
increased cardiac output, and reduced peripheral resistance. Patients cytoplasmic antibody; SMA, smooth-muscle antibody.
with long-standing cirrhosis and portal hypertension are prone to
develop the hepatopulmonary syndrome, which is defined by the triad
of liver disease, hypoxemia, and pulmonary arteriovenous shunting. unclear despite thorough clinical and laboratory investigation. Liver
The hepatopulmonary syndrome is characterized by platypnea and biopsy can be helpful in diagnosing drug-induced liver disease and
orthodeoxia: shortness of breath and oxygen desaturation that occur acute alcoholic hepatitis.
The most common causes of chronic liver disease, in general order of
paradoxically upon the assumption of an upright position. Measure-
frequency, are chronic hepatitis C, alcoholic liver disease, nonalcoholic
ment of oxygen saturation by pulse oximetry is a reliable screening test
steatohepatitis, chronic hepatitis B, autoimmune hepatitis, sclerosing
for hepatopulmonary syndrome.
cholangitis, primary biliary cholangitis, hemochromatosis, and Wilson
Several skin disorders and changes are common in liver disease.
disease. Hepatitis E virus is a rare cause of chronic hepatitis, with cases
Hyperpigmentation is typical of advanced chronic cholestatic diseases
occurring mostly in persons who are immunosuppressed or immuno-
such as primary biliary cholangitis and sclerosing cholangitis. In these
deficient. Strict diagnostic criteria have not been developed for most
same conditions, xanthelasma and tendon xanthomata occur as a result
liver diseases, but liver biopsy plays an important role in the diagnosis
of retention and high serum levels of lipids and cholesterol. Slate-gray
of autoimmune hepatitis, primary biliary cholangitis, nonalcoholic
pigmentation of the skin is also seen with hemochromatosis if iron
and alcoholic steatohepatitis, and Wilson disease (with a quantitative
levels are high for a prolonged period. Mucocutaneous vasculitis with
hepatic copper level in the last instance).
palpable purpura, especially on the lower extremities, is typical of
cryoglobulinemia of chronic hepatitis C but can also occur in chronic Laboratory Testing Diagnosis of liver disease is greatly aided
hepatitis B. by the availability of reliable and sensitive tests of liver injury and
Some physical signs point to specific liver diseases. Kayser-Fleischer function. A typical battery of blood tests used for initial assessment of
rings occur in Wilson disease and consist of a golden-brown copper liver disease includes measurement of levels of serum alanine (ALT)
pigment deposited in Descemet’s membrane at the periphery of the and aspartate aminotransferases (AST), alkaline phosphatase (AlkP),
cornea; they are best seen by slit-lamp examination. Dupuytren con- direct and total serum bilirubin and albumin, and prothrombin time.
tracture and parotid enlargement are suggestive of chronic alcoholism The pattern of abnormalities generally points to hepatocellular versus
and alcoholic liver disease. In metastatic liver disease or primary cholestatic liver disease and helps determine whether the disease is
hepatocellular carcinoma, signs of cachexia and wasting as well as firm acute or chronic and whether cirrhosis and hepatic failure are present.
hepatomegaly and a hepatic bruit may be prominent. On the basis of these results, further testing over time may be necessary.
Other laboratory tests may be helpful, such as γ-glutamyl transpep-
■■DIAGNOSIS OF LIVER DISEASE tidase (γ GT) to define whether AlkP elevations are due to liver disease;
The major causes of liver disease and key diagnostic features are out- hepatitis serology to define the type of viral hepatitis; and autoimmune
lined in Table 329-3, and an algorithm for evaluation of the patient with markers to diagnose primary biliary cholangitis (antimitochondrial
suspected liver disease is shown in Fig. 329-1. Specifics of diagnosis antibody), sclerosing cholangitis (peripheral antineutrophil cytoplas-
are discussed in later chapters. The most common causes of acute mic antibody), and autoimmune hepatitis (antinuclear, smooth-muscle,
liver disease are viral hepatitis (particularly hepatitis A, B, and C), and liver-kidney microsomal antibody). A simple delineation of labora-
drug-induced liver injury, cholangitis, and alcoholic liver disease. Liver tory abnormalities and common liver diseases is given in Table 329-3.
biopsy usually is not needed in the diagnosis and management of acute The use and interpretation of liver function tests are summarized
liver disease, exceptions being situations where the diagnosis remains in Chap. 330.

2336 for detecting choledocholithiasis but is less specific.
EVALUATION OF ABNORMAL LIVER TESTS
MRCP is useful in the diagnosis of bile duct obstruc-
Suspected Liver Disease tion and congenital biliary abnormalities, but ERCP
is more valuable in evaluating ampullary lesions and
primary sclerosing cholangitis. ERCP permits biopsy,
Abnormal liver tests direct visualization of the ampulla and common bile
duct, and intraductal ultrasonography and brushings
for cytological evaluation of malignancy. It also provides
several therapeutic options in patients with obstructive
Acute Chronic
< 6 months > 6 months jaundice, such as sphincterotomy, stone extraction, and
placement of nasobiliary catheters and biliary stents.
Doppler US and MRI are used to assess hepatic vascu-
lature and hemodynamics and to monitor surgically or
Hepatitic: ⇑⇑ALT Cholestatic: Hepatitic: ⇑⇑ALT Cholestatic:
radiologically placed vascular shunts, including trans-
Mixed: ↑ALT, ⇑⇑AlkP, Mixed: ↑ALT, ⇑⇑AlkP, jugular intrahepatic portosystemic shunts. Multidetector
↑AlkP ⇑⇑gGT, ↑AlkP ⇑⇑gGT, or spiral CT and MRI with contrast-enhancement are the
↑ALT ↑ALT procedures of choice for the identification and evalua-
tion of hepatic masses, the staging of liver tumors, and
Diagnostic Diagnostic Diagnostic Diagnostic
preoperative assessment. With regard to mass lesions,
evaluation evaluation evaluation evaluation the sensitivity of hepatic imaging continues to increase;
1. IgM Anti-HAV 1. AMA 1. HBsAg 1. Drug history unfortunately, specificity remains a problem, and often
2. HBsAg 2. Drug history 2. Anti-HCV 2. AMA two and sometimes three studies are needed before a
3. IgM Anti-HBc 3. Ultrasound/MRI 3. Fe saturation, 3. P-ANCA
4. Anti-HCV 4. MRCP/ERCP ferritin 4. Ultrasound diagnosis can be reached. An emerging imaging modal-
5. ANA, SMA 4. Ceruloplasmin 5. MRCP/ERCP ity for the investigation of hepatic lesions is contrast-
6. Monospot, 5. α1AT enhanced US. This procedure permits enhancement of
heterophile 6. ANA, SMA
7. Ceruloplasmin 7. Ultrasound liver lesions in a similar fashion as contrast-enhanced,
8. Alcohol history 8. Alcohol history cross-sectional CT, or MR imaging. Major advantages
9. Drug history are real-time assessment of liver perfusion throughout
the vascular phases without risk of nephrotoxicity and
PART 10
radiation exposure. Other advantages are its widespread

Liver biopsy in acute liver disease: Liver biopsy in chronic liver disease: availability and lower cost. Limitations include body
Reserved for patients in whom the diagnosis Often valuable for diagnosis as well as
remains unclear despite medical evaluation staging and grading liver disease habitus of the patient and skill of the operator. US is the
recommended modality for hepatocellular carcinoma
FIGURE 329-1 Algorithm for evaluation of abnormal liver tests. For patients with suspected
screening. Contrast-enhanced US, CT, and MRI are
liver disease, an appropriate approach to evaluation is initial routine liver testing—for example, appropriate for further investigation of lesions detected
measurement of serum bilirubin, albumin, alanine aminotransferase (ALT), AST, and AlkP. These on screening US. The American College of Radiologists
results (sometimes complemented by testing of γ-glutamyl transpeptidase; gGT) will establish has developed a Liver Imaging Reporting and Data
whether the pattern of abnormalities is hepatic, cholestatic, or mixed. In addition, the duration of System (LI-RADS) to standardize the reporting and data
symptoms or abnormalities will indicate whether the disease is acute or chronic. If the disease is collection of CT, MR, and contrast-enhanced US imaging
acute and if history, laboratory tests, and imaging studies do not reveal a diagnosis, liver biopsy
for hepatocellular carcinoma (HCC). This system allows
is appropriate to help establish the diagnosis. If the disease is chronic, liver biopsy can be helpful
not only for diagnosis but also for grading of the activity and staging the progression of disease. for more consistent reporting and reduces imaging inter-
This approach is generally applicable to patients without immune deficiency. In patients with pretation variability and errors.
HIV infection or recipients of bone marrow or solid organ transplants, the diagnostic evaluation Recently, US transient elastography has been approved
should also include evaluation for opportunistic infections (e.g., with adenovirus, cytomegalovirus, for the measurement of hepatic stiffness—providing an
Coccidioides, hepatitis E virus) as well as for vascular and immunologic conditions (venoocclusive indirect assessment of fibrosis and cirrhosis; this tech-
disease, graft-versus-host disease). α1 AT, α1 antitrypsin; AMA; antimitochondrial antibody; nique can eliminate the need for liver biopsy if the only
ANA, antinuclear antibody; anti-HBc, antibody to hepatitis B core (antigen); ERCP, endoscopic
retrograde cholangiopancreatography; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; indication is the assessment of disease stage. MR elas-
HCV, hepatitis C virus; MRCP, magnetic resonance cholangiopancreatography; P-ANCA, peripheral tography is more sensitive than US elastography, but is
antineutrophil cytoplasmic antibody; SMA, smooth-muscle antibody. also more expensive and requires advanced scheduling
and special equipment. Studies are ongoing to determine
whether hepatic elastography is an appropriate means
Diagnostic Imaging Great advances have been made in hepa- of monitoring fibrosis and disease progression. Finally, interventional
tobiliary imaging, although no method is adequately accurate in radiologic techniques allow the biopsy of solitary lesions, the radio-
demonstrating underlying cirrhosis in its early stages. Of the many frequency ablation and chemoembolization of cancerous lesions, the
modalities available for imaging the liver, US, computerized tomog- insertion of drains into hepatic abscesses, the measurement of portal
raphy (CT), and magnetic resonance imaging (MRI) are the most com- pressure, and the creation of vascular shunts in patients with portal
monly employed and are complementary to one another. In general, hypertension. Which modality to use depends on factors such as avail-
US and CT are highly sensitive for detecting biliary duct dilation and ability, cost, and experience of the radiologist with each technique.
are the first-line options for investigating cases of suspected obstructive Liver Biopsy Liver biopsy remains the gold standard in the eval-
jaundice. All three modalities can detect a fatty liver, which appears uation of patients with liver disease, particularly chronic liver disease.
bright on imaging studies. Modifications of CT and MRI can be used Liver biopsy is necessary for diagnosis in selected instances but is more
to quantify liver fat, and this information may ultimately be valuable often useful for assessment of the severity (grade) and stage of liver dam-
in monitoring therapy in patients with fatty liver disease. Magnetic age, prediction of prognosis, and monitoring of the response to treat-
resonance cholangiopancreatography (MRCP) and endoscopic retro- ment. The size of the liver biopsy sample is an important determinant
grade cholangiopancreatography (ERCP) are the procedures of choice of reliability; a length of 1.5–2 cm is necessary for accurate assessment of
for visualization of the biliary tree. MRCP offers several advantages fibrosis. Because liver biopsy is an invasive procedure and not without
over ERCP: there is no need for contrast media or ionizing radiation, complications, it should be used only when it will contribute materially
images can be acquired faster, the procedure is less operator dependent, to decisions about management and therapy. In the future, noninvasive
and it carries no risk of pancreatitis. MRCP is superior to US and CT means of assessing disease activity (batteries of blood tests) and fibrosis

(elastography and fibrosis markers) may replace liver biopsy for the breath tests using 13C-labeled compounds have been proposed as a 2337
staging and grading of disease. means of detecting early stages of fibrosis and liver dysfunction, but
their reliability and reproducibility remain to be proven. A major lim-
■■GRADING AND STAGING OF LIVER DISEASE itation of noninvasive markers is that they can be affected by disease
Grading refers to an assessment of the severity or activity of liver activity. Even elastography is limited in this regard, in that it measures
disease, whether acute or chronic; active or inactive; and mild, mod- liver stiffness, not fibrosis per se, and can be affected by inflammation,
erate, or severe. Liver biopsy is the most accurate means of assessing edema, hepatocyte necrosis, and intrasinusoidal cellularity (inflamma-
severity, particularly in chronic liver disease. Serum aminotransferase tory, malignant, or sickled cells). Thus, at present, mild to moderate
levels serve as convenient and noninvasive markers for disease activity stages of hepatic fibrosis are detectable only by liver biopsy. In the
but do not always reliably reflect disease severity. Thus, normal serum assessment of stage, the degree of fibrosis is usually used as the quan-
aminotransferase levels in patients with hepatitis B surface antigen in titative measure. The amount of fibrosis is generally staged on a scale
serum may indicate the inactive carrier state or may reflect mild chronic of 0 to 4+ (METAVIR scale) or 0 to 6+ (Ishak scale). The importance of
hepatitis B or hepatitis B with fluctuating disease activity. Serum test- staging relates primarily to prognosis, recommendation of therapy and
ing for hepatitis B e antigen and hepatitis B virus DNA can help sort to optimal management of complications. Patients with cirrhosis are
out these different patterns, but these markers can also fluctuate and candidates for screening and surveillance for esophageal varices and
change over time. Similarly, in chronic hepatitis C, serum aminotrans- hepatocellular carcinoma. Patients without advanced fibrosis need not
ferase levels can be normal despite moderate disease activity. Finally, in undergo screening.
both alcoholic and nonalcoholic steatohepatitis, aminotransferase lev- Once cirrhosis develops, other scoring systems are employed to
els are quite unreliable in reflecting severity. In these conditions, liver assess compensated versus decompensated disease and prognosis. The
biopsy is helpful in guiding management and identifying appropriate initial staging system used for this purpose was the modified Child-
therapy, particularly if treatment is difficult, prolonged, and expensive, Pugh classification, with a scoring system of 5–15: scores of 5 and 6 rep-
as is often the case in chronic viral hepatitis. Of the several well-verified resent Child-Pugh class A (consistent with “compensated cirrhosis”),
numerical scales for grading activity in chronic liver disease, the most scores of 7–9 represent class B, and scores of 10–15 represent class C
commonly used are the METAVIR, histology activity index and the (Table 329-5). This scoring system was initially devised to stratify
Ishak fibrosis scale. patients with cirrhosis into risk groups before portal decompressive
Liver biopsy is also the most accurate means of assessing stage of surgery. The Child-Pugh score is a reasonably reliable predictor of
disease as early or advanced, precirrhotic, and cirrhotic. Staging of survival in many liver diseases and predicts the likelihood of major
disease pertains largely to chronic liver diseases in which progression complications of cirrhosis, such as bleeding from varices and spon-

to cirrhosis and end-stage disease can occur but may require years taneous bacterial peritonitis. This classification scheme was used to
or decades. Clinical features, biochemical tests, and hepatic imaging assess prognosis in cirrhosis and to provide standard criteria for listing
studies are helpful in assessing stage but generally become abnormal a patient as a candidate for liver transplantation (Child-Pugh class B).
only in the middle to late stages of cirrhosis. Noninvasive tests that More recently, the Child-Pugh system has been replaced by the Model
suggest advanced fibrosis include mild elevations of bilirubin, prolon- for End-Stage Liver Disease (MELD) system for the latter purpose.
gation of prothrombin time, slight decreases in serum albumin, and The MELD score is a prospectively derived system designed to predict
mild thrombocytopenia (which is often the first indication of worsen- the prognosis of patients with liver disease and portal hypertension.
ing fibrosis). Combinations of blood test results that include clinical Initially, this score was calculated from three noninvasive variables:
features, routine laboratory tests, and special laboratory tests such as the prothrombin time expressed as the international normalized ratio
serum proteins or small molecules that are affected by or involved with (INR), the serum bilirubin level, and the serum creatinine concen-
fibrogenesis have been used to create models for predicting advanced tration. The ability of the MELD score to predict outcome after liver
liver disease, but these models are not reliable enough to use on a reg- transplantation is regularly monitored and was modified to increase
ular basis or for repeated measures and only separate advanced from its accuracy and improve allocation of donated livers. These modifica-
early disease (Table 329-4). Recently, elastography and noninvasive tions include serum sodium concentration as a factor in the model and
a reweighting of the MELD components. A separate scoring system
pediatric end-stage liver disease (PELD) is used for children (<12 years
TABLE 329-4 Selected Noninvasive Methods of Assessing Hepatic of age). Transient elastography has also been used to stage cirrhosis
Fibrosis and Cirrhosis
and has been shown to be useful in predicting complications such as
ADVANCED variceal hemorrhage, ascites development and liver-related death.
METHOD PARAMETERS FIBROSIS CIRRHOSIS
APRI AST, platelet count >1 >1.5 (1–2)
ELF Age, hyaluronic acid, MMP-3, >7.7 >9.3 TABLE 329-5 Child-Pugh Classification of Cirrhosis
TIMP-1
POINTS TOWARD TOTAL SCORE
FIB-4 Age, AST, ALT, platelet count >1.45 >3.25
FACTOR UNITS 1 2 3
*Fibro Haptoglobin, α2-macroglobulin, >0.45 >0.63
Serum bilirubin μmol/L <34 34–51 >51
Test apolipoprotein A1, γGT, total
bilirubin mg/dL <2.0 2.0–3.0 >3.0
TE Measures speed of a shear >7.3 kPa >15 kPa Serum albumin g/L >35 30–35 <30
wave generated by vibration (9–26.5 kPa) g/dL >3.5 3.0–3.5 <3.0
through liver tissue Prothrombin seconds <4 4–6 >6
ARFI Measures speed of shear wave >1.3 m/s >1.87 m/s time prolonged
generated by acoustic radiation INRa <1.7 1.7–2.3 >2.3
force through liver tissue
Ascites None Easily Poorly controlled
*Patented models. controlled
Note: The cutpoints presented in the table were mostly derived from patients Hepatic None Minimal Advanced
with chronic hepatitis C. The cutpoints for the non-invasive models and tests encephalopathy
presented in the table varies among different liver disease and among patients
with the same disease among different populations. International normalized ratio.
a
Abbreviations: ALT, alanine aminotransferase; APRI, AST-to-Platelet Ratio; Note: The Child-Pugh score is calculated by adding the scores for the five factors
ARFI, acoustic radiation force imaging; AST, aspartate aminotransferase; ELF, and can range from 5 to 15. The resulting Child-Pugh class can be A (a score of
Enhanced Liver Fibrosis Panel; γGT, gamma glutamyl-transpeptidase; MMP-3, 5–6), B (7–9), or C (≥10). Decompensation indicates cirrhosis, with a Child-Pugh
metalloproteinase-3; TIMP-1, tissue inhibitor of metalloproteinase-1; TE, Transient score of ≥7 (class B). This level has been the accepted criterion for listing a
Elastography. patient for liver transplantation.

2338 The MELD system provides a more objective means of assess- of these functions. In fact, many tests, such as the aminotransferases
ing disease severity and has less center-to-center variation than the and alkaline phosphatase, do not measure liver function at all. Rather,
Child-Pugh score as well as a wider range of values. The MELD and they detect liver cell damage or interference with bile flow. Thus, no
PELD systems are currently used to establish priority listing for liver one biochemical test enables the clinician to accurately assess the liver’s
transplantation in the United States. Convenient MELD and PELD total functional capacity.
calculators are available via the internet: (http://optn.transplant.hrsa.gov/ To increase the sensitivity and the specificity of biochemical tests in
resources/MeldPeldCalculator.asp?index=98). the detection of liver disease, it is best to use them as a battery. Tests
usually employed in clinical practice include the bilirubin, aminotrans-
■■NONSPECIFIC ISSUES IN THE MANAGEMENT OF ferases, alkaline phosphatase, albumin, and prothrombin time tests.
PATIENTS WITH LIVER DISEASE When more than one of these tests provide abnormal findings or the
Specifics on the management of different forms of acute or chronic findings are persistently abnormal on serial determinations, the prob-
liver disease are supplied in subsequent chapters, but certain issues are ability of liver disease is high. When all test results are normal, the
applicable to any patient with liver disease. These issues include advice probability of missing occult liver disease is low.
regarding alcohol use, medication use, vaccination, and surveillance
for complications of liver disease. Alcohol should be used sparingly, if Serum Bilirubin (See also Chap. 45) Bilirubin, a breakdown
at all, by patients with liver disease. Abstinence from alcohol should be product of the porphyrin ring of heme-containing proteins, is found in
encouraged for all patients with alcohol-related liver disease, patients the blood in two fractions—conjugated and unconjugated. The uncon-
with cirrhosis, and patients receiving interferon-based therapy for jugated fraction, also termed the indirect fraction, is insoluble in water
hepatitis B and during antiviral therapy of hepatitis C. With regard and is bound to albumin in the blood. The conjugated (direct) bilirubin
to vaccinations, all patients with liver disease should receive hepatitis fraction is water-soluble and can therefore be excreted by the kidney.
A vaccine, and those with risk factors should receive hepatitis B vac- Normal values of total serum bilirubin are reported between 1 and
cine as well. Influenza and pneumococcal vaccination should also be 1.5 mg/dL with 95% of a normal population falling between 0.2 and
encouraged, with adherence to the recommendations of the Centers 0.9 mg/dL. If the direct-acting fraction is <15% of the total, the biliru-
for Disease Control and Prevention. Patients with liver disease should bin can be considered to all be indirect. The most frequently reported
exercise caution in using any medications other than those that are upper limit of normal for conjugated bilirubin is 0.3 mg/dL.
most necessary. Drug-induced hepatotoxicity can mimic many forms Elevation of the unconjugated fraction of bilirubin is rarely due to
of liver disease and can cause exacerbations of chronic hepatitis and liver disease. An isolated elevation of unconjugated bilirubin is seen
cirrhosis; drugs should be suspected in any situation in which the primarily in hemolytic disorders and in a number of genetic conditions
cause of exacerbation is unknown. Finally, consideration should be such as Crigler-Najjar and Gilbert’s syndromes (Chap. 45). Isolated
given to surveillance for complications of chronic liver disease such as unconjugated hyperbilirubinemia (bilirubin elevated but <15% direct)
PART 10
variceal hemorrhage and hepatocellular carcinoma. Cirrhosis warrants should prompt a workup for hemolysis (Fig. 330-1). In the absence of
upper endoscopy to assess the presence of varices, and the patient hemolysis, an isolated, unconjugated hyperbilirubinemia in an other-
should receive chronic therapy with beta blockers or should be offered wise healthy patient can be attributed to Gilbert’s syndrome, and no
endoscopic obliteration if large varices are found. Moreover, cirrhosis further evaluation is required.
warrants screening and long-term surveillance for development of In contrast, conjugated hyperbilirubinemia almost always implies
hepatocellular carcinoma. While the optimal regimen for such surveil- liver or biliary tract disease. The rate-limiting step in bilirubin metab-
lance has not been established, an appropriate approach is US of the olism is not conjugation of bilirubin, but rather the transport of conju-
liver at 6- to 12-month intervals. gated bilirubin into the bile canaliculi. Thus, elevation of the conjugated
fraction may be seen in any type of liver disease including fulminant
■■FURTHER READING liver failure. In most liver diseases, both conjugated and unconjugated
Patel K, Bedossa P, Castera L: Diagnosis of liver fibrosis: Present and fractions of the bilirubin tend to be elevated. Except in the presence of a
future. Semin Liver Dis 35:166, 2015. purely unconjugated hyperbilirubinemia, fractionation of the bilirubin
is rarely helpful in determining the cause of jaundice.
Although the degree of elevation of the serum bilirubin has not been
critically assessed as a prognostic marker, it is important in a number
of conditions. In viral hepatitis, the higher the serum bilirubin, the
greater is the hepatocellular damage. Total serum bilirubin correlates
330
with poor outcomes in alcoholic hepatitis. It is also a critical compo-
Evaluation of Liver nent of the Model for End-Stage Liver Disease (MELD) score, a tool
Function used to estimate survival of patients with end-stage liver disease and
assess operative risk of patients with cirrhosis. An elevated total serum
Daniel S. Pratt bilirubin in patients with drug-induced liver disease indicates more
severe injury.
Unconjugated bilirubin always binds to albumin in the serum and is
not filtered by the kidney. Therefore, any bilirubin found in the urine is
There are a number of tests that can be used to evaluate liver function.
conjugated bilirubin; the presence of bilirubinuria implies the presence
These tests include biochemical tests, radiologic tests, and pathologic
of liver disease. A urine dipstick test can theoretically give the same
tests.
information as fractionation of the serum bilirubin. This test is almost
Serum biochemical tests, also commonly referred to as “liver
100% accurate. Phenothiazines may give a false-positive reading with
function tests,” can be used to (1) detect the presence of liver disease,
the Ictotest tablet. In patients recovering from jaundice, the urine biliru-
(2) distinguish among different types of liver disorders, (3) gauge the
bin clears prior to the serum bilirubin.
extent of known liver damage, and (4) follow the response to treatment.
However, serum biochemical tests have shortcomings. They lack sensi- Serum Enzymes The liver contains thousands of enzymes, some
tivity and specificity; they can be normal in patients with serious liver of which are also present in the serum in very low concentrations.
disease and abnormal in patients with diseases that do not affect the These enzymes have no known function in the serum and behave
liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest like other serum proteins. They are distributed in the plasma and in
a general category of liver disease, such as hepatocellular or cholestatic, interstitial fluid and have characteristic half-lives, which are usually
which then further directs the evaluation. The liver carries out thou- measured in days. Very little is known about the catabolism of serum
sands of biochemical functions, most of which cannot be easily mea- enzymes, although they are probably cleared by cells in the reticuloen-
sured by blood tests. Laboratory tests measure only a limited number dothelial system. The elevation of a given enzyme activity in the serum

2339
EVALUATION OF CHRONICALLY ABNORMAL LIVER TESTS
Liver Tests
Isolated elevation Cholestatic pattern

of the bilirubin (see Table 330-1) Isolated elevation
of the alkaline
phosphatase
Review drugs
Ultrasound
Fractionate
bilirubin Ducts not Dilated ducts
dilated
>15% Direct <15% Direct Check AMA CT/MRCP/ERCP

AMA AMA positive
Dubin-Johnson or Evaluation for negative
Rotor syndrome hemolysis
ERCP/Liver Bx Liver Bx
W/U
W/U negative
positive
Fractionate the alkaline
Gilbert’s Hemolysis Hepatocellular phosphatase or check
syndrome pattern GGT or 5' nucleotidase
(see Table 330-1) to assess origin of
alkaline phosphatase
Review drug list
Hepatitis C antibody Alkaline phos.
Alkaline phos.
Hepatitis B surface Ag of bone origin
of liver origin
Iron, TIBC, ferritin
ANA, SPEP
Ceruloplasmin Ultrasound Bone Eval
CHAPTER 330 Evaluation of Liver Function

(if patient < 40) Review drug list
Ultrasound to look Check AMA
for fatty liver Ducts not dilated Dilated ducts
W/U negative and/or AMA positive
R/O Celiac disease

Consider other Liver biopsy MRCP
nonhepatic cause
W/U negative
Consider liver biopsy
FIGURE 330-1 Algorithm for the evaluation of chronically abnormal liver tests. AMA, antimitochondrial antibody; ANA, antinuclear antibody; Bx, biopsy; CT, computed
tomography; ERCP, endoscopic retrograde cholangiopancreatography; GGT, γ glutamyl transpeptidase; MRCP, magnetic resonance cholangiopancreatography; R/O, rule
out; SPEP, serum protein electrophoresis; TIBC, total iron-binding capacity; W/U, workup.
is thought to primarily reflect its increased rate of entrance into serum standards exist to establish upper limits of normal for ALT and AST.
from damaged liver cells. Some have recommended revisions of normal limits of the aminotrans-
Serum enzyme tests can be grouped into two categories: (1) enzymes ferases to adjust for sex and body mass index, but others have noted
whose elevation in serum reflects damage to hepatocytes and (2) enzymes the potential costs and unclear benefits of implementing this change.
whose elevation in serum reflects cholestasis. Any type of liver cell injury can cause modest elevations in the
ENZYMES THAT REFLECT DAMAGE TO HEPATOCYTES The aminotransfer- serum aminotransferases. Levels of up to 300 IU/L are nonspecific
ases (transaminases) are sensitive indicators of liver cell injury and and may be found in any type of liver disorder. Minimal ALT ele-
are most helpful in recognizing acute hepatocellular diseases such as vations in asymptomatic blood donors rarely indicate severe liver
hepatitis. They include aspartate aminotransferase (AST) and alanine disease; studies have shown that fatty liver disease is the most likely
aminotransferase (ALT). AST is found in the liver, cardiac muscle, explanation. Striking elevations—that is, aminotransferases >1000
skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and ery- IU/L—occur almost exclusively in disorders associated with exten-
throcytes in decreasing order of concentration. ALT is found primarily sive hepatocellular injury such as (1) viral hepatitis, (2) ischemic liver
in the liver and is therefore a more specific indicator of liver injury. The injury (prolonged hypotension or acute heart failure), or (3) toxin- or
aminotransferases are normally present in the serum in low concentra- drug-induced liver injury.
tions. These enzymes are released into the blood in greater amounts The pattern of the aminotransferase elevation can be helpful diag-
when there is damage to the liver cell membrane resulting in increased nostically. In most acute hepatocellular disorders, the ALT is higher
permeability. Liver cell necrosis is not required for the release of the than or equal to the AST. Whereas the AST:ALT ratio is typically <1
aminotransferases, and there is a poor correlation between the degree in patients with chronic viral hepatitis and nonalcoholic fatty liver
of liver cell damage and the level of the aminotransferases. Thus, the disease, a number of groups have noted that as cirrhosis develops,
absolute elevation of the aminotransferases is of no prognostic signifi- this ratio rises to >1. An AST:ALT ratio >2:1 is suggestive, whereas a
cance in acute hepatocellular disorders. ratio >3:1 is highly suggestive, of alcoholic liver disease. The AST in
The normal range for aminotransferases varies widely among labo- alcoholic liver disease is rarely >300 IU/L, and the ALT is often normal.
ratories, but generally ranges from 10 to 40 IU/L. The interlaboratory A low level of ALT in the serum is due to an alcohol-induced deficiency
variation in normal range is due to technical reasons; no reference of pyridoxal phosphate.

2340 The aminotransferases are usually not greatly elevated in obstruc- not a good indicator of acute or mild hepatic dysfunction; only minimal
tive jaundice. One notable exception occurs during the acute phase of changes in the serum albumin are seen in acute liver conditions such as
biliary obstruction caused by the passage of a gallstone into the com- viral hepatitis, drug-related hepatotoxicity, and obstructive jaundice. In
mon bile duct. In this setting, the aminotransferases can briefly be in hepatitis, albumin levels <3 g/dL should raise the possibility of chronic
the 1000–2000 IU/L range. However, aminotransferase levels decrease liver disease. Hypoalbuminemia is more common in chronic liver
quickly, and the biochemical tests rapidly evolve into those typical of disorders such as cirrhosis and usually reflects severe liver damage
cholestasis. and decreased albumin synthesis. One exception is the patient with
ENZYMES THAT REFLECT CHOLESTASIS The activities of three enzymes— ascites in whom synthesis may be normal or even increased, but levels
alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase are low because of the increased volume of distribution. However,
(GGT)—are usually elevated in cholestasis. Alkaline phosphatase and hypoalbuminemia is not specific for liver disease and may occur in
5′-nucleotidase are found in or near the bile canalicular membrane of protein malnutrition of any cause, as well as protein-losing enterop-
hepatocytes, whereas GGT is located in the endoplasmic reticulum and athies, nephrotic syndrome, and chronic infections that are associated
in bile duct epithelial cells. Reflecting its more diffuse localization in with prolonged increases in levels of serum interleukin 1 and/or
the liver, GGT elevation in serum is less specific for cholestasis than tumor necrosis factor, cytokines that inhibit albumin synthesis. Serum
albumin should not be measured for screening in patients in whom
are elevations of alkaline phosphatase or 5′-nucleotidase. Some have
there is no suspicion of liver disease. A general medical clinic study of
advocated the use of GGT to identify patients with occult alcohol use.
consecutive patients in whom no indications were present for albumin
Its lack of specificity makes its use in this setting questionable.
measurement showed that although 12% of patients had abnormal test
The normal serum alkaline phosphatase consists of many distinct
results, the finding was of clinical importance in only 0.4%.
isoenzymes found in the liver, bone, placenta, and, less commonly, in
the small intestine. Patients over age 60 can have a mildly elevated Serum Globulins Serum globulins are a group of proteins made up
alkaline phosphatase (1–1.5 times normal), whereas individuals with of γ globulins (immunoglobulins) produced by B lymphocytes and α and
blood types O and B can have an elevation of the serum alkaline β globulins produced primarily in hepatocytes. γ globulins are increased
phosphatase after eating a fatty meal due to the influx of intestinal in chronic liver disease, such as chronic hepatitis and cirrhosis. In cirrho-
alkaline phosphatase into the blood. It is also elevated in children and sis, the increased serum γ globulin concentration is due to the increased
adolescents undergoing rapid bone growth because of bone alkaline synthesis of antibodies, some of which are directed against intestinal bac-
phosphatase, and late in normal pregnancies due to the influx of pla- teria. This occurs because the cirrhotic liver fails to clear bacterial antigens
cental alkaline phosphatase. that normally reach the liver through the hepatic circulation.
Elevation of liver-derived alkaline phosphatase is not totally specific Increases in the concentration of specific isotypes of γ globulins
for cholestasis, and a less than threefold elevation can be seen in almost are often helpful in the recognition of certain chronic liver diseases.
PART 10
any type of liver disease. Alkaline phosphatase elevations greater than Diffuse polyclonal increases in IgG levels are common in autoimmune
four times normal occur primarily in patients with cholestatic liver hepatitis; increases >100% should alert the clinician to this possibility.
disorders, infiltrative liver diseases such as cancer and amyloidosis, Increases in the IgM levels are common in primary biliary cirrhosis,
and bone conditions characterized by rapid bone turnover (e.g., Paget’s whereas increases in the IgA levels occur in alcoholic liver disease.
disease). In bone diseases, the elevation is due to increased amounts of

the bone isoenzymes. In liver diseases, the elevation is almost always ■■COAGULATION FACTORS
due to increased amounts of the liver isoenzyme. With the exception of factor VIII, which is produced by vascular endo-
If an elevated serum alkaline phosphatase is the only abnormal thelial cells, the blood clotting factors are made exclusively in hepato-
finding in an apparently healthy person, or if the degree of elevation is cytes. Their serum half-lives are much shorter than albumin, ranging
higher than expected in the clinical setting, identification of the source from 6 h for factor VII to 5 days for fibrinogen. Because of their rapid
of elevated isoenzymes is helpful (Fig. 330-1). This problem can be turnover, measurement of the clotting factors is the single best acute
approached in two ways. First, and most precise, is the fractionation measure of hepatic synthetic function and helpful in both diagnosis
of the alkaline phosphatase by electrophoresis. The second, best sub- and assessing the prognosis of acute parenchymal liver disease. Useful
stantiated, and most available approach involves the measurement of for this purpose is the serum prothrombin time, which collectively mea-
serum 5′-nucleotidase or GGT. These enzymes are rarely elevated in sures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and X
conditions other than liver disease. depends on vitamin K. The international normalized ratio (INR) is used
In the absence of jaundice or elevated aminotransferases, an elevated to express the degree of anticoagulation on warfarin therapy. The INR
alkaline phosphatase of liver origin often, but not always, suggests standardizes prothrombin time measurement according to the charac-
early cholestasis and, less often, hepatic infiltration by tumor or gran- teristics of the thromboplastin reagent used in a particular lab, which
ulomata. Other conditions that cause isolated elevations of the alkaline is expressed as an International Sensitivity Index (ISI); the ISI is then
phosphatase include Hodgkin’s disease, diabetes, hyperthyroidism, used in calculating the INR.
congestive heart failure, amyloidosis, and inflammatory bowel disease. The prothrombin time may be elevated in hepatitis and cirrhosis as
The level of serum alkaline phosphatase elevation is not helpful well as in disorders that lead to vitamin K deficiency such as obstruc-
in distinguishing between intrahepatic and extrahepatic cholestasis. tive jaundice or fat malabsorption of any kind. Marked prolongation of
There is essentially no difference among the values found in obstruc- the prothrombin time, >5 s above control and not corrected by paren-
tive jaundice due to cancer, common duct stone, sclerosing cholangitis, teral vitamin K administration, is a poor prognostic sign in acute viral
or bile duct stricture. Values are similarly increased in patients with hepatitis and other acute and chronic liver diseases. The INR, along
intrahepatic cholestasis due to drug-induced hepatitis, primary biliary with the total serum bilirubin and creatinine, are components of the
cirrhosis, rejection of transplanted livers, and, rarely, alcohol-induced MELD score, which is used as a measure of hepatic decompensation
steatohepatitis. Values are also greatly elevated in hepatobiliary dis- and to allocate organs for liver transplantation.
orders seen in patients with AIDS (e.g., AIDS cholangiopathy due to
cytomegalovirus or cryptosporidial infection and tuberculosis with ■■OTHER DIAGNOSTIC TESTS
hepatic involvement). Although tests may direct the physician to a category of liver disease,
additional biochemical testing, radiologic testing, and procedures are
■■TESTS THAT MEASURE BIOSYNTHETIC FUNCTION often necessary to make the proper diagnosis, as shown in Fig. 330-1.
OF THE LIVER The most commonly used ancillary tests are reviewed here, as are the
noninvasive tests available for assessing hepatic fibrosis.
Serum Albumin Serum albumin is synthesized exclusively by
hepatocytes. Serum albumin has a long half-life: 18–20 days, with ~4% Ammonia Ammonia is produced in the body during normal pro-
degraded per day. Because of this slow turnover, the serum albumin is tein metabolism and by intestinal bacteria, primarily those in the colon.

The liver plays a role in the detoxification of ammonia by converting it multiparameter blood tests. The test incorporates haptoglobin, bilirubin, 2341
to urea, which is excreted by the kidneys. Striated muscle also plays a GGT, apolipoprotein A-I, and α2-macroglobulin and has been found
role in detoxification of ammonia, where it is combined with glutamic to have high positive and negative predictive values for diagnosing
acid to form glutamine. Patients with advanced liver disease typically advanced fibrosis in patients with chronic hepatitis C, chronic hepatitis
have significant muscle wasting, which likely contributes to hyper- B, and alcoholic liver disease and patients taking methotrexate for pso-
ammonemia. Some physicians use the blood ammonia for detecting riasis. Transient elastography (TE), marketed as FibroScan, and mag-
encephalopathy or for monitoring hepatic synthetic function, although netic resonance elastography (MRE) both have gained U.S. Food and
its use for either of these indications has problems. There is very Drug Administration approval for use in the management of patients
poor correlation between either the presence or the severity of acute with liver disease. TE uses ultrasound waves to measure hepatic stiff-
encephalopathy and elevation of blood ammonia; it can be occasionally ness noninvasively. TE has been shown to be accurate for identifying
useful for identifying occult liver disease in patients with mental status advanced fibrosis in patients with chronic hepatitis C, primary biliary
changes. There is also a poor correlation of the blood serum ammonia cirrhosis, hemochromatosis, nonalcoholic fatty liver disease, and recur-
and hepatic function. The ammonia can be elevated in patients with rent chronic hepatitis after liver transplantation. MRE has been found
severe portal hypertension and portal blood shunting around the to be superior to TE for staging liver fibrosis in patients with a variety
liver even in the presence of normal or near-normal hepatic function. of chronic liver diseases, but requires access to a magnetic resonance
Elevated arterial ammonia levels have been shown to correlate with imaging scanner.
outcome in fulminant hepatic failure.
Ultrasonography Ultrasonography is the first diagnostic test
Liver Biopsy Percutaneous biopsy of the liver is a safe procedure to use in patients whose liver tests suggest cholestasis, to look for
that can be easily performed at the bedside with local anesthesia and the presence of a dilated intrahepatic or extrahepatic biliary tree or
ultrasound guidance. Liver biopsy is of proven value in the following to identify gallstones. In addition, it shows space-occupying lesions
situations: (1) hepatocellular disease of uncertain cause, (2) prolonged within the liver, enables the clinician to distinguish between cystic and
hepatitis with the possibility of autoimmune hepatitis, (3) unexplained solid masses, and helps direct percutaneous biopsies. Ultrasound with
hepatomegaly, (4) unexplained splenomegaly, (5) hepatic lesions Doppler imaging can detect the patency of the portal vein, hepatic
uncharacterized by radiologic imaging, (6) fever of unknown origin, artery, and hepatic veins and determine the direction of blood flow.
and (7) staging of malignant lymphoma. Liver biopsy is most accu- This is the first test ordered in patients suspected of having Budd-
rate in disorders causing diffuse changes throughout the liver and is Chiari syndrome.
subject to sampling error in focal disorders. Liver biopsy should not
be the initial procedure in the diagnosis of cholestasis. The biliary tree ■■USE OF LIVER TESTS
CHAPTER 330 Evaluation of Liver Function

should first be assessed for signs of obstruction. Contraindications to As previously noted, the best way to increase the sensitivity and
performing a percutaneous liver biopsy include significant ascites and specificity of laboratory tests in the detection of liver disease is to
prolonged INR. Under these circumstances, the biopsy can be per- employ a battery of tests that includes the aminotransferases, alkaline
formed via the transjugular approach. phosphatase, bilirubin, albumin, and prothrombin time along with the
judicious use of the other tests described in this chapter. Table 330-1
Noninvasive Tests to Detect Hepatic Fibrosis Although liver shows how patterns of liver tests can lead the clinician to a category
biopsy is the standard for the assessment of hepatic fibrosis, noninvasive of disease that will direct further evaluation. However, it is important
measures of hepatic fibrosis have been developed and show promise. to remember that no single set of liver tests will necessarily provide a
These measures include multiparameter tests aimed at detecting and diagnosis. It is often necessary to repeat these tests on several occasions
staging the degree of hepatic fibrosis and imaging techniques. FibroTest over days to weeks for a diagnostic pattern to emerge. Figure 330-1 is
(marketed as FibroSure in the United States) is the best evaluated of the an algorithm for the evaluation of chronically abnormal liver tests.
TABLE 330-1 Liver Test Patterns in Hepatobiliary Disorders

TYPE OF DISORDER BILIRUBIN AMINOTRANSFERASES ALKALINE PHOSPHATASE ALBUMIN PROTHROMBIN TIME
Hemolysis/Gilbert’s Normal to 86 μmol/L Normal Normal Normal Normal
syndrome (5 mg/dL)
85% due to indirect fractions
No bilirubinuria
Acute hepatocellular necrosis Both fractions may be Elevated, often >500 IU, Normal to <3× normal Normal Usually normal. If >5×
(viral and drug hepatitis, elevated ALT > AST elevation above control and not
hepatotoxins, acute heart Peak usually follows corrected by parenteral
failure) aminotransferases vitamin K, suggests
poor prognosis
Bilirubinuria
Chronic hepatocellular Both fractions may be Elevated, but usually Normal to <3× normal Often decreased Often prolonged
disorders elevated <300 IU elevation Fails to correct with
Bilirubinuria parenteral vitamin K
Alcoholic hepatitis, cirrhosis Both fractions may be AST:ALT >2 suggests Normal to <3× normal Often decreased Often prolonged
elevated alcoholic hepatitis or elevation Fails to correct with
Bilirubinuria cirrhosis parenteral vitamin K
Intra- and extrahepatic Both fractions may be Normal to moderate Elevated, often >4× Normal, unless Normal
cholestasis elevated elevation normal elevation chronic If prolonged, will correct
with parenteral vitamin
K
(Obstructive jaundice) Bilirubinuria Rarely >500 IU Elevated, often >4× Normal Normal
Infiltrative diseases (tumor, Usually normal Normal to slight elevation normal elevation
granulomata); partial bile Fractionate, or confirm
duct obstruction liver origin with
5′-nucleotidase or γ
glutamyl transpeptidase

2342 ■■GLOBAL CONSIDERATIONS 1. Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has car-
The tests and principles presented in this chapter are applica- rier-mediated kinetics. Although a number of candidate bilirubin
ble worldwide. The causes of liver test abnormalities vary transporters have been proposed, the actual transporter remains
according to region. In developing nations, infectious diseases elusive.
are more commonly the etiology of abnormal serum liver tests than in 2. Intracellular binding: Within the hepatocyte, bilirubin is kept in solu-
developed nations. tion by binding as a nonsubstrate ligand to several of the glutathi-
one-S-transferases, formerly called ligandins.
■■Acknowledgment 3. Conjugation: Bilirubin is conjugated with one or two glucuronic acid
This chapter represents a revised version of a chapter in previous moieties by a specific UDP-glucuronosyltransferase to form biliru-
editions of Harrison’s in which Marshall M. Kaplan was a co-author. bin mono- and diglucuronide, respectively. Conjugation disrupts
the internal hydrogen bonding that limits aqueous solubility of bil-
■■FURTHER READING irubin, and the resulting glucuronide conjugates are highly soluble
Kamath PS, Kim WR: The Model for End-Stage Liver Disease (MELD).
in water. Conjugation is obligatory for excretion of bilirubin across
Hepatology 45:797, 2007.
the bile canalicular membrane into bile. The UDP-glucuronosyl-
Kaplan M: Alkaline phosphatase. Gastroenterology 62:452, 1972.
transferases have been classified into gene families based on the
Martínez SM et al: Noninvasive assessment of liver fibrosis.
degree of homology among the mRNAs for the various isoforms.
Hepatology 53:325, 2011.
Those that conjugate bilirubin and certain other substrates have
Prati D et al: Updated definitions of healthy ranges for serum alanine
been designated the UGT1 family. These are expressed from a single
aminotransferase levels. Ann Intern Med 137:1, 2002.
gene complex by alternative promoter usage. This gene complex
contains multiple substrate-specific first exons, designated A1, A2,
etc. (Fig. 331-2), each with its own promoter and each encoding the
amino-terminal half of a specific isoform. In addition, there are four
common exons (exons 2–5) that encode the shared carboxyl-terminal
half of all of the UGT1 isoforms. The various first exons encode the
331 The Hyperbilirubinemias

Allan W. Wolkoff
specific aglycone substrate binding sites for each isoform, while the
shared exons encode the binding site for the sugar donor, UDP-
glucuronic acid, and the transmembrane domain. Exon A1 and the
four common exons, collectively designated as the UGT1A1 gene
(Fig. 331-2), encode the physiologically critical enzyme biliru-
PART 10
bin-UDP-glucuronosyltransferase (UGT1A1). A functional corollary

■■BILIRUBIN METABOLISM
of the organization of the UGT1 gene is that a mutation in one of the
The details of bilirubin metabolism are presented in Chap. 45. How-
first exons will affect only a single enzyme isoform. By contrast, a
ever, the hyperbilirubinemias are best understood in terms of pertur-
mutation in exons 2–5 will alter all isoforms encoded by the UGT1
bations of specific aspects of bilirubin metabolism and transport, and
gene complex.
these will be briefly reviewed here as depicted in Fig. 331-1.

4. Biliary excretion: It has been thought until recently that bilirubin
Bilirubin is the end product of heme degradation. Some 70–90% of
mono- and diglucuronides are excreted directly across the canalicu-
bilirubin is derived from degradation of the hemoglobin of senescent
lar plasma membrane into the bile canaliculus by an ATP-dependent
red blood cells. Bilirubin produced in the periphery is transported to
transport process mediated by a canalicular membrane protein
the liver within the plasma, where, due to its insolubility in aqueous
called multidrug resistance–associated protein 2 (MRP2). Mutations of
solutions, it is tightly bound to albumin. Under normal circumstances,
MRP2 result in the Dubin-Johnson syndrome (see below). However,
bilirubin is removed from the circulation rapidly and efficiently by
studies in patients with Rotor syndrome (see below) indicate that
hepatocytes. Transfer of bilirubin from blood to bile involves four dis-
after formation, a portion of the glucuronides is transported into the
tinct but interrelated steps (Fig. 331-1).
portal circulation by a sinusoidal membrane protein called multidrug
resistance–associated protein 3 (MRP3) and is subjected to reuptake
into the hepatocyte by the sinusoidal membrane uptake transporters
organic anion transport protein 1B1 (OATP1B1) and OATP1B3.
OATP1B1
ALB
OATP1B3
■■EXTRAHEPATIC ASPECTS OF BILIRUBIN
BMG
UCB
UGT1A1 BMG
DISPOSITION
BDG
MRP3 GST:UCB Bilirubin in the Gut Following secretion into bile, conjugated
UCB UGT1A1
MRP2
BMG bilirubin reaches the duodenum and passes down the gastroin-
BDG testinal tract without reabsorption by the intestinal mucosa. An
BT UCB BDG
+ appreciable fraction is converted by bacterial metabolism in the gut
ALB:UCB GST to the water-soluble colorless compound urobilinogen. Urobilinogen
undergoes enterohepatic cycling. Urobilinogen not taken up by the
Space
of liver reaches the systemic circulation, from which some is cleared
Sinusoid Disse by the kidneys. Unconjugated bilirubin ordinarily does not reach
FIGURE 331-1 Hepatocellular bilirubin transport. Albumin-bound bilirubin in the gut except in neonates or, by ill-defined alternative pathways,
sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte in the presence of severe unconjugated hyperbilirubinemia (e.g.,
surface, entering the cell by both facilitated and simple diffusional processes. Crigler-Najjar syndrome, type I [CN-I]). Unconjugated bilirubin that
Within the cell, it is bound to glutathione-S-transferases and conjugated by reaches the gut is partly reabsorbed, amplifying any underlying
bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono- and diglucuronides, hyperbilirubinemia.
which are actively transported across the canalicular membrane into the bile. In
addition to this direct excretion of bilirubin glucuronides, a portion are transported Renal Excretion of Bilirubin Conjugates Unconjugated
into the portal circulation by MRP3 and subjected to reuptake into the hepatocyte bilirubin is not excreted in urine, as it is too tightly bound to albumin
by OATP1B1 and OATP1B3. ALB, albumin; BDG, bilirubin diglucuronide; BMG,
bilirubin monoglucuronide; BT, proposed bilirubin transporter; GST, glutathione-S-
for effective glomerular filtration and there is no tubular mechanism
transferase; MRP2 and MRP3, multidrug resistance–associated proteins 2 and for its renal secretion. In contrast, the bilirubin conjugates are readily
3; OATP1B1 and OATP1B3, organic anion transport proteins 1B1 and 1B3; UCB, filtered at the glomerulus and can appear in urine in disorders charac-
unconjugated bilirubin; UGT1A1, bilirubin-UDP-glucuronosyltransferase. terized by increased bilirubin conjugates in the circulation. It should

5′ 500 kb 3′ ■■DECREASED HEPATIC 2343
BILIRUBIN CLEARANCE
Variable (Substrate Specific) First Exons Common Exons
Decreased Hepatic Uptake
2 3 4 5 Decreased hepatic bilirubin uptake is
believed to contribute to the unconju-
gated hyperbilirubinemia of Gilbert’s
A13 A12 A11 A10 A9 A8 A7 A6 A5 A4 A3 A2 A1 syndrome (GS), although the molecular
basis for this finding remains unclear (see
~286 AA ~245 AA below). Several drugs, including flavas-
A(TA)6TAA pidic acid, novobiocin, and rifampin, as
well as various cholecystographic con-
TATA Box
trast agents, have been reported to inhibit
FIGURE 331-2 Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 bilirubin uptake. The resulting unconju-
contains at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are pseudogenes, nine UGT1 gated hyperbilirubinemia resolves with
isoforms with differing substrate specificities are expressed. Each exon 1 has its own promoter and encodes the
amino-terminal substrate-specific ~286 amino acids of the various UGT1-encoded isoforms, and common exons
cessation of the medication.
2–5 that encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms Impaired Conjugation • PHYSI-
are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting OLOGIC NEONATAL JAUNDICE Bilirubin
message encodes a complete enzyme, in this particular case bilirubin-UDP-glucuronosyltransferase (UGT1A1).
Mutations in a first exon affect only a single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 produced by the fetus is cleared by the
complex. placenta and eliminated by the maternal
liver. Immediately after birth, the neona-
tal liver must assume responsibility for
be kept in mind that the kidney can serve as an “overflow valve” for bilirubin clearance and excretion. However, many hepatic physiologic
conjugated bilirubin. Consequently, the level of jaundice in individuals processes are incompletely developed at birth. Levels of UGT1A1 are
with conjugated hyperbilirubinemia can be amplified in the presence low, and alternative excretory pathways allow passage of unconjugated
of renal failure. bilirubin into the gut. Since the intestinal flora that convert bilirubin
to urobilinogen are also undeveloped, an enterohepatic circulation
DISORDERS OF BILIRUBIN METABOLISM of unconjugated bilirubin ensues. As a consequence, most neonates
CHAPTER 331 The Hyperbilirubinemias

LEADING TO UNCONJUGATED develop mild unconjugated hyperbilirubinemia between days 2 and 5
after birth. Peak levels are typically <85–170 μmol/L (5–10 mg/dL) and
HYPERBILIRUBINEMIA decline to normal adult concentrations within 2 weeks, as mechanisms
■■INCREASED BILIRUBIN PRODUCTION required for bilirubin disposition mature. Prematurity, often associated
with more profound immaturity of hepatic function and hemolysis,
Hemolysis Increased destruction of erythrocytes leads to increased can result in higher levels of unconjugated hyperbilirubinemia. A
bilirubin turnover and unconjugated hyperbilirubinemia; the hyperbi- rapidly rising unconjugated bilirubin concentration, or absolute levels
lirubinemia is usually modest in the presence of normal liver function. >340 μmol/L (20 mg/dL), puts the infant at risk for bilirubin enceph-
In particular, the bone marrow is only capable of a sustained eightfold alopathy, or kernicterus. Under these circumstances, bilirubin crosses
increase in erythrocyte production in response to a hemolytic stress. an immature blood-brain barrier and precipitates in the basal ganglia
Therefore, hemolysis alone cannot result in a sustained hyperbi- and other areas of the brain. The consequences range from appreciable
lirubinemia of more than ~68 μmol/L (4 mg/dL). Higher values neurologic deficits to death. Treatment options include phototherapy,
imply concomitant hepatic dysfunction. When hemolysis is the only which converts bilirubin into water-soluble photoisomers that are
abnormality in an otherwise healthy individual, the result is a purely excreted directly into bile, and exchange transfusion. The canalicular
unconjugated hyperbilirubinemia, with the direct-reacting fraction as mechanisms responsible for bilirubin excretion are also immature at
measured in a typical clinical laboratory being ≤15% of the total serum birth, and their maturation may lag behind that of UGT1A1; this can
bilirubin. In the presence of systemic disease, which may include a lead to transient conjugated neonatal hyperbilirubinemia, especially in
degree of hepatic dysfunction, hemolysis may produce a component infants with hemolysis.
of conjugated hyperbilirubinemia in addition to an elevated uncon-
ACQUIRED CONJUGATION DEFECTS A modest reduction in bilirubin con-
jugated bilirubin concentration. Prolonged hemolysis may lead to the
jugating capacity may be observed in advanced hepatitis or cirrhosis.
precipitation of bilirubin salts within the gallbladder or biliary tree,
However, in this setting, conjugation is better preserved than other
resulting in the formation of gallstones in which bilirubin, rather than
aspects of bilirubin disposition, such as canalicular excretion. Various
cholesterol, is the major component. Such pigment stones may lead to
drugs, including pregnanediol, novobiocin, chloramphenicol, gentami-
acute or chronic cholecystitis, biliary obstruction, or any other biliary
cin, and atazanavir may produce unconjugated hyperbilirubinemia
tract consequence of calculous disease.
by inhibiting UGT1A1 activity. Bilirubin conjugation may be inhibited
Ineffective Erythropoiesis During erythroid maturation, small by certain fatty acids that are present in breast milk, but not serum of
amounts of hemoglobin may be lost at the time of nuclear extrusion, mothers whose infants have excessive neonatal hyperbilirubinemia
and a fraction of developing erythroid cells is destroyed within the (breast milk jaundice). Alternatively, there may be increased enterohe-
marrow. These processes normally account for a small proportion of patic circulation of bilirubin in these infants. The pathogenesis of breast
bilirubin that is produced. In various disorders, including thalassemia milk jaundice appears to differ from that of transient familial neonatal
major, megaloblastic anemias due to folate or vitamin B12 deficiency, hyperbilirubinemia (Lucey-Driscoll syndrome), in which there may be
congenital erythropoietic porphyria, lead poisoning, and various a UGT1A1 inhibitor in maternal serum.
congenital and acquired dyserythropoietic anemias, the fraction of
total bilirubin production derived from ineffective erythropoiesis is ■■HEREDITARY DEFECTS IN BILIRUBIN CONJUGATION
increased, reaching as much as 70% of the total. This may be sufficient Three familial disorders characterized by differing degrees of uncon-
to produce modest degrees of unconjugated hyperbilirubinemia. jugated hyperbilirubinemia have long been recognized. The defining
clinical features of each are described below (Table 331-1). While these
Miscellaneous Degradation of the hemoglobin of extravascu- disorders have been recognized for decades to reflect differing degrees
lar collections of erythrocytes, such as those seen in massive tissue of deficiency in the ability to conjugate bilirubin, recent advances in
infarctions or large hematomas, may lead transiently to unconjugated the molecular biology of the UGT1 gene complex have elucidated their
hyperbilirubinemia. interrelationships and clarified previously puzzling features.

2344 TABLE 331-1 Principal Differential Characteristics of Gilbert’s and Crigler-Najjar Syndromes
CRIGLER-NAJJAR SYNDROME
FEATURE TYPE I TYPE II GILBERT’S SYNDROME
Total serum bilirubin, μmol/L (mg/dL) 310–755 (usually >345) (18–45 100–430 (usually ≤345) (6–25 Typically ≤70 μmol/L (≤4 mg/dL) in
[usually >20]) [usually ≤20]) absence of fasting or hemolysis
Routine liver tests Normal Normal Normal
Response to phenobarbital None Decreases bilirubin by >25% Decreases bilirubin to normal
Kernicterus Usual Rare No
Hepatic histology Normal Normal Usually normal; increased lipofuscin
pigment in some
Bile characteristics
Color Pale or colorless Pigmented Normal dark color
Bilirubin fractions >90% unconjugated Largest fraction (mean: 57%) Mainly diconjugates but
monoconjugates monoconjugates increased (mean:
23%)
Bilirubin UDP-glucuronosyltransferase Typically absent; traces in some Markedly reduced: 0–10% of normal Reduced: typically 10–33% of normal
activity patients Predominantly recessive Promoter mutation: recessive
Inheritance (all autosomal) Recessive Missense mutations: 7 of 8 dominant;
1 reportedly recessive
Crigler-Najjar Syndrome, Type I CN-I is characterized by marked unconjugated hyperbilirubinemia in the absence of abnormal-
striking unconjugated hyperbilirubinemia of about 340–765 μmol/L ities of other conventional hepatic biochemical tests, hepatic histology,
(20–45 mg/dL) that appears in the neonatal period and persists for or hemolysis. It differs from CN-I in several specific ways (Table 331-1):
life. Other conventional hepatic biochemical tests such as serum (1) Although there is considerable overlap, average bilirubin concen-
aminotransferases and alkaline phosphatase are normal, and there is trations are lower in CN-II; (2) accordingly, CN-II is only infrequently
no evidence of hemolysis. Hepatic histology is also essentially nor- associated with kernicterus; (3) bile is deeply colored, and bilirubin
mal except for the occasional presence of bile plugs within canaliculi. glucuronides are present, with a striking, characteristic increase in the
PART 10
Bilirubin glucuronides are virtually absent from the bile, and there is proportion of monoglucuronides; (4) UGT1A1 in liver is usually pres-
no detectable constitutive expression of UGT1A1 activity in hepatic ent at reduced levels (typically ≤10% of normal); and (5) while typically
tissue. Neither UGT1A1 activity nor the serum bilirubin concentration detected in infancy, hyperbilirubinemia was not recognized in some
responds to administration of phenobarbital or other enzyme inducers. cases until later in life and, in one instance, at age 34. As with CN-I,
most CN-II cases exhibit abnormalities in the conjugation of other
Unconjugated bilirubin accumulates in plasma, from which it is elimi-

nated very slowly by alternative pathways that include direct passage compounds, such as salicylamide and menthol, but in some instances,
into the bile and small intestine, possibly via bilirubin photoisomers. the defect appears limited to bilirubin. Reduction of serum bilirubin
This accounts for the small amount of urobilinogen found in feces. No concentrations by >25% in response to enzyme inducers such as pheno-
bilirubin is found in the urine. First described in 1952, the disorder barbital distinguishes CN-II from CN-I, although this response may not
is rare (estimated prevalence, 0.6–1.0 per million). Many patients are be elicited in early infancy and often is not accompanied by measurable
from geographically or socially isolated communities in which consan- UGT1A1 induction. Bilirubin concentrations during phenobarbital
guinity is common, and pedigree analyses show an autosomal reces- administration do not return to normal but are typically in the range
sive pattern of inheritance. The majority of patients (type IA) exhibit of 51–86 μmol/L (3–5 mg/dL). Although the incidence of kernicterus
defects in the glucuronide conjugation of a spectrum of substrates in in CN-II is low, instances have occurred, not only in infants but also in
addition to bilirubin, including various drugs and other xenobiotics. adolescents and adults, often in the setting of an intercurrent illness,
These individuals have mutations in one of the common exons (2–5) of fasting, or another factor that temporarily raises the serum bilirubin
the UGT1 gene (Fig. 331-2). In a smaller subset (type IB), the defect is concentration above baseline and reduces serum albumin levels. For
limited largely to bilirubin conjugation, and the causative mutation is this reason, phenobarbital therapy is widely recommended, a single
in the bilirubin-specific exon A1. Estrogen glucuronidation is mediated bedtime dose often sufficing to maintain clinically safe serum bilirubin
by UGT1A1 and is defective in all CN-I patients. More than 30 different concentrations.
genetic lesions of UGT1A1 responsible for CN-I have been identified, Over 100 different mutations in the UGT1 gene have been identified
including deletions, insertions, alterations in intron splice donor and as causing CN-I or CN-II. It was found that missense mutations are
acceptor sites, exon skipping, and point mutations that introduce pre- more common in CN-II patients, as would be expected in this less
mature stop codons or alter critical amino acids. Their common feature severe phenotype. Their common feature is that they encode for a
is that they all encode proteins with absent or, at most, traces of biliru- bilirubin-UDP-glucuronosyltransferase with markedly reduced, but
bin-UDP-glucuronosyltransferase enzymatic activity. detectable, enzymatic activity. The spectrum of residual enzyme activ-
Prior to the use of phototherapy, most patients with CN-I died of ity explains the spectrum of phenotypic severity of the resulting hyper-
bilirubin encephalopathy (kernicterus) in infancy or early childhood. A bilirubinemia. Molecular analysis has established that a large majority
few lived as long as early adult life without overt neurologic damage, of CN-II patients are either homozygotes or compound heterozygotes
although more subtle testing usually indicated mild but progressive for CN-II mutations and that individuals carrying one mutated and one
brain damage. In the absence of liver transplantation, death eventually entirely normal allele have normal bilirubin concentrations.
supervened from late-onset bilirubin encephalopathy, which often
followed a nonspecific febrile illness. Although isolated hepatocyte Gilbert’s Syndrome This syndrome is characterized by mild
transplantation has been used in a small number of cases of CN-I, early unconjugated hyperbilirubinemia, normal values for standard hepatic
liver transplantation (Chap. 338) remains the best hope to prevent brain biochemical tests, and normal hepatic histology other than a mod-
injury and death at present. It is anticipated that gene replacement est increase of lipofuscin pigment in some patients. Serum bilirubin
therapy may be an option in the future. concentrations are most often <51 μmol/L (<3 mg/dL), although
both higher and lower values are frequent. The clinical spectrum of
Crigler-Najjar Syndrome, Type II (CN-II) This condition hyperbilirubinemia fades into that of CN-II at serum bilirubin concen-
was recognized as a distinct entity in 1962 and is characterized by trations of 86–136 μmol/L (5–8 mg/dL). At the other end of the scale,

the distinction between mild cases of GS and a normal state is often be necessary, but not sufficient, for clinically expressed GS, since 15% of 2345
blurred. Bilirubin concentrations may fluctuate substantially in any normal controls were also homozygous for this variant. While normal
given individual, and at least 25% of patients will exhibit temporarily by standard criteria, these individuals had somewhat higher bilirubin
normal values during prolonged follow-up. More elevated values are concentrations than the rest of the controls studied. Heterozygotes
associated with stress, fatigue, alcohol use, reduced caloric intake, and for this abnormality had bilirubin concentrations identical to those
intercurrent illness, while increased caloric intake or administration of homozygous for the normal A[TA]6TAA allele. The prevalence of the
enzyme-inducing agents produces lower bilirubin levels. GS is most A[TA]7TAA allele in a general Western population is 30%, in which case
often diagnosed at or shortly after puberty or in adult life during 9% would be homozygotes. This is slightly higher than the prevalence
routine examinations that include multichannel biochemical analyses. of GS based on purely phenotypic parameters. It was suggested that
UGT1A1 activity is typically reduced to 10–35% of normal, and bile pig- additional variables, such as mild hemolysis or a defect in bilirubin
ments exhibit a characteristic increase in bilirubin monoglucuronides. uptake, might be among the factors enhancing phenotypic expression
Studies of radiobilirubin kinetics indicate that hepatic bilirubin clear- of the defect.
ance is reduced to an average of one-third of normal. Administration Phenotypic expression of GS due solely to the A[TA]7TAA promoter
of phenobarbital normalizes both the serum bilirubin concentration abnormality is inherited as an autosomal recessive trait. A number of
and hepatic bilirubin clearance; however, failure of UGT1A1 activity CN-II kindreds have been identified in whom there is also an allele
to improve in many such instances suggests the possible coexistence containing a normal coding region but the A[TA]7TAA promoter abnor-
of an additional defect. Compartmental analysis of bilirubin kinetic mality. CN-II heterozygotes, who have the A[TA]6TAA promoter, are
data suggests that GS patients may have a defect in bilirubin uptake phenotypically normal, whereas those with the A[TA]7TAA promoter
as well as in conjugation, although this has not been shown directly. express the phenotypic picture of GS. GS in such kindreds may also
Defect(s) in the hepatic uptake of other organic anions that at least result from homozygosity for the A[TA]7TAA promoter abnormality.
partially share an uptake mechanism with bilirubin, such as sulfobro- Seven different missense mutations in the UGT1 gene that reportedly
mophthalein and indocyanine green (ICG), are observed in a minority cause GS with dominant inheritance have been found in Japanese
of patients. The metabolism and transport of bile acids that do not individuals. Another Japanese patient with mild unconjugated hyper-
utilize the bilirubin uptake mechanism are normal. The magnitude of bilirubinemia was homozygous for a missense mutation in exon 5. GS
changes in the serum bilirubin concentration induced by provocation in her family appeared to be recessive.
tests such as 48 hours of fasting or the IV administration of nicotinic
acid have been reported to be of help in separating GS patients from DISORDERS OF BILIRUBIN METABOLISM
normal individuals. Other studies dispute this assertion. Moreover, on LEADING TO MIXED OR PREDOMINANTLY
CHAPTER 331 The Hyperbilirubinemias

theoretical grounds, the results of such studies should provide no more
information than simple measurements of the baseline serum bilirubin
CONJUGATED HYPERBILIRUBINEMIA
In hyperbilirubinemia due to acquired liver disease (e.g., acute hep-
concentration. Family studies indicate that GS and hereditary hemo-
atitis, common bile duct stone), there are usually elevations in the
lytic anemias such as hereditary spherocytosis, glucose-6-phosphate
serum concentrations of both conjugated and unconjugated bilirubin.
dehydrogenase deficiency, and β-thalassemia trait sort independently.
Although biliary tract obstruction or hepatocellular cholestatic injury
Reports of hemolysis in up to 50% of GS patients are believed to reflect
may present on occasion with a predominantly conjugated hyperbi-
better case finding, since patients with both GS and hemolysis have
lirubinemia, it is generally not possible to differentiate intrahepatic
higher bilirubin concentrations, and are more likely to be jaundiced,
from extrahepatic causes of jaundice based on the serum levels or
than patients with either defect alone.
relative proportions of unconjugated and conjugated bilirubin. The
GS is common, with many series placing its prevalence as high
major reason for determining the amounts of conjugated and uncon-
as 8%. Males predominate over females by reported ratios ranging
jugated bilirubin in the serum is for the initial differentiation of
from 1.5:1 to >7:1. However, these ratios may have a large artifactual
hepatic parenchymal and obstructive disorders (mixed conjugated and
component since normal males have higher mean bilirubin levels than
unconjugated hyperbilirubinemia) from the inheritable and hemolytic
normal females, but the diagnosis of GS is often based on comparison
disorders discussed above that are associated with unconjugated
to normal ranges established in men. The high prevalence of GS in the
hyperbilirubinemia.
general population may explain the reported frequency of mild uncon-
jugated hyperbilirubinemia in liver transplant recipients. The dispo- ■■FAMILIAL DEFECTS IN HEPATIC EXCRETORY
sition of most xenobiotics metabolized by glucuronidation appears to FUNCTION
be normal in GS, as is oxidative drug metabolism in the majority of
reported studies. The principal exception is the metabolism of the anti- Dubin-Johnson Syndrome (DJS) This benign, relatively rare
tumor agent irinotecan (CPT-11), whose active metabolite (SN-38) is disorder is characterized by low-grade, predominantly conjugated
glucuronidated specifically by bilirubin-UDP-glucuronosyltransferase. hyperbilirubinemia (Table 331-2). Total bilirubin concentrations are
Administration of CPT-11 to patients with GS has resulted in several typically between 34 and 85 μmol/L (2 and 5 mg/dL) but on occa-
toxicities, including intractable diarrhea and myelosuppression. Some sion can be in the normal range or as high as 340–430 μmol/L
reports also suggest abnormal disposition of menthol, estradiol ben- (20–25 mg/dL) and can fluctuate widely in any given patient. The
zoate, acetaminophen, tolbutamide, and rifamycin SV. Although some degree of hyperbilirubinemia may be increased by intercurrent illness,
of these studies have been disputed, and there have been no reports oral contraceptive use, and pregnancy. Because the hyperbilirubinemia
of clinical complications from use of these agents in GS, prudence is due to a predominant rise in conjugated bilirubin, bilirubinuria is
should be exercised in prescribing them, or any agents metabolized characteristically present. Aside from elevated serum bilirubin levels,
primarily by glucuronidation in this condition. It should also be noted other routine laboratory tests are normal. Physical examination is usu-
that the HIV protease inhibitors indinavir and atazanavir (Chap. 197) ally normal except for jaundice, although an occasional patient may
can inhibit UGT1A1, resulting in hyperbilirubinemia that is most pro- have hepatosplenomegaly.
nounced in patients with preexisting GS. Patients with DJS are usually asymptomatic, although some may
Most older pedigree studies of GS were consistent with autosomal have vague constitutional symptoms. These latter patients have usu-
dominant inheritance with variable expressivity. However, studies of ally undergone extensive and often unnecessary diagnostic exami-
the UGT1 gene in GS have indicated a variety of molecular genetic nations for unexplained jaundice and have high levels of anxiety. In
bases for the phenotypic picture and several different patterns of women, the condition may be subclinical until the patient becomes
inheritance. Studies in Europe and the United States found that nearly pregnant or receives oral contraceptives, at which time chemical hyper-
all patients had normal coding regions for UGT1A1, but were homozy- bilirubinemia becomes frank jaundice. Even in these situations, other
gous for the insertion of an extra TA (i.e., A[TA]7TAA rather than routine liver function tests, including serum alkaline phosphatase and
A[TA]6TAA) in the promoter region of the first exon. This appeared to transaminase activities, are normal.

2346 TABLE 331-2 Principal Differential Characteristics of Inheritable Disorders of Bile Canalicular Function
DJS ROTOR PFIC1 BRIC1 PFIC2 BRIC2 PFIC3
Gene ABCCA SLCO1B1/SLCO1B3 ATP8B1 ATP8B1 ABCB11 ABCB11 ABCB4
Protein MRP2 OATP1B1/1B3 FIC1 FIC1 BSEP BSEP MDR3
Cholestasis No No Yes Episodic Yes Episodic Yes
Serum GGT Normal Normal Normal Normal Normal Normal ↑↑
Serum bile acids Normal Normal ↑↑ ↑↑ during ↑↑ ↑↑ during ↑↑
episodes episodes
Clinical features Mild conjugated Mild conjugated Severe Recurrent Severe Recurrent Severe
hyperbilirubinemia; hyperbilirubinemia; cholestasis episodes of cholestasis episodes of cholestasis
otherwise normal otherwise normal liver beginning in cholestasis beginning in cholestasis beginning in
liver function; dark function; liver without childhood beginning at any childhood beginning at childhood;
pigment in liver; abnormal pigmentation age any age decreased
characteristic phospholipids
pattern of urinary in bile
coproporphyrins
Abbreviations: BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt excretory protein; DJS, Dubin-Johnson syndrome; GGT, γ-glutamyltransferase;
MRP2, multidrug resistance–associated protein 2; OATP1A/1B, organic anion transport proteins 1B1 and 1B3; PFIC, progressive familial intrahepatic cholestasis;
↑↑, increased.
A cardinal feature of DJS is the accumulation in the lysosomes of of total serum bilirubin, due to a predominant rise in conjugated bil-
centrilobular hepatocytes of dark, coarsely granular pigment. As a irubin. This is accompanied by bilirubinuria. Several additional fea-
result, the liver may be grossly black in appearance. This pigment tures differentiate Rotor syndrome from DJS. In Rotor syndrome, the
is thought to be derived from epinephrine metabolites that are not gallbladder is usually visualized on oral cholecystography, in contrast
excreted normally. The pigment may disappear during bouts of viral to the nonvisualization that is typical of DJS. The pattern of urinary
hepatitis, only to reaccumulate slowly after recovery. coproporphyrin excretion also differs. The pattern in Rotor syndrome
Biliary excretion of a number of anionic compounds is compro- resembles that of many acquired disorders of hepatobiliary function,
mised in DJS. These include various cholecystographic agents, as in which coproporphyrin I, the major coproporphyrin isomer in bile,
PART 10
well as sulfobromophthalein (Bromsulphalein, BSP), a synthetic dye refluxes from the hepatocyte back into the circulation and is excreted
formerly used in a test of liver function. In this test, the rate of dis- in urine. Thus, total urinary coproporphyrin excretion is substantially
appearance of BSP from plasma was determined following bolus IV increased in Rotor syndrome, in contrast to the normal levels seen in
administration. BSP is conjugated with glutathione in the hepatocyte; DJS. Although the fraction of coproporphyrin I in urine is elevated, it
the resulting conjugate is normally excreted rapidly into the bile is usually <70% of the total, compared with ≥80% in DJS. The disorders
canaliculus. Patients with DJS exhibit characteristic rises in plasma also can be distinguished by their patterns of BSP excretion. Although
concentrations at 90 min after injection, due to reflux of conjugated clearance of BSP from plasma is delayed in Rotor syndrome, there is no
BSP into the circulation from the hepatocyte. Dyes such as ICG that reflux of conjugated BSP back into the circulation as seen in DJS. Kinetic
are taken up by hepatocytes but are not further metabolized prior to analysis of plasma BSP infusion studies suggests the presence of a
biliary excretion do not show this reflux phenomenon. Continuous defect in intrahepatocellular storage of this compound. This has never
BSP infusion studies suggest a reduction in the time to maximum been demonstrated directly. Recent studies indicate that the molecular
plasma concentration (tmax) for biliary excretion. Bile acid disposition, basis of Rotor syndrome results from simultaneous deficiency of the
including hepatocellular uptake and biliary excretion, is normal in hepatocyte plasma membrane transporters OATP1B1 and OATP1B3.
DJS. These patients have normal serum and biliary bile acid concen- This results in reduced reuptake by these transporters of conjugated
trations and do not have pruritus. bilirubin that has been pumped out of the hepatocyte into the portal
By analogy with findings in several mutant rat strains, the selective circulation by MRP3 (Fig. 331-1).
defect—in biliary excretion of bilirubin conjugates and certain other
classes of organic compounds, but not of bile acids—that characterizes
Benign Recurrent Intrahepatic Cholestasis (BRIC) This
rare disorder is characterized by recurrent attacks of pruritus and
DJS in humans was found to reflect defective expression of MRP2, an
jaundice. The typical episode begins with mild malaise and elevations
ATP-dependent canalicular membrane transporter. Several different
in serum aminotransferase levels, followed rapidly by rises in alka-
mutations in the MRP2 gene produce the Dubin-Johnson phenotype,
line phosphatase and conjugated bilirubin and onset of jaundice and
which has an autosomal recessive pattern of inheritance. Although
itching. The first one or two episodes may be misdiagnosed as acute
MRP2 is undoubtedly important in the biliary excretion of conjugated
viral hepatitis. The cholestatic episodes, which may begin in childhood
bilirubin, the fact that this pigment is still excreted in the absence of
or adulthood, can vary in duration from several weeks to months,
MRP2 suggests that other, as yet uncharacterized, transport proteins
followed by a complete clinical and biochemical resolution. Intervals
may serve in a secondary role in this process.
between attacks may vary from several months to years. Between
Patients with DJS also have a diagnostic abnormality in urinary
episodes, physical examination is normal, as are serum levels of bile
coproporphyrin excretion. There are two naturally occurring copro-
acids, bilirubin, transaminases, and alkaline phosphatase. The disorder
porphyrin isomers, I and III. Normally, ~75% of the coproporphyrin
is familial and has an autosomal recessive pattern of inheritance. BRIC
in urine is isomer III. In urine from DJS patients, total coproporphyrin
is considered a benign disorder in that it does not lead to cirrhosis or
content is normal, but >80% is isomer I. Heterozygotes for the syn-
end-stage liver disease. However, the episodes of jaundice and pruritus
drome show an intermediate pattern. The molecular basis for this
can be prolonged and debilitating, and some patients have undergone
phenomenon remains unclear.
liver transplantation to relieve the intractable and disabling symptoms.
Rotor Syndrome This benign, autosomal recessive disorder is Treatment during the cholestatic episodes is symptomatic; there is no
clinically similar to DJS (Table 331-2), although it is seen even less fre- specific treatment to prevent or shorten the occurrence of episodes.
quently. A major phenotypic difference is that the liver in patients with A gene termed FIC1 was recently identified and found to be mutated
Rotor syndrome has no increased pigmentation and appears totally in patients with BRIC. Curiously, this gene is expressed strongly in the
normal. The only abnormality in routine laboratory tests is an elevation small intestine but only weakly in the liver. The protein encoded by

FIC1 shows little similarity to those that have been shown to play a role 2347
in bile canalicular excretion of various compounds. Rather, it appears to
be a member of a P-type ATPase family that transports aminophospho-
lipids from the outer to the inner leaflet of a variety of cell membranes.
332 Acute Viral Hepatitis
Jules L. Dienstag
Its relationship to the pathobiology of this disorder remains unclear.
A second phenotypically identical form of BRIC, termed BRIC type 2,
has been described resulting from mutations in the bile salt excretory
Acute viral hepatitis is a systemic infection affecting the liver predomi-
protein (BSEP), the protein that is defective in progressive familial
nantly. Almost all cases of acute viral hepatitis are caused by one of five
intrahepatic cholestasis (PFIC) type 2 (Table 331-2). How some muta-
viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C
tions in this protein result in the episodic BRIC phenotype is unknown.
virus (HCV), the HBV-associated delta agent or hepatitis D virus
Progressive Familial Intrahepatic Cholestasis (FIC) This (HDV), and hepatitis E virus (HEV). All these human hepatitis viruses
name is applied to three phenotypically related syndromes (Table 331-2). are RNA viruses, except for hepatitis B, which is a DNA virus but
PFIC type 1 (Byler disease) presents in early infancy as cholestasis that replicates like a retrovirus. Although these agents can be distinguished
may be initially episodic. However, in contrast to BRIC, Byler disease by their molecular and antigenic properties, all types of viral hepatitis
progresses to malnutrition, growth retardation, and end-stage liver produce clinically similar illnesses. These range from asymptomatic
disease during childhood. This disorder is also a consequence of a FIC1 and inapparent to fulminant and fatal acute infections common to all
mutation. The functional relationship of the FIC1 protein to the patho- types, on the one hand, and from subclinical persistent infections to
genesis of cholestasis in these disorders is unknown. Two other types of rapidly progressive chronic liver disease with cirrhosis and even hepa-
PFIC (types 2 and 3) have been described. PFIC type 2 is associated with tocellular carcinoma, common to the bloodborne types (HBV, HCV, and
a mutation in the protein originally named sister of p-glycoprotein, now HDV), on the other.
known as bile salt excretory protein, which is the major bile canalicular
exporter of bile acids. As noted above, some mutations of this protein ■■ VIROLOGY AND ETIOLOGY
are associated with BRIC type 2, rather than the progressive FIC type 2 Hepatitis A HAV is a nonenveloped 27-nm, heat-, acid-, and
phenotype. Progressive FIC type 3 has been associated with a mutation ether-resistant RNA virus in the Hepatovirus genus of the picornavi-
of MDR3, a protein that is essential for normal hepatocellular excretion rus family (Fig. 332-1). Its virion contains four capsid polypeptides,
of phospholipids across the bile canaliculus. Although all three types designated VP1–VP4, which are cleaved posttranslationally from the
of PFIC have similar clinical phenotypes, only type 3 is associated with polyprotein product of a 7500-nucleotide genome. Inactivation of viral
high serum levels of γ-glutamyltransferase (GGT) activity. In contrast,
CHAPTER 332 Acute Viral Hepatitis

activity can be achieved by boiling for 1 min, by contact with formal-
activity of this enzyme is normal or only mildly elevated in symptom- dehyde and chlorine, or by ultraviolet irradiation. Despite nucleotide
atic BRIC and progressive FIC types 1 and 2. Interestingly, mutations in sequence variation of up to 20% among isolates of HAV, and despite the
FIC1 or BSEP are not found in approximately one-third of patients with recognition of four genotypes affecting humans, all strains of this virus
clinical PFIC and normal GGT. Recent studies have shown that patients are immunologically indistinguishable and belong to one serotype.
with mutations in NR1H4, the gene encoding the farnesoid X receptor Human HAV can infect and cause hepatitis in chimpanzees, tamarins
(FXR), a nuclear hormone receptor activated by bile acids, have a syn- (marmosets), and several monkey species. Recently, a hepatotropic
drome identical to PFIC2 with absent expression of BSEP. Mutations in Hepatovirus related to, and likely to have shared common evolution-
tight junction protein 2 (TJP2) have also been associated with severe ary ancestry with, human HAV has been identified in several species
cholestasis with normal GGT levels, likely due to disruption of tight of harbor seals, albeit without histologic evidence for liver injury or
junctions at the bile canaliculus. inflammation. Hepatitis A has an incubation period of ~4 weeks. Its
replication is limited to the liver, but the virus is present in the liver,
■■FURTHER READING bile, stools, and blood during the late incubation period and acute
Canu G et al: Gilbert and Crigler Najjar syndromes: An update of the preicteric/presymptomatic phase of illness. Despite slightly longer
UDP-glucuronosyltransferase 1A1 (UGT1A1) gene mutation data- persistence of virus in the liver, fecal shedding, viremia, and infectivity
base. Blood Cells Mol Dis 50:273, 2013. diminish rapidly once jaundice becomes apparent. HAV can be culti-
Erlinger S, Arias IM, Dhumeaux D: Inherited disorders of bilirubin vated reproducibly in vitro.
transport and conjugation: New insights into molecular mechanisms Antibodies to HAV (anti-HAV) can be detected during acute illness
and consequences. Gastroenterology 146:1625, 2014. when serum aminotransferase activity is elevated and fecal HAV
Gomez-Ospina N et al: Mutations in the nuclear bile acid receptor FXR shedding is still occurring. This early antibody response is predomi-
cause progressive familial intrahepatic cholestasis. Nat Commun nantly of the IgM class and persists for several (~3) months, rarely for
7:10713, 2016. 6–12 months. During convalescence, however, anti-HAV of the IgG
Hansen TW: Biology of bilirubin photoisomers. Clin Perinatol 43:277, class becomes the predominant antibody (Fig. 332-2). Therefore, the
2016. diagnosis of hepatitis A is made during acute illness by demonstrating
Lamola AA: A pharmacologic view of phototherapy. Clin Perinatol anti-HAV of the IgM class. After acute illness, anti-HAV of the IgG class
43:259, 2016. remains detectable indefinitely, and patients with serum anti-HAV are
Memon N et al: Inherited disorders of bilirubin clearance. Pediatr Res immune to reinfection. Neutralizing antibody activity parallels the
79:378, 2016. appearance of anti-HAV, and the IgG anti-HAV present in immune
Rodrigues C et al: Impact of UGT1A1 gene variants on total bilirubin globulin accounts for the protection it affords against HAV infection.
levels in Gilbert syndrome patients and in healthy subjects. Blood
Cells Mol Dis 48:166, 2012. Hepatitis B HBV is a DNA virus with a remarkably compact
Sambrotta M et al: Mutations in TJP2 cause progressive cholestatic genomic structure; despite its small, circular, 3200-bp size, HBV DNA
liver disease. Nat Genet 46:326, 2014. codes for four sets of viral products with a complex, multiparticle
Soroka CJ, Boyer JL: Biosynthesis and trafficking of the bile salt export structure. HBV achieves its genomic economy by relying on an efficient
pump, BSEP: Therapeutic implications of BSEP mutations. Mol strategy of encoding proteins from four overlapping genes: S, C, P, and
Aspects Med 37:3, 2014. X (Fig. 332-3), as detailed below. Once thought to be unique among
van de Steeg E et al: Complete OATP1B1 and OATP1B3 deficiency viruses, HBV is now recognized as one of a family of animal viruses,
causes human Rotor syndrome by interrupting conjugated bilirubin hepadnaviruses (hepatotropic DNA viruses), and is classified as hepad-
reuptake into the liver. J Clin Invest 122:519, 2012. navirus type 1. Similar viruses infect certain species of woodchucks,
Wolkoff AW: Organic anion uptake by hepatocytes. Compr Physiol ground and tree squirrels, and Pekin ducks, to mention the most
4:1715, 2014. carefully characterized; genetic evidence of ancient HBV-like virus

2348 smaller spherical and tubular structures
is referred to as hepatitis B surface antigen
(HBsAg). The concentration of HBsAg
and virus particles in the blood may reach
500 μg/mL and 10 trillion particles per
milliliter, respectively. The envelope pro-
tein, HBsAg, is the product of the S gene
of HBV.
Envelope HBsAg subdeterminants
include a common group-reactive antigen,
a, shared by all HBsAg isolates and one
of several subtype-specific antigens—d or
y, w or r—as well as other specificities.
FIGURE 332-1 Electron micrographs of hepatitis A virus particles and serum from a patient with hepatitis B. Left:
27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A and aggregated by antibody
Hepatitis B isolates fall into one of at least
to hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, demonstrating the 42-nm virions, 8 subtypes and 10 genotypes (A–J). Geo-
tubular forms, and spherical 22-nm particles of hepatitis B surface antigen. 132,000×. (Hepatitis D resembles graphic distribution of genotypes and sub-
42-nm virions of hepatitis B but is smaller, 35–37 nm; hepatitis E resembles hepatitis A virus but is slightly larger, types varies; genotypes A (corresponding
32–34 nm; hepatitis C has been visualized as a 55-nm particle.) to subtype adw) and D (ayw) predominate
in the United States and Europe, whereas
genotypes B (adw) and C (adr) predomi-
forbears has been found in fossils of ancient birds, and a HBV-like virus nate in Asia. Clinical course and outcome are independent of subtype, but
has been identified in contemporary fish. Like HBV, all have the same genotype B appears to be associated with less rapidly progressive liver
distinctive three morphologic forms, have counterparts to the envelope disease and cirrhosis and a lower likelihood, or delayed appearance, of
and nucleocapsid virus antigens of HBV, replicate in the liver but exist hepatocellular carcinoma than genotype C or D. Patients with genotype
in extrahepatic sites, contain their own endogenous DNA polymerase, A are more likely to clear circulating viremia and achieve hepatitis B e
have partially double-strand and partially single-strand genomes, are antigen (HBeAg) and HBsAg seroconversion, both spontaneously and
associated with acute and chronic hepatitis and hepatocellular carci- in response to antiviral therapy. In addition, “precore” mutations are
noma, and rely on a replicative strategy unique among DNA viruses favored by certain genotypes (see below).
but typical of retroviruses. Entry of HBV into hepatocytes is mediated Upstream of the S gene are the pre-S genes (Fig. 332-3), which code
PART 10
by binding to the sodium taurocholate cotransporting polypeptide for pre-S gene products, including receptors on the HBV surface for
receptor. Instead of DNA replication directly from a DNA template, polymerized human serum albumin and for hepatocyte membrane
hepadnaviruses rely on reverse transcription (effected by the DNA proteins. The pre-S region actually consists of both pre-S1 and pre-S2.
polymerase) of minus-strand DNA from a “pregenomic” RNA inter- Depending on where translation is initiated, three potential HBsAg
mediate. Then, plus-strand DNA is transcribed from the minus-strand gene products are synthesized. The protein product of the S gene is
DNA template by the DNA-dependent DNA polymerase and con- HBsAg (major protein), the product of the S region plus the adjacent pre-
verted in the hepatocyte nucleus to a covalently closed circular DNA, S2 region is the middle protein, and the product of the pre-S1 plus pre-S2
which serves as a template for messenger RNA and pregenomic RNA. plus S regions is the large protein. Compared with the smaller spherical
Viral proteins are translated by the messenger RNA, and the proteins and tubular particles of HBV, complete 42-nm virions are enriched in
and genome are packaged into virions and secreted from the hepatoc- the large protein. Both pre-S proteins and their respective antibodies
yte. Although HBV is difficult to cultivate in vitro in the conventional can be detected during HBV infection, and the period of pre-S anti-
sense from clinical material, several cell lines have been transfected genemia appears to coincide with other markers of virus replication,
with HBV DNA. Such transfected cells support in vitro replication of
the intact virus and its component proteins.
Pre-S2
VIRAL PROTEINS AND PARTICLES Of the three particulate forms of HBV
Pre-S1
(Table 332-1), the most numerous are the 22-nm particles, which appear
as spherical or long filamentous forms; these are antigenically indis-
tinguishable from the outer surface or envelope protein of HBV and P
S
are thought to represent excess viral envelope protein. Outnumbered
in serum by a factor of 100 or 1000 to 1 compared with the spheres
and tubules are large, 42-nm, double-shelled spherical particles,
which represent the intact hepatitis B virion (Fig. 332-1). The enve-
lope protein expressed on the outer surface of the virion and on the
C
Jaundice
Pre-C
ALT IgG Anti-HAV
IgM Anti-HAV
Fecal HAV
X
FIGURE 332-3 Compact genomic structure of hepatitis B virus (HBV). This
structure, with overlapping genes, permits HBV to code for multiple proteins.
The S gene codes for the “major” envelope protein, HBsAg. Pre-S1 and pre-S2,
upstream of S, combine with S to code for two larger proteins, “middle” protein,
the product of pre-S2 + S, and “large” protein, the product of pre-S1 + pre-S2
+ S. The largest gene, P, codes for DNA polymerase. The C gene codes for two
0 4 8 12 16 20 nucleocapsid proteins, HBeAg, a soluble, secreted protein (initiation from the
pre-C region of the gene), and HBcAg, the intracellular core protein (initiation after
Weeks after exposure
pre-C). The X gene codes for HBxAg, which can transactivate the transcription of
FIGURE 332-2 Scheme of typical clinical and laboratory features of hepatitis A cellular and viral genes; its clinical relevance is not known, but it may contribute
virus (HAV). ALT, alanine aminotransferase. to carcinogenesis by binding to p53.

TABLE 332-1 Nomenclature and Features of Hepatitis Viruses 2349
VIRUS
HEPATITIS PARTICLE,
TYPE nm MORPHOLOGY GENOMEa CLASSIFICATION ANTIGEN(s) ANTIBODIES REMARKS
HAV 27 Icosahedral 7.5-kb RNA, linear, Hepatovirus HAV Anti-HAV Early fecal shedding
nonenveloped ss, + Diagnosis: IgM anti-HAV
Previous infection: IgG anti-HAV
HBV 42 Double-shelled 3.2-kb DNA, Hepadnavirus HBsAg Anti-HBs Bloodborne virus; carrier state
virion (surface and circular, ss/ds HBcAg Anti-HBc Acute diagnosis: HBsAg, IgM anti-HBc
core) spherical
HBeAg Anti-HBe Chronic diagnosis: IgG anti-HBc, HBsAg
Markers of replication: HBeAg, HBV DNA
Liver, lymphocytes, other organs
27 Nucleocapsid core HBcAg Anti-HBc Nucleocapsid contains DNA and DNA
HBeAg Anti-HBe polymerase; present in hepatocyte nucleus;
HBcAg does not circulate; HBeAg (soluble,
nonparticulate) and HBV DNA circulate—
correlate with infectivity and complete
virions
22 Spherical and HBsAg Anti-HBs HBsAg detectable in >95% of patients with
filamentous; acute hepatitis B; found in serum, body
represents excess fluids, hepatocyte cytoplasm; anti-HBs
virus coat material appears following infection—protective
antibody
HCV Approx. Enveloped 9.4-kb RNA, linear, Hepacivirus HCV core Anti-HCV Bloodborne agent, formerly labeled non-A,
50–80 ss, + antigen non-B hepatitis
Acute diagnosis: anti-HCV, HCV RNA
Chronic diagnosis: anti-HCV, HCV RNA;
cytoplasmic location in hepatocytes

HDV 35–37 Enveloped hybrid 1.7-kb RNA, Resembles viroids HBsAg Anti-HBs Defective RNA virus, requires helper function
particle with circular, ss, – and plant satellite HDAg Anti-HDV of HBV (hepadnaviruses); HDV antigen
HBsAg coat and viruses (genus (HDAg) present in hepatocyte nucleus
HDV core Deltavirus) Diagnosis: anti-HDV, HDV RNA; HBV/HDV
co-infection—IgM anti-HBc and anti-HDV;
HDV superinfection—IgG anti-HBc and
anti-HDV
HEV 32–34 Nonenveloped 7.6-kb RNA, linear, Hepevirus HEV antigen Anti-HEV Agent of enterically transmitted hepatitis;
icosahedral ss, + rare in the United States; occurs in Asia,
Mediterranean countries, Central America
Diagnosis: IgM/IgG anti-HEV (assays not
routinely available); virus in stool, bile,
hepatocyte cytoplasm
ss, single-strand; ss/ds, partially single-strand, partially double-strand; −, minus-strand; +, plus-strand.
a
Note: See text for abbreviations.
as detailed below; however, pre-S proteins have little clinical relevance HBsAg-positive serum containing HBeAg is more likely to be highly
and are not included in routine serologic testing repertoires. infectious and to be associated with the presence of hepatitis B virions
The intact 42-nm virion contains a 27-nm nucleocapsid core parti- (and detectable HBV DNA, see below) than HBeAg-negative or anti-
cle. Nucleocapsid proteins are coded for by the C gene. The antigen HBe-positive serum. For example, HBsAg-positive mothers who are
expressed on the surface of the nucleocapsid core is hepatitis B core HBeAg-positive almost invariably (>90%) transmit hepatitis B infection
antigen (HBcAg), and its corresponding antibody is anti-HBc. A third to their offspring, whereas HBsAg-positive mothers with anti-HBe
HBV antigen is HBeAg, a soluble, nonparticulate, nucleocapsid protein rarely (10–15%) infect their offspring.
that is immunologically distinct from intact HBcAg but is a product of Early during the course of acute hepatitis B, HBeAg appears tran-
the same C gene. The C gene has two initiation codons: a precore and a siently; its disappearance may be a harbinger of clinical improvement
core region (Fig. 332-3). If translation is initiated at the precore region, and resolution of infection. Persistence of HBeAg in serum beyond the
the protein product is HBeAg, which has a signal peptide that binds it to first 3 months of acute infection may be predictive of the development
the smooth endoplasmic reticulum, the secretory apparatus of the cell, of chronic infection, and the presence of HBeAg during chronic hepa-
leading to its secretion into the circulation. If translation begins at the titis B tends to be associated with ongoing viral replication, infectivity,
core region, HBcAg is the protein product; it has no signal peptide and and inflammatory liver injury (except during the early decades after
is not secreted, but it assembles into nucleocapsid particles, which bind perinatally acquired HBV infection; see below).
to and incorporate RNA, and which, ultimately, contain HBV DNA. Also The third and largest of the HBV genes, the P gene (Fig. 332-3),
packaged within the nucleocapsid core is a DNA polymerase, which codes for HBV DNA polymerase; as noted above, this enzyme has both
directs replication and repair of HBV DNA. When packaging within DNA-dependent DNA polymerase and RNA-dependent reverse tran-
viral proteins is complete, synthesis of the incomplete plus strand stops; scriptase activities. The fourth gene, X, codes for a small, nonparticulate
this accounts for the single-strand gap and for differences in the size of protein, hepatitis B x antigen (HBxAg), that is capable of transactivating
the gap. HBcAg particles remain in the hepatocyte, where they are read- the transcription of both viral and cellular genes (Fig. 332-3). In the
ily detectable by immunohistochemical staining and are exported after cytoplasm, HBxAg effects calcium release (possibly from mitochondria),
encapsidation by an envelope of HBsAg. Therefore, naked core particles which activates signal-transduction pathways that lead to stimulation
do not circulate in the serum. The secreted nucleocapsid protein, HBeAg, of HBV reverse transcription and HBV DNA replication. Such trans-
provides a convenient, readily detectable, qualitative marker of HBV activation may enhance the replication of HBV, leading to the clinical
replication and relative infectivity. association observed between the expression of HBxAg and antibodies

2350 to it in patients with severe chronic hepatitis and hepatocellular carci- remote past as well as those with chronic HBV infection, anti-HBc is
noma. The transactivating activity can enhance the transcription and predominantly of the IgG class. Infrequently, in ≤1–5% of patients with
replication of other viruses besides HBV, such as HIV. Cellular processes acute HBV infection, levels of HBsAg are too low to be detected; in
transactivated by X include the human interferon-γ gene and class I such cases, the presence of IgM anti-HBc establishes the diagnosis of
major histocompatibility genes; potentially, these effects could contrib- acute hepatitis B. When isolated anti-HBc occurs in the rare patient with
ute to enhanced susceptibility of HBV-infected hepatocytes to cytolytic chronic hepatitis B whose HBsAg level is below the sensitivity threshold
T cells. The expression of X can also induce programmed cell death of contemporary immunoassays (a low-level carrier), anti-HBc is of the
(apoptosis). The clinical relevance of HBxAg is limited, however, and IgG class. Generally, in persons who have recovered from hepatitis B,
testing for it is not part of routine clinical practice. anti-HBs and anti-HBc persist indefinitely.
SEROLOGIC AND VIROLOGIC MARKERS After a person is infected with
The temporal association between the appearance of anti-HBs and
HBV, the first virologic marker detectable in serum within 1–12 weeks, resolution of HBV infection as well as the observation that persons with
usually between 8 and 12 weeks, is HBsAg (Fig. 332-4). Circulating anti-HBs in serum are protected against reinfection with HBV suggests
HBsAg precedes elevations of serum aminotransferase activity and that anti-HBs is the protective antibody. Therefore, strategies for preven-
clinical symptoms by 2–6 weeks and remains detectable during the tion of HBV infection are based on providing susceptible persons with
entire icteric or symptomatic phase of acute hepatitis B and beyond. circulating anti-HBs (see below). Occasionally, in ~10% of patients with
In typical cases, HBsAg becomes undetectable 1–2 months after the chronic hepatitis B, low-level, low-affinity anti-HBs can be detected.
onset of jaundice and rarely persists beyond 6 months. After HBsAg This antibody is directed against a subtype determinant different from
disappears, antibody to HBsAg (anti-HBs) becomes detectable in that represented by the patient’s HBsAg; its presence is thought to
serum and remains detectable indefinitely thereafter. Because HBcAg reflect the stimulation of a related clone of antibody-forming cells, but
is intracellular and, when in the serum, sequestered within an HBsAg it has no clinical relevance and does not signal imminent clearance of
coat, naked core particles do not circulate in serum, and therefore hepatitis B. These patients with HBsAg and such nonneutralizing anti-
HBcAg is not detectable routinely in the serum of patients with HBV HBs should be categorized as having chronic HBV infection.
infection. By contrast, anti-HBc is readily demonstrable in serum, The other readily detectable serologic marker of HBV infection,
beginning within the first 1–2 weeks after the appearance of HBsAg HBeAg, appears concurrently with or shortly after HBsAg. Its appear-
and preceding detectable levels of anti-HBs by weeks to months. ance coincides temporally with high levels of virus replication and
Because variability exists in the time of appearance of anti-HBs after reflects the presence of circulating intact virions and detectable HBV
HBV infection, occasionally a gap of several weeks or longer may DNA (with the notable exception of patients with precore mutations
separate the disappearance of HBsAg and the appearance of anti-HBs. who cannot synthesize HBeAg—see “Molecular Variants”). Pre-S1
During this “gap” or “window” period, anti-HBc may represent the and pre-S2 proteins are also expressed during periods of peak replica-
PART 10
only serologic evidence of current or recent HBV infection, and blood tion, but assays for these gene products are not routinely available. In
containing anti-HBc in the absence of HBsAg and anti-HBs has been self-limited HBV infections, HBeAg becomes undetectable shortly after
implicated in transfusion-associated hepatitis B. In part because the peak elevations in aminotransferase activity, before the disappearance
sensitivity of immunoassays for HBsAg and anti-HBs has increased, of HBsAg, and anti-HBe then becomes detectable, coinciding with a
however, this window period is rarely encountered. In some persons, period of relatively lower infectivity (Fig. 332-4). Because markers of
years after HBV infection, anti-HBc may persist in the circulation lon- HBV replication appear transiently during acute infection, testing for
ger than anti-HBs. Therefore, isolated anti-HBc does not necessarily such markers is of little clinical utility in typical cases of acute HBV
indicate active virus replication; most instances of isolated anti-HBc infection. In contrast, markers of HBV replication provide valuable
represent hepatitis B infection in the remote past. Rarely, however, information in patients with protracted infections.
isolated anti-HBc represents low-level hepatitis B viremia, with HBsAg Departing from the pattern typical of acute HBV infections, in
below the detection threshold, and, occasionally, isolated anti-HBc chronic HBV infection, HBsAg remains detectable beyond 6 months,
represents a cross-reacting or false-positive immunologic specificity. anti-HBc is primarily of the IgG class, and anti-HBs is either undetect-
Recent and remote HBV infections can be distinguished by determi- able or detectable at low levels (see “Laboratory Features”) (Fig. 332-5).
nation of the immunoglobulin class of anti-HBc. Anti-HBc of the IgM
class (IgM anti-HBc) predominates during the first 6 months after acute
infection, whereas IgG anti-HBc is the predominant class of anti-HBc
beyond 6 months. Therefore, patients with current or recent acute hep-
atitis B, including those in the anti-HBc window, have IgM anti-HBc ALT
in their serum. In patients who have recovered from hepatitis B in the
HBeAg Anti-HBe
Jaundice HBV DNA
ALT HBsAg
HBeAg Anti-HBe Anti-HBc

IgG Anti-HBc
IgM anti-HBc
HBsAg
0 1 2 3 4 5 6 12 24 36 48 60 120
Anti-HBs Months after exposure
IgM Anti-HBc FIGURE 332-5 Scheme of typical laboratory features of wild-type chronic
hepatitis B. HBeAg and hepatitis B virus (HBV) DNA can be detected in serum
during the relatively replicative phase of chronic infection, which is associated
with infectivity and liver injury. Seroconversion from the replicative phase to the
0 4 8 12 16 20 24 28 32 36 52 100 relatively nonreplicative phase occurs at a rate of ~10% per year and is heralded
by an acute hepatitis–like elevation of alanine aminotransferase (ALT) activity;
Weeks after exposure
during the nonreplicative phase, infectivity and liver injury are limited. In HBeAg-
FIGURE 332-4 Scheme of typical clinical and laboratory features of acute negative chronic hepatitis B associated with mutations in the precore region of
hepatitis B. ALT, alanine aminotransferase. the HBV genome, replicative chronic hepatitis B occurs in the absence of HBeAg.

During early chronic HBV infection, HBV DNA can be detected both in in the precore region is now the most frequently encountered form of 2351
serum and in hepatocyte nuclei, where it is present in free or episomal hepatitis B in Mediterranean countries and in Europe. In the United
form. This relatively highly replicative stage of HBV infection is the time States, where HBV genotype A (less prone to G1896A mutation) is prev-
of maximal infectivity and liver injury; HBeAg is a qualitative marker alent, precore-mutant HBV is much less common; however, as a result of
and HBV DNA a quantitative marker of this replicative phase, during immigration from Asia and Europe, the proportion of HBeAg-negative
which all three forms of HBV circulate, including intact virions. Over hepatitis B–infected individuals has increased in the United States,
time, the relatively replicative phase of chronic HBV infection gives and they now represent ~30–40% of patients with chronic hepatitis B.
way to a relatively nonreplicative phase. This occurs at a rate of ~10% Characteristic of such HBeAg-negative chronic hepatitis B are lower
per year and is accompanied by seroconversion from HBeAg to anti- levels of HBV DNA (usually ≤105 IU/mL) and one of several patterns of
HBe. In many cases, this seroconversion coincides with a transient, aminotransferase activity—persistent elevations, periodic fluctuations
usually mild, acute hepatitis-like elevation in aminotransferase activity, above the normal range, and periodic fluctuations between the normal
believed to reflect cell-mediated immune clearance of virus-infected and elevated range.
hepatocytes. In the nonreplicative phase of chronic infection, when The second important category of HBV mutants consists of escape
HBV DNA is demonstrable in hepatocyte nuclei, it tends to be inte- mutants, in which a single amino acid substitution, from glycine to
grated into the host genome. In this phase, only spherical and tubular arginine, occurs at position 145 of the immunodominant a determi-
forms of HBV, not intact virions, circulate, and liver injury tends to nant common to all HBsAg subtypes. This HBsAg alteration leads to
subside. Most such patients would be characterized as inactive HBV a critical conformational change that results in a loss of neutralizing
carriers. In reality, the designations replicative and nonreplicative are only activity by anti-HBs. This specific HBV/a mutant has been observed
relative; even in the so-called nonreplicative phase, HBV replication in two situations, active and passive immunization, in which humoral
can be detected at levels of approximately ≤103 virions/mL with highly immunologic pressure may favor evolutionary change (“escape”) in
sensitive amplification probes such as the polymerase chain reaction the virus—in a small number of hepatitis B vaccine recipients who
(PCR); below this replication threshold, liver injury and infectivity of acquired HBV infection despite the prior appearance of neutralizing
HBV are limited to negligible. Still, the distinctions are pathophysio- anti-HBs and in HBV-infected liver transplant recipients treated with a
logically and clinically meaningful. Occasionally, nonreplicative HBV high-potency human monoclonal anti-HBs preparation. Although such
infection converts back to replicative infection. Such spontaneous mutants have not been recognized frequently, their existence raises
reactivations are accompanied by reexpression of HBeAg and HBV a concern that may complicate vaccination strategies and serologic
DNA, and sometimes of IgM anti-HBc, as well as by exacerbations of diagnosis.
liver injury. Because high-titer IgM anti-HBc can reappear during acute Different types of mutations emerge during antiviral therapy of

exacerbations of chronic hepatitis B, relying on IgM anti-HBc versus chronic hepatitis B with nucleoside analogues; such “YMDD” and
IgG anti-HBc to distinguish between acute and chronic hepatitis B similar mutations in the polymerase motif of HBV are described in
infection, respectively, may not always be reliable; in such cases, patient Chap. 334.
history and additional follow-up monitoring over time are invaluable EXTRAHEPATIC SITES Hepatitis B antigens and HBV DNA have been
in helping to distinguish de novo acute hepatitis B infection from acute identified in extrahepatic sites, including the lymph nodes, bone
exacerbation of chronic hepatitis B infection. marrow, circulating lymphocytes, spleen, and pancreas. Although the
MOLECULAR VARIANTS Variation occurs throughout the HBV genome,
virus does not appear to be associated with tissue injury in any of
and clinical isolates of HBV that do not express typical viral proteins these extrahepatic sites, its presence in these “remote” reservoirs has
have been attributed to mutations in individual or even multiple gene been invoked (but is not necessary) to explain the recurrence of HBV
locations. For example, variants have been described that lack nucleo- infection after orthotopic liver transplantation. The clinical relevance of
capsid proteins (commonly), envelope proteins (very rarely), or both. such extrahepatic HBV is limited.
Two categories of naturally occurring HBV variants have attracted the Hepatitis D The delta hepatitis agent, or HDV, the only member
most attention. One of these was identified initially in Mediterranean of the genus Deltavirus, is a defective RNA virus that co-infects with
countries among patients with severe chronic HBV infection and and requires the helper function of HBV (or other hepadnaviruses)
detectable HBV DNA, but with anti-HBe instead of HBeAg. These for its replication and expression. Slightly smaller than HBV, HDV
patients were found to be infected with an HBV mutant that contained is a formalin-sensitive, 35- to 37-nm virus with a hybrid structure.
an alteration in the precore region rendering the virus incapable of Its nucleocapsid expresses HDV antigen (HDAg), which bears no
encoding HBeAg. Although several potential mutation sites exist in antigenic homology with any of the HBV antigens, and contains the
the pre-C region, the region of the C gene necessary for the expres- virus genome. The HDV core is “encapsidated” by an outer envelope
sion of HBeAg (see “Virology and Etiology”), the most commonly of HBsAg, indistinguishable from that of HBV except in its relative
encountered in such patients is a single base substitution, from G to A compositions of major, middle, and large HBsAg component proteins.
in the second to last codon of the pre-C gene at nucleotide 1896. This The genome is a small, 1700-nucleotide, circular, single-strand RNA
substitution results in the replacement of the TGG tryptophan codon of negative polarity that is nonhomologous with HBV DNA (except
by a stop codon (TAG), which prevents the translation of HBeAg. for a small area of the polymerase gene) but that has features and
Another mutation, in the core-promoter region, prevents transcrip- the rolling circle model of replication common to genomes of plant
tion of the coding region for HBeAg and yields an HBeAg-negative satellite viruses or viroids. HDV RNA contains many areas of internal
phenotype. Patients with such mutations in the precore region and complementarity; therefore, it can fold on itself by internal base pairing
who are unable to secrete HBeAg may have severe liver disease that to form an unusual, very stable, rodlike structure that contains a very
progresses more rapidly to cirrhosis, or alternatively, they are identified stable, self-cleaving and self-ligating ribozyme. HDV RNA requires
clinically later in the course of the natural history of chronic hepatitis host RNA polymerase II for its replication in the hepatocyte nucleus
B, when the disease is more advanced. Both “wild-type” HBV and via RNA-directed RNA synthesis by transcription of genomic RNA to a
precore-mutant HBV can coexist in the same patient, or mutant HBV complementary antigenomic (plus strand) RNA; the antigenomic RNA,
may arise late during wild-type HBV infection. In addition, clusters of in turn, serves as a template for subsequent genomic RNA synthesis
fulminant hepatitis B in Israel and Japan were attributed to common- effected by host RNA polymerase I. HDV RNA has only one open read-
source infection with a precore mutant. Fulminant hepatitis B in North ing frame, and HDAg, a product of the antigenomic strand, is the only
America and western Europe, however, occurs in patients infected known HDV protein; HDAg exists in two forms: a small, 195-amino-
with wild-type HBV, in the absence of precore mutants, and both pre- acid species, which plays a role in facilitating HDV RNA replication,
core mutants and other mutations throughout the HBV genome occur and a large, 214-amino-acid species, which appears to suppress rep-
commonly, even in patients with typical, self-limited, milder forms lication but is required for assembly of the antigen into virions. HDV
of HBV infection. HBeAg-negative chronic hepatitis with mutations antigens have been shown to bind directly to RNA polymerase II,

2352 resulting in stimulation of transcription. Although complete hepatitis in an immunodeficient mouse model containing explants of human
D virions and liver injury require the cooperative helper function of liver and in transgenic mouse and rat models. Although in vitro rep-
HBV, intracellular replication of HDV RNA can occur without HBV. lication is difficult, replicons in hepatocellular carcinoma–derived cell
Genomic heterogeneity among HDV isolates has been described; lines support replication of genetically manipulated, truncated, or full-
however, pathophysiologic and clinical consequences of this genetic length HCV RNA (but not intact virions); infectious pseudotyped ret-
diversity have not been recognized. The clinical spectrum of hepatitis D roviral HCV particles have been shown to yield functioning envelope
is common to all eight genotypes identified, the predominant of which proteins. In 2005, complete replication of HCV and intact 55-nm virions
is genotype 1. were described in cell culture systems. HCV entry into the hepatocyte
HDV can either infect a person simultaneously with HBV (co-infec- occurs via the nonliver-specific CD81 receptor and the liver-specific
tion) or superinfect a person already infected with HBV (superinfection); tight junction protein claudin-1. A growing list of additional host recep-
when HDV infection is transmitted from a donor with one HBsAg tors to which HCV binds on cell entry includes occludin, low-density
subtype to an HBsAg-positive recipient with a different subtype, HDV lipoprotein receptors, glycosaminoglycans, scavenger receptor B1, and
assumes the HBsAg subtype of the recipient, rather than the donor. epidermal growth factor receptor, among others. Relying on the same
Because HDV relies absolutely on HBV, the duration of HDV infection assembly and secretion pathway as low-density and very-low-density
is determined by the duration of (and cannot outlast) HBV infection. lipoproteins, HCV is a lipoviroparticle and masquerades as a lipopro-
HDV replication tends to suppress HBV replication; therefore, patients tein, which may limit its visibility to the adaptive immune system and
with hepatitis D tend to have lower levels of HBV replication. HDV explain its ability to evade immune containment and clearance. After
antigen is expressed primarily in hepatocyte nuclei and is occasionally viral entry and uncoating, translation is initiated by the IRES on the
detectable in serum. During acute HDV infection, anti-HDV of the IgM endoplasmic reticulum membrane, and the HCV polyprotein is cleaved
class predominates, and 30–40 days may elapse after symptoms appear during translation and posttranslationally by host cellular proteases as
before anti-HDV can be detected. In self-limited infection, anti-HDV is well as HCV NS2-3 and NS3-4A proteases. Host cofactors involved in
low-titer and transient, rarely remaining detectable beyond the clear- HCV replication include cyclophilin A, which binds to NS5A and yields
ance of HBsAg and HDV antigen. In chronic HDV infection, anti-HDV conformational changes required for viral replication, and liver-specific
circulates in high titer, and both IgM and IgG anti-HDV can be detected. host microRNA miR-122.
HDV antigen in the liver and HDV RNA in serum and liver can be At least six distinct major genotypes (and a minor genotype 7), as
detected during HDV replication. well as >50 subtypes within genotypes, of HCV have been identified by
nucleotide sequencing. Genotypes differ from one another in sequence
Hepatitis C Hepatitis C virus, which, before its identification homology by ≥30%, and subtypes differ by ~20%. Because divergence
was labeled “non-A, non-B hepatitis,” is a linear, single-strand, pos- of HCV isolates within a genotype or subtype and within the same host
itive-sense, 9600-nucleotide RNA virus, the genome of which is sim-
PART 10
may vary insufficiently to define a distinct genotype, these intrageno-

ilar in organization to that of flaviviruses and pestiviruses; HCV is typic differences are referred to as quasispecies and differ in sequence
the only member of the genus Hepacivirus in the family Flaviviridae. homology by only a few percent. The genotypic and quasispecies
The HCV genome contains a single, large open reading frame (ORF) diversity of HCV, resulting from its high mutation rate, interferes with
(gene) that codes for a virus polyprotein of ~3000 amino acids, which effective humoral immunity. Neutralizing antibodies to HCV have
is cleaved after translation to yield 10 viral proteins. The 5′ end of the been demonstrated, but they tend to be short-lived, and HCV infection
genome consists of an untranslated region (containing an internal does not induce lasting immunity against reinfection with different
ribosomal entry site [IRES]) adjacent to the genes for three structural virus isolates or even the same virus isolate. Thus, neither heterologous
proteins, the nucleocapsid core protein, C, and two envelope glyco- nor homologous immunity appears to develop commonly after acute
proteins, E1 and E2. The 5′ untranslated region and core gene are HCV infection. Some HCV genotypes are distributed worldwide,
highly conserved among genotypes, but the envelope proteins are whereas others are more geographically confined (see “Epidemiology
coded for by the hypervariable region, which varies from isolate to and Global Features”). In addition, differences exist among genotypes
isolate and may allow the virus to evade host immunologic contain- in responsiveness to antiviral therapy but not in pathogenicity or clin-
ment directed at accessible virus-envelope proteins. The 3′ end of the ical progression (except for genotype 3, in which hepatic steatosis and
genome also includes an untranslated region and contains the genes clinical progression are more likely).
for seven nonstructural (NS) proteins: p7, NS2, NS3, NS4A, NS4B, Currently available, third-generation immunoassays, which incor-
NS5A, and NS5B. p7 is a membrane ion channel protein necessary porate proteins from the core, NS3, and NS5 regions, detect anti-HCV
for efficient assembly and release of HCV. The NS2 cysteine protease antibodies during acute infection. The most sensitive indicator of
cleaves NS3 from NS2, and the NS3-4A serine protease cleaves all the HCV infection is the presence of HCV RNA, which requires molecular
downstream proteins from the polyprotein. Important NS proteins amplification by PCR or transcription-mediated amplification (TMA)
involved in virus replication include the
NS3 helicase; NS3-4A serine protease; 500 1000 1500 2000 2500 3000
the multifunctional membrane-associ- AA
ated phosphoprotein NS5A, an essen- Envelope Serine
Helicase
RNA-dependent
tial component of the viral replication Core glycoproteins protease RNA polymerase
membranous web (along with NS4B);
and the NS5B RNA-dependent RNA 5' C E1 E2 NS2 NS3 NS4B NS5A NS5B 3'
polymerase (Fig. 332-6). Because HCV
does not replicate via a DNA interme-
p7 NS4A
diate, it does not integrate into the host
genome. Because HCV tends to circulate Conserved Hypervariable
in relatively low titer, 103−107 virions/ region region
mL, visualization of the 50- to 80-nm FIGURE 332-6 Organization of the hepatitis C virus genome and its associated, 3000-amino-acid (AA) proteins.
virus particles remains difficult. Still, the The three structural genes at the 5′ end are the core region, C, which codes for the nucleocapsid, and the envelope
replication rate of HCV is very high, 1012 regions, E1 and E2, which code for envelope glycoproteins. The 5′ untranslated region and the C region are highly
virions per day; its half-life is 2.7 h. The conserved among isolates, whereas the envelope domain E2 contains the hypervariable region. At the 3′ end are
chimpanzee is a helpful but cumbersome seven nonstructural (NS) regions—p7, a membrane protein adjacent to the structural proteins that appears to
function as an ion channel; NS2, which codes for a cysteine protease; NS3, which codes for a serine protease
animal model. Although a robust, repro- and an RNA helicase; NS4 and NS4B; NS5A, a multifunctional membrane-associated phosphoprotein, an essential
ducible, small animal model is lacking, component of the viral replication membranous web; and NS5B, which codes for an RNA-dependent RNA polymerase.
HCV replication has been documented After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases.

clinical manifestations and outcomes after acute liver injury associated 2353
Anti-HCV with viral hepatitis are determined by the immunologic responses of
the host. Among the viral hepatitides, the immunopathogenesis of
HCV RNA hepatitis B and C has been studied most extensively.
Hepatitis B For HBV, the existence of inactive hepatitis B carriers
ALT
with normal liver histology and function suggests that the virus is
not directly cytopathic. The fact that patients with defects in cellular
immune competence are more likely to remain chronically infected
rather than to clear HBV supports the role of cellular immune
responses in the pathogenesis of hepatitis B–related liver injury. The
0 1 2 3 4 5 6 12 24 36 48 60 120 model that has the most experimental support involves cytolytic T cells
sensitized specifically to recognize host and hepatitis B viral antigens
Months after exposure
on the liver cell surface. Nucleocapsid proteins (HBcAg and possibly
FIGURE 332-7 Scheme of typical laboratory features during acute hepatitis C HBeAg), present on the cell membrane in minute quantities, are the
progressing to chronicity. Hepatitis C virus (HCV) RNA is the first detectable
viral target antigens that, with host antigens, invite cytolytic T cells to
event, preceding alanine aminotransferase (ALT) elevation and the appearance
of anti-HCV. destroy HBV-infected hepatocytes. Differences in the robustness and
broad polyclonality of CD8+ cytolytic T cell responsiveness; in the
level of HBV-specific helper CD4+ T cells; in attenuation, depletion,
(Fig. 332-7). To allow standardization of the quantification of HCV RNA and exhaustion of virus-specific T cells; in viral T cell epitope escape
among laboratories and commercial assays, HCV RNA is reported as mutations that allow the virus to evade T cell containment; and in
international units (IUs) per milliliter; quantitative assays with a broad the elaboration of antiviral cytokines by T cells have been invoked to
dynamic range are available that allow detection of HCV RNA with a explain differences in outcomes between those who recover after acute
sensitivity as low as 5 IU/mL. HCV RNA can be detected within a few hepatitis and those who progress to chronic hepatitis, or between those
days of exposure to HCV—well before the appearance of anti-HCV— with mild and those with severe (fulminant) acute HBV infection.
and tends to persist for the duration of HCV infection. Application of Although a robust cytolytic T cell response occurs and eliminates
sensitive molecular probes for HCV RNA has revealed the presence of virus-infected liver cells during acute hepatitis B, >90% of HBV DNA
replicative HCV in peripheral blood lymphocytes of infected persons; has been found in experimentally infected chimpanzees to disappear
however, as is the case for HBV in lymphocytes, the clinical relevance from the liver and blood before maximal T cell infiltration of the

of HCV lymphocyte infection is not known. liver and before most of the biochemical and histologic evidence of
liver injury. This observation suggests that components of the innate
Hepatitis E Previously labeled epidemic or enterically transmitted
immune system and inflammatory cytokines, independent of cyto-
non-A, non-B hepatitis, HEV is an enterically transmitted virus that
pathic antiviral mechanisms, participate in the early immune response
causes clinically apparent hepatitis primarily in India, Asia, Africa,
to HBV infection; this effect has been shown to represent elimination
and Central America; in those geographic areas, HEV is the most
of HBV replicative intermediates from the cytoplasm and covalently
common cause of acute hepatitis; one-third of the global population
closed circular viral DNA from the nucleus of infected hepatocytes. In
appears to have been infected. This agent, with epidemiologic fea-
turn, the innate immune response to HBV infection is mediated largely
tures resembling those of hepatitis A, is a 27- to 34-nm, nonenveloped,
by natural killer (NK) cell cytotoxicity, activated by immunosuppres-
heat-stable, HAV-like virus with a 7200-nucleotide, single-strand,
sive cytokines (e.g., interleukin [IL] 10 and transforming growth factor
positive-sense RNA genome. HEV has three overlapping ORFs (genes),
[TGF] β), reduced signals from inhibitory receptor expression (e.g.,
the largest of which, ORF1, encodes nonstructural proteins involved in
major histocompatibility complex), or increased signals from acti-
virus replication (viral replicase). A middle-sized gene, ORF2, encodes
the nucleocapsid protein, the major structural protein, and the smallest, vating receptor expression on infected hepatocytes. In addition, NK
ORF3, encodes a small structural protein involved in virus particle cells reduce helper CD4+ cells, which results in reduced CD8+ cells
secretion. All HEV isolates appear to belong to a single serotype, despite and exhaustion of the virus-specific T cell response to HBV infection.
genomic heterogeneity of up to 25% and the existence of five genotypes, Ultimately, HBV-HLA–specific cytolytic T cell responses of the adap-
only four of which have been detected in humans; genotypes 1 and 2 tive immune system are felt to be responsible for recovery from HBV
(common in developing countries) appear to be more virulent, whereas infection.
genotypes 3 (the most common in the United States and Europe) and Debate continues over the relative importance of viral and host fac-
4 (seen in China) are more attenuated and account for subclinical tors in the pathogenesis of HBV-associated liver injury and its outcome.
infections. Contributing to the perpetuation of this virus are animal As noted above, precore genetic mutants of HBV have been associated
reservoirs, most notably in swine but also in camels, deer, rats, and rab- with the more severe outcomes of HBV infection (severe chronic and
bits, among others. No genomic or antigenic homology, however, exists fulminant hepatitis), suggesting that, under certain circumstances,
between HEV and HAV or other picornaviruses; and HEV, although relative pathogenicity is a property of the virus, not the host. The facts
resembling caliciviruses, is sufficiently distinct from any known agent that concomitant HDV and HBV infections are associated with more
to merit its own classification as a unique genus, Hepevirus, within the severe liver injury than HBV infection alone and that cells transfected
family Hepeviridae. The virus has been detected in stool, bile, and liver, in vitro with the gene for HDV antigen express HDV antigen and then
and is excreted in the stool during the late incubation period. Both IgM become necrotic in the absence of any immunologic influences are also
anti-HEV during early acute infection and IgG anti-HEV predominat- consistent with a viral effect on pathogenicity. Similarly, in patients
ing after the first 3 months can be detected. The presence of HEV RNA who undergo liver transplantation for end-stage chronic hepatitis B,
in serum and stool accompanies acute infection; viremia resolves as occasionally, rapidly progressive liver injury appears in the new liver.
clinical-biochemical recovery ensues, while HEV RNA in stool may This clinical pattern is associated with an unusual histologic pattern
outlast viremia by several weeks. Currently, availability and reliability in the new liver, fibrosing cholestatic hepatitis, which, ultrastructurally,
of serologic/virologic testing for HEV infection is limited—and not appears to represent a choking of the cell with overwhelming quanti-
FDA-approved or licensed—but can be done in specialized laboratories ties of HBsAg. This observation suggests that, under the influence of
(e.g., the Centers for Disease Control and Prevention). the potent immunosuppressive agents required to prevent allograft
rejection, HBV may have a direct cytopathic effect on liver cells, inde-
■■PATHOGENESIS pendent of the immune system.
Under ordinary circumstances, none of the hepatitis viruses is known Although the precise mechanism of liver injury in HBV infection
to be directly cytopathic to hepatocytes. Evidence suggests that the remains elusive, studies of nucleocapsid proteins have shed light on

2354 the profound immunologic tolerance to HBV of babies born to moth- effective, and more long lasting) in those who recover from HCV
ers with highly replicative (HBeAg-positive), chronic HBV infection. infection than in those who have chronic infection. Contributing to
In HBeAg-expressing transgenic mice, in utero exposure to HBeAg, chronic infection are a CD4+ proliferative defect that results in rapid
which is sufficiently small to traverse the placenta, induces T cell tol- contraction of CD4+ responses, mutations in CD8+ T cell–targeted
erance to both nucleocapsid proteins. This, in turn, may explain why, viral epitopes that allow HCV to escape immune-mediated clearance,
when infection occurs so early in life, immunologic clearance does not and upregulation of inhibitory receptors on functionally impaired,
occur, and protracted, lifelong infection ensues. An alternative explana- exhausted T cells. Although attention has focused on adaptive immu-
tion proposed to explain why robust liver injury does not accompany nity, HCV proteins have been shown to interfere with innate immunity
neonatal HBV infection but predisposes to chronic infection is defective by resulting in blocking of type 1 interferon responses and inhibition
priming of HBV-specific T cells during in utero exposure to HBV. of interferon signaling and effector molecules in the interferon signal-
An important distinction should be drawn between HBV infection ing cascade. Several HLA alleles have been linked with self-limited
acquired at birth, common in endemic areas, such as East Asia, and hepatitis C, the most convincing of which is the CC haplotype of the
infection acquired in adulthood, common in the West. Infection in the IL28B gene, which codes for interferon λ3, a component of innate
neonatal period is associated with the acquisition of what appears immune antiviral defense. The IL28B association is even stronger when
to be a high level of immunologic tolerance to HBV and absence of combined with HLA class II DQB1*03:01. The link between non-CC
an acute hepatitis illness, but the almost invariable establishment of IL28B polymorphisms and failure to clear HCV infection has been
chronic, often lifelong infection. Neonatally acquired HBV infection explained by a chromosome 19q13.13 frameshift variant upstream
can culminate decades later in cirrhosis and hepatocellular carcinoma of IL28B, the ΔG polymorphism of which creates an ORF in a novel
(see “Complications and Sequelae”). In contrast, when HBV infection interferon gene (IFN-l4) associated with impaired HCV clearance. Also
is acquired during adolescence or early adulthood, the host immune shown to contribute to limiting HCV infection are NK cells of the innate
response to HBV-infected hepatocytes tends to be robust, an acute immune system that function when HLA class I molecules required for
hepatitis-like illness is the rule, and failure to recover is the exception. successful adaptive immunity are underexpressed. Both peripheral
After adulthood-acquired infection, chronicity is uncommon, and the cytotoxicity and intrahepatic NK cell cytotoxicity are dysfunctional
risk of hepatocellular carcinoma is very low. Based on these observa- in persistent HCV infection. Adding to the complexity of the immune
tions, some authorities categorize HBV infection into an “immunotoler- response, HCV core, NS4B, and NS5B have been shown to suppress
ant” phase, an “immunoreactive” phase, and an “inactive” phase. This the immunoregulatory nuclear factor (NF)-κB pathway, resulting in
somewhat simplistic formulation does not apply at all to the typical reduced antiapoptotic proteins and a resultant increased vulnerability
adult in the West with self-limited acute hepatitis B, in whom no period to tumor necrosis factor (TNF) α–mediated cell death. Patients with
of immunologic tolerance occurs. Even among those with neonatally hepatitis C and unfavorable (non-CC, associated with reduced HCV
PART 10
acquired HBV infection, in whom immunologic tolerance appears to clearance) IL28B alleles have been shown to have depressed NK cell/
be established definitively, immunologic responses to HBV infection innate immune function. Of note, the emergence of substantial viral
have been demonstrated, and intermittent bursts of hepatic necroin- quasispecies diversity and HCV sequence variation allow the virus to
flammatory activity punctuate the early decades of life during which evade attempts by the host to contain HCV infection by both humoral
liver injury appears to be quiescent (labeled by some as the “immuno- and cellular immunity.
tolerant” phase; however, it more accurately is a period of dissociation Finally, cross-reactivity between viral antigens (HCV NS3 and
between high-level HBV replication and a paucity of inflammatory liver NS5A) and host autoantigens (cytochrome P450 2D6) has been invoked
injury). In addition, even when clinically apparent liver injury and pro- to explain the association between hepatitis C and a subset of patients
gressive fibrosis emerge during later decades (the so-called immunore- with autoimmune hepatitis and antibodies to liver-kidney microsomal
active, or immunointolerant, phase), the level of immunologic tolerance (LKM) antigen (anti-LKM) (Chap. 334).
to HBV remains substantial. More accurately, in patients with neonatally
acquired HBV infection, a dynamic equilibrium exists between tolerance ■■EXTRAHEPATIC MANIFESTATIONS
and intolerance, the outcome of which determines the clinical expres- Immune complex–mediated tissue damage appears to play a patho-
genetic role in the extrahepatic manifestations of acute hepatitis B.
sion of chronic infection. Persons infected as neonates tend to have a
The occasional prodromal serum sickness–like syndrome observed
relatively higher level of immunologic tolerance (high replication,
in acute hepatitis B appears to be related to the deposition in tissue
low necroinflammatory activity) during the early decades of life and a
blood vessel walls of HBsAg-anti-HBs circulating immune complexes,
relatively lower level (but only rarely a loss) of tolerance (and necroin-
leading to activation of the complement system and depressed serum
flammatory activity reflecting the level of virus replication) in the later
complement levels.
decades of life.
In patients with chronic hepatitis B, other types of immune-complex
Hepatitis C Cell-mediated immune responses and elaboration by disease may be seen. Glomerulonephritis with the nephrotic syndrome
T cells of antiviral cytokines contribute to the multicellular innate and is observed occasionally; HBsAg, immunoglobulin, and C3 deposition
adaptive immune responses involved in the containment of infection has been found in the glomerular basement membrane. Whereas gen-
and pathogenesis of liver injury associated with hepatitis C. The fact eralized vasculitis (polyarteritis nodosa) develops in considerably <1%
that HCV is so efficient in evading these immune mechanisms is a tes- of patients with chronic HBV infection, 20–30% of patients with pol-
tament to its highly evolved ability to disrupt host immune responses yarteritis nodosa have HBsAg in serum (Chap. 356). In these patients,
at multiple levels. After exposure to HCV, the host cell identifies viral the affected small- and medium-size arterioles contain HBsAg, immu-
product motifs (pattern recognition receptors) that distinguish the noglobulins, and complement components. Another extrahepatic man-
virus from “self,” resulting in the elaboration of interferons and other ifestation of viral hepatitis, essential mixed cryoglobulinemia (EMC),
cytokines that result in activation of innate and adaptive immune was reported initially to be associated with hepatitis B. The disorder
responses. Intrahepatic HLA class I–restricted cytolytic T cells directed is characterized clinically by arthritis, cutaneous vasculitis (palpable
at nucleocapsid, envelope, and nonstructural viral protein antigens purpura), and, occasionally, glomerulonephritis and serologically by the
have been demonstrated in patients with chronic hepatitis C; how- presence of circulating cryoprecipitable immune complexes of more than
ever, such virus-specific cytolytic T cell responses do not correlate one immunoglobulin class (Chaps. 308 and 356). Many patients with
adequately with the degree of liver injury or with recovery. Yet, a this syndrome have chronic liver disease, but the association with HBV
consensus has emerged supporting a role in the pathogenesis of infection is limited; instead, a substantial proportion has chronic HCV
HCV-associated liver injury of virus-activated CD4+ helper T cells infection, with circulating immune complexes containing HCV RNA.
that stimulate, via the cytokines they elaborate, HCV-specific CD8+ Immune-complex glomerulonephritis is another recognized extrahe-
cytotoxic T cells. These responses appear to be more robust (higher in patic manifestation of chronic hepatitis C. Immune-complex disorders
number, more diverse in viral antigen specificity, more functionally have been linked, albeit rarely, with both hepatitis A and E. In hepatitis E,

rare neurologic complications have been postulated to result from both Hepatitis A This agent is transmitted almost exclusively by the fecal-oral 2355
immunologic mechanisms and/or direct CNS infection with the virus. route. Person-to-person spread of HAV is enhanced by poor personal
hygiene and overcrowding; large outbreaks as well as sporadic cases
■■PATHOLOGY have been traced to contaminated food, water, milk, frozen raspberries
The typical morphologic lesions of all types of viral hepatitis are and strawberries, green onions imported from Mexico, and shellfish
similar and consist of panlobular infiltration with mononuclear cells, (e.g., scallops imported from the Philippines used to make sushi,
hepatic cell necrosis, hyperplasia of Kupffer cells, and variable degrees the culprit identified in a 2016 Hawaiian outbreak). Intrafamily and
of cholestasis. Hepatic cell regeneration is present, as evidenced by intrainstitutional spreads are also common. Early epidemiologic obser-
numerous mitotic figures, multinucleated cells, and “rosette” or “pseu- vations supported a predilection for hepatitis A to occur in late fall and
doacinar” formation. The mononuclear infiltration consists primarily early winter. In temperate zones, epidemic waves have been recorded
of small lymphocytes, although plasma cells and eosinophils occasion- every 5–20 years as new segments of nonimmune population appeared;
ally are present. Liver cell damage consists of hepatic cell degeneration however, in developed countries, the incidence of hepatitis A has been
and necrosis, cell dropout, ballooning of cells, and acidophilic degen- declining, presumably as a function of improved sanitation, and these
eration of hepatocytes (forming so-called Councilman or apoptotic cyclic patterns are no longer observed. No HAV carrier state has been
bodies). Large hepatocytes with a ground-glass appearance of the identified after acute hepatitis A; perpetuation of the virus in nature
cytoplasm may be seen in chronic but not in acute HBV infection; these depends presumably on nonepidemic, inapparent subclinical infection,
cells contain HBsAg and can be identified histochemically with orcein ingestion of contaminated food or water in, or imported from, endemic
or aldehyde fuchsin. In uncomplicated viral hepatitis, the reticulin areas, and/or contamination linked to environmental reservoirs.
framework is preserved. In the general population, anti-HAV, a marker for previous HAV
In hepatitis C, the histologic lesion is often remarkable for a relative infection, increases in prevalence as a function of increasing age and
paucity of inflammation, a marked increase in activation of sinusoidal of decreasing socioeconomic status. In the 1970s, serologic evidence
lining cells, lymphoid aggregates, the presence of fat (more frequent in of prior hepatitis A infection occurred in ~40% of urban populations
genotype 3 and linked to increased fibrosis), and, occasionally, bile duct in the United States, most of whose members never recalled having
lesions in which biliary epithelial cells appear to be piled up without had a symptomatic case of hepatitis. In subsequent decades, however,
interruption of the basement membrane. Occasionally, microvesicular the prevalence of anti-HAV has been declining in the United States. In
steatosis occurs in hepatitis D. In hepatitis E, a common histologic developing countries, exposure, infection, and subsequent immunity
feature is marked cholestasis. A cholestatic variant of slowly resolving are almost universal in childhood. As the frequency of subclinical
acute hepatitis A also has been described. childhood infections declines in developed countries, a susceptible

A more severe histologic lesion, bridging hepatic necrosis, also termed cohort of adults emerges. Hepatitis A tends to be more symptomatic
subacute or confluent necrosis or interface hepatitis, is observed occasion- in adults; therefore, paradoxically, as the frequency of HAV infection
ally in acute hepatitis. “Bridging” between lobules results from large declines, the likelihood of clinically apparent, even severe, HAV ill-
areas of hepatic cell dropout, with collapse of the reticulin frame- nesses increases in the susceptible adult population. Travel to endemic
work. Characteristically, the bridge consists of condensed reticulum, areas is a common source of infection for adults from nonendemic
inflammatory debris, and degenerating liver cells that span adjacent areas. More recently recognized epidemiologic foci of HAV infection
portal areas, portal to central veins, or central vein to central vein. This include child care centers, neonatal intensive care units, promiscuous
lesion had been thought to have prognostic significance; in many of men who have sex with men, injection drug users, and unvaccinated
the originally described patients with this lesion, a subacute course close contacts of newly arrived international adopted children, most
terminated in death within several weeks to months, or severe chronic of whom emanate from countries with intermediate-to-high hepatitis
hepatitis and cirrhosis developed; however, the association between A endemicity. Although hepatitis A is rarely bloodborne, several out-
bridging necrosis and a poor prognosis in patients with acute hepa- breaks have been recognized in recipients of clotting-factor concen-
titis has not been upheld. Therefore, although demonstration of this trates. In the United States, the introduction of hepatitis A vaccination
lesion in patients with chronic hepatitis has prognostic significance programs among children from high-incidence states has resulted in
(Chap. 334), its demonstration during acute hepatitis is less meaning- a >70% reduction in the annual incidence of new HAV infections and
ful, and liver biopsies to identify this lesion are no longer undertaken has shifted the burden of new infections from children to adults. In the
routinely in patients with acute hepatitis. In massive hepatic necrosis 2007–2012 U.S. Public Health Service National Health and Nutrition
(fulminant hepatitis, “acute yellow atrophy”), the striking feature at Examination Survey (NHANES), the prevalence of anti-HAV in the
postmortem examination is the finding of a small, shrunken, soft liver. U.S. population aged ≥20 years had declined to 24.2% from the 29.5%
Histologic examination reveals massive necrosis and dropout of liver measured in NHANES 1999–2006. While universal childhood vaccina-
cells of most lobules with extensive collapse and condensation of the tion accounted for a high prevalence of vaccine-induced immunity in
reticulin framework. When histologic documentation is required in children aged 2–19 years, the lowest age-specific prevalence of anti-
the management of fulminant or very severe hepatitis, a biopsy can be HAV (16.1–17.6%) occurred in adults in the fourth and fifth decades,
done by the angiographically guided transjugular route, which permits respectively (aged 30–49 years). This is a subgroup of the population
the performance of this invasive procedure in the presence of severe who remain susceptible to acute hepatitis A acquired during travel to
coagulopathy. endemic areas and from contaminated foods, especially those imported
Immunohistochemical and electron-microscopic studies have local- from endemic countries.
ized HBsAg to the cytoplasm and plasma membrane of infected liver
cells. In contrast, HBcAg predominates in the nucleus, but, occasion- Hepatitis B Percutaneous inoculation has long been recognized as a
ally, scant amounts are also seen in the cytoplasm and on the cell mem- major route of hepatitis B transmission, but the outmoded designation
brane. HDV antigen is localized to the hepatocyte nucleus, whereas “serum hepatitis” is an inaccurate label for the epidemiologic spectrum
HAV, HCV, and HEV antigens are localized to the cytoplasm. of HBV infection. As detailed below, most of the hepatitis transmitted
by blood transfusion is not caused by HBV; moreover, in approximately
■■EPIDEMIOLOGY AND GLOBAL FEATURES two-thirds of patients with acute type B hepatitis, no history of an iden-
Before the availability of serologic tests for hepatitis viruses, tifiable percutaneous exposure can be elicited. We now recognize that
all viral hepatitis cases were labeled either as “infectious” or many cases of hepatitis B result from less obvious modes of nonpercu-
“serum” hepatitis. Modes of transmission overlap, however, taneous or covert percutaneous transmission. HBsAg has been identi-
and a clear distinction among the different types of viral hepatitis cannot be fied in almost every body fluid from infected persons, and at least some
made solely on the basis of clinical or epidemiologic features (Table 332-2). of these body fluids—most notably semen and saliva—are infectious,
The most accurate means to distinguish the various types of viral albeit less so than serum, when administered percutaneously or non-
hepatitis involves specific serologic testing. percutaneously to experimental animals. Among the nonpercutaneous

2356 TABLE 332-2 Clinical and Epidemiologic Features of Viral Hepatitis
FEATURE HAV HBV HCV HDV HEV
Incubation (days) 15–45, mean 30 30–180, mean 60–90 15–160, mean 50 30–180, mean 60–90 14–60, mean 40
Onset Acute Insidious or acute Insidious or acute Insidious or acute Acute
Age preference Children, young adults Young adults (sexual and Any age, but more Any age (similar to HBV) Epidemic cases: young
percutaneous), babies, common in adults adults (20–40 years);
toddlers sporadic cases: older
adults (>60)
Transmission
Fecal-oral +++ − − − +++
Percutaneous Unusual +++ +++ +++ −
Perinatal − +++ ±a + −
Sexual ± ++ ±a ++ −
Clinical
Severity Mild Occasionally severe Moderate Occasionally severe Mild
Fulminant 0.1% 0.1–1% 0.1% 5–20%b 1–2%e
Progression to None Occasional (1–10%) Common (85%) Commond Nonef
chronicity (90% of neonates)
Carrier None 0.1–30%c 1.5–3.2% Variableg None
Cancer None + (neonatal infection) + ± None
Prognosis Excellent Worse with age, debility Moderate Acute, good Chronic, poor Good
Prophylaxis Ig, inactivated vaccine HBIG, recombinant None HBV vaccine (none for Vaccine
vaccine HBV carriers)
Therapy None Interferon Pegylated interferon Pegylated interferon ± Nonej
Lamivudine ribavirin telaprevir,i
boceprevir,i simeprevir,
Adefovir
sofosbuvir, ledipasvir,
Pegylated interferonh paritaprevir/ritonavir
Entecavirh ombitasvir, dasabuvir
PART 10
Telbivudine daclatasvir, velpatasvir,

grazoprevir, elbasvir
Tenofovirh
a
Primarily with HIV co-infection and high-level viremia in index case; more likely in persons with multiple sex partners or sexually transmitted diseases; risk ~5%. bUp to
5% in acute HBV/HDV co-infection; up to 20% in HDV superinfection of chronic HBV infection.c Varies considerably throughout the world and in subpopulations within
countries; see text. dIn acute HBV/HDV co-infection, the frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable. e10–20%
in pregnant women. fExcept as observed in immunosuppressed liver allograft recipients or other immunosuppressed hosts. gCommon in Mediterranean countries; rare
in North America and western Europe. hFirst-line agents. iNo longer recommended. jAnecdotal reports and retrospective studies suggest that pegylated interferon and/
or ribavirin are effective in treating chronic hepatitis E, observed in immunocompromised persons; ribavirin monotherapy has been used successfully in acute, severe
hepatitis E.
Abbreviation: HBIG, hepatitis B immunoglobulin. See text for other abbreviations.
modes of HBV transmission, oral ingestion has been documented as a disease, or polyarteritis nodosa; in patients with chronic renal disease
potential but inefficient route of exposure. By contrast, the two nonper- on hemodialysis; and in injection drug users.
cutaneous routes considered to have the greatest impact are intimate Other groups with high rates of HBV infection include spouses of
(especially sexual) contact and perinatal transmission. acutely infected persons; sexually promiscuous persons (especially
In sub-Saharan Africa, intimate contact among toddlers is consid- promiscuous men who have sex with men); health care workers
ered instrumental in contributing to the maintenance of the high fre- exposed to blood; persons who require repeated transfusions espe-
quency of hepatitis B in the population. Perinatal transmission occurs cially with pooled blood-product concentrates (e.g., hemophiliacs);
primarily in infants born to mothers with chronic hepatitis B or (rarely) residents and staff of custodial institutions for the developmentally
mothers with acute hepatitis B during the third trimester of preg- handicapped; prisoners; and, to a lesser extent, family members of
nancy or during the early postpartum period. Perinatal transmission chronically infected patients. In volunteer blood donors, the prevalence
is uncommon in North America and western Europe but occurs with of anti-HBs, a reflection of previous HBV infection, ranges from 5% to
great frequency and is the most important mode of HBV perpetuation 10%, but the prevalence is higher in lower socioeconomic strata, older
in East Asia and developing countries. Although the precise mode of age groups, and persons—including those mentioned above—exposed
perinatal transmission is unknown, and although ~10% of infections to blood products. Because of highly sensitive virologic screening of
may be acquired in utero, epidemiologic evidence suggests that most donor blood, the risk of acquiring HBV infection from a blood transfu-
infections occur approximately at the time of delivery and are not sion is 1 in 230,000.
related to breast-feeding (which is not contraindicated in women Prevalence of infection, modes of transmission, and human behav-
with hepatitis B). The likelihood of perinatal transmission of HBV ior conspire to mold geographically different epidemiologic patterns
correlates with the presence of HBeAg and high-level viral replication; of HBV infection. In East Asia and Africa, hepatitis B, a disease of the
90% of HBeAg-positive mothers but only 10–15% of anti-HBe-positive newborn and young children, is perpetuated by a cycle of maternal-
mothers transmit HBV infection to their offspring. In most cases, acute neonatal spread. In North America and western Europe, hepatitis B is
infection in the neonate is clinically asymptomatic, but the child is very primarily a disease of adolescence and early adulthood, the time of life
likely to remain chronically infected. when intimate sexual contact and recreational and occupational percu-
The >350–400 million persons with chronic HBV infection in the taneous exposures tend to occur. To some degree, however, this dichot-
world constitute the main reservoir of hepatitis B in human beings. omy between high-prevalence and low-prevalence geographic regions
Whereas serum HBsAg is infrequent (0.1–0.5%) in normal populations has been minimized by immigration from high-prevalence to low-prev-
in the United States and western Europe, a prevalence of up to 5–20% alence areas. For example, in the United States, NHANES data from
has been found in East Asia and in some tropical countries; in persons 2007 to 2012 revealed an overall prevalence of current HBV infection
with Down’s syndrome, lepromatous leprosy, leukemia, Hodgkin’s (detectable HBsAg) of 0.3%; however, the prevalence in Asian persons,

TABLE 332-3 High-Risk Populations for Whom HBV Infection reservoir has been sustained by survivors infected during 1970–1980 2357
Screening Is Recommended and recent immigrants from still-endemic (e.g., Eastern Europe and
Persons born in countries/regions with a high (≥8%) and intermediate (≥2%) Central Asia) to less-endemic countries.
prevalence of HBV infection including immigrants and adopted children and
including persons born in the United States who were not vaccinated as Hepatitis C Routine screening of blood donors for HBsAg and the
infants and whose parents emigrated from areas of high HBV endemicity elimination of commercial blood sources in the early 1970s reduced the
Household and sexual contacts of persons with hepatitis B frequency of, but did not eliminate, transfusion-associated hepatitis.
Babies born to HBsAg-positive mothers During the 1970s, the likelihood of acquiring hepatitis after transfusion
Persons who have used injection drugs
of voluntarily donated, HBsAg-screened blood was ~10% per patient
(up to 0.9% per unit transfused); 90–95% of these cases were classified,
Persons with multiple sexual contacts or a history of sexually transmitted
disease based on serologic exclusion of hepatitis A and B, as “non-A, non-B”
Men who have sex with men
hepatitis. For patients requiring transfusion of pooled products, such
as clotting factor concentrates, the risk was even higher, up to 20–30%.
Inmates of correctional facilities
During the 1980s, voluntary self-exclusion of blood donors with
Persons with elevated alanine or aspartate aminotransferase levels
risk factors for AIDS and then the introduction of donor screening
Blood/plasma/organ/tissue/semen donors for anti-HIV reduced further the likelihood of transfusion-associated
Persons with HCV or HIV infection hepatitis to <5%. During the late 1980s and early 1990s, the introduc-
Hemodialysis patients tion first of “surrogate” screening tests for non-A, non-B hepatitis
Pregnant women (alanine aminotransferase [ALT] and anti-HBc, both shown to identify
Persons who are the source of blood or body fluids that would be an indication blood donors with a higher likelihood of transmitting non-A, non-B
for postexposure prophylaxis (e.g., needlestick, mucosal exposure, sexual hepatitis to recipients) and, subsequently, after the discovery of HCV,
assault) first-generation immunoassays for anti-HCV reduced the frequency
Persons who require immunosuppressive or cytotoxic therapy (including of transfusion-associated hepatitis even further. A prospective anal-
anti–tumor necrosis factor α therapy for rheumatologic or inflammatory bowel
disorders)
ysis of transfusion-associated hepatitis conducted between 1986 and
1990 showed that the frequency of transfusion-associated hepatitis at
one urban university hospital fell from a baseline of 3.8% per patient
(0.45% per unit transfused) to 1.5% per patient (0.19% per unit) after
93% of whom were foreign-born, was 10-fold higher, 3.1%, representing the introduction of surrogate testing and to 0.6% per patient (0.03%
50% of the U.S. national disease burden. The introduction of hepatitis B

per unit) after the introduction of first-generation anti-HCV assays.
vaccine in the early 1980s and adoption of universal childhood vaccina- The introduction of second-generation anti-HCV assays reduced the
tion policies in many countries resulted in a dramatic, ~90% decline in frequency of transfusion-associated hepatitis C to almost imperceptible
the incidence of new HBV infections in those countries as well as in the levels—1 in 100,000—and these gains were reinforced by the applica-
dire consequences of chronic infection, including hepatocellular carci- tion of third-generation anti-HCV assays and of automated PCR testing
noma. In the United States, as demonstrated in NHANES 2007–2012, of donated blood for HCV RNA, which has resulted in a reduction
following the 1991 implementation of universal childhood vaccination, in the risk of transfusion-associated HCV infection to 1 in 2.3 million
HBsAg seropositivity had declined in children aged 6–19 years to as transfusions.
low as 0.03%, an ~85% reduction. Populations and groups for whom
In addition to being transmitted by transfusion, hepatitis C can be
HBV infection screening is recommended are listed in Table 332-3.
transmitted by other percutaneous routes, such as injection drug use.
Hepatitis D Infection with HDV has a worldwide distribution, but In addition, this virus can be transmitted by occupational exposure to
two epidemiologic patterns exist. In Mediterranean countries (northern blood, and the likelihood of infection is increased in hemodialysis units.
Africa, southern Europe, the Middle East), HDV infection is endemic Although the frequency of transfusion-associated hepatitis C fell as a
among those with hepatitis B, and the disease is transmitted predom- result of blood-donor screening, the overall frequency of hepatitis C
inantly by nonpercutaneous means, especially close personal contact. remained the same until the early 1990s, when the overall frequency of
In nonendemic areas, such as the United States (where hepatitis D is reported cases fell by 80%, in parallel with a reduction in the number
rare among persons with chronic hepatitis B) and northern Europe, of new cases in injection drug users. After the exclusion of anti-HCV-
HDV infection is confined to persons exposed frequently to blood positive plasma units from the donor pool, rare, sporadic instances
and blood products, primarily injection drug users, (especially so in have occurred of hepatitis C among recipients of immunoglobulin
HIV-infected injection drug users) and hemophiliacs. In the United preparations for intravenous (but not intramuscular) use.
States, the prevalence of HDV infection in the national population Serologic evidence for HCV infection occurs in 90% of patients with
is 0.02% (NHANES 1999–2012); however, among HBsAg-positive a history of transfusion-associated hepatitis (almost all occurring before
persons, the prevalence of HDV infection is highest in injection drug 1992, when second-generation HCV screening tests were introduced);
users (11%) and hemophiliacs (19%). HDV infection can be introduced hemophiliacs and others treated with clotting factors; injection drug
into a population through drug users or by migration of persons from users; 60–70% of patients with sporadic “non-A, non-B” hepatitis who
endemic to nonendemic areas. Thus, patterns of population migration lack identifiable risk factors; 0.5% of volunteer blood donors; and, in
and human behavior facilitating percutaneous contact play important the NHANES survey conducted in the United States between 1999 and
roles in the introduction and amplification of HDV infection. Occasion- 2002, 1.6% of the general population in the United States, which trans-
ally, the migrating epidemiology of hepatitis D is expressed in explo- lates into 4.1 million persons (3.2 million with viremia), the majority
sive outbreaks of severe hepatitis, such as those that have occurred in of whom are unaware of their infections. Moreover, such population
remote South American villages (e.g., “Lábrea fever” in the Amazon surveys do not include higher-risk groups such as incarcerated per-
basin) as well as in urban centers in the United States. Ultimately, such sons, homeless persons, and active injection drug users, indicating that
outbreaks of hepatitis D—either of co-infections with acute hepatitis the actual prevalence is even higher. Comparable frequencies of HCV
B or of superinfections in those already infected with HBV—may blur infection occur in most countries around the world, with 170 million
the distinctions between endemic and nonendemic areas. On a global persons infected worldwide, but extraordinarily high prevalences of
scale, HDV infection declined at the end of the 1990s. Even in Italy, an HCV infection occur in certain countries such as Egypt, where >20%
HDV-endemic area, public health measures introduced to control HBV of the population (as high as 50% in persons born prior to 1960) in
infection (e.g., mass hepatitis B vaccination) resulted during the 1990s some cities is infected. The high frequency in Egypt is attributable
in a 1.5%/year reduction in the prevalence of HDV infection. Still, to contaminated equipment used for medical procedures and unsafe
the frequency of HDV infection during the first decade of the twenty- injection practices in the 1950s to 1980s (during a campaign to eradicate
first century has not fallen below levels reached during the 1990s; the schistosomiasis with intravenous tartar emetic). In the United States,

2358 African Americans and Mexican Americans have higher frequencies of TABLE 332-4 High-Risk Populations for Whom HCV-Infection
HCV infection than whites. Data from NHANES showed that between Screening is Recommended
1988 and 1994, 30- to 40-year-old men had the highest prevalence of Persons born between 1945 and 1965
HCV infection; however, in a survey conducted between 1999 and 2002, Persons who have ever used injection drugs
the peak age decile had shifted to those age 40–49 years; an increase in Persons with HIV infection
hepatitis C–related mortality has paralleled this secular trend, increas-
Hemophiliacs treated with clotting factor concentrates prior to 1987
ing since 1995 predominantly in the 45- to 65-year age group. Thus,
Persons who have ever undergone long-term hemodialysis
despite an 80% reduction in new HCV infections during the 1990s, the
prevalence of HCV infection in the population was sustained by an Persons with unexplained elevations of aminotransferase levels
aging cohort that had acquired their infections three to four decades Transfusion or transplantation recipients prior to July 1992
earlier, during the 1960s and 1970s, as a result predominantly of self- Recipients of blood or organs from a donor found to be positive for hepatitis C
inoculation with recreational drugs. Retrospective phylogenetic map- Children born to women with hepatitis C
ping of >45,000 HCV genotype 1a isolates revealed that the hepatitis C Health care, public safety, and emergency medical personnel following needle
epidemic emerged in the United States between 1940 and 1965, peaking injury or mucosal exposure to HCV-contaminated blood
in 1950 and aligning temporally with the post-World-War-II expansion Sexual partners of persons with hepatitis C infection
of medical procedures (including re-use of glass syringes). Thus, HCV
was amplified iatrogenically not only in Egypt but also in the United
States; in the United States, the seeds sewn by medical procedures in
such subgroups as persons with multiple sexual partners and sexually
the 1950s were reaped in the 1960s and 1970s among transfusion recip-
transmitted diseases; for example, isolated clusters of sexually trans-
ients and injection drug users, even those whose drug use was confined
mitted HCV infection have been reported in HIV-infected men who
to brief adolescent experimentation.
have sex with men. Breast-feeding does not increase the risk of HCV
In NHANES 2003–2010, the prevalence of HCV infection (HCV RNA
infection between an infected mother and her infant. Infection of health
reactivity) in the United States had actually fallen to 1% (2.7 million per-
workers is not dramatically higher than among the general population;
sons) from 1.3% (3.2 million) the decade before (NHANES 1999–2002),
however, health workers are more likely to acquire HCV infection
attributable to deaths among the HCV-infected population. As death
through accidental needle punctures, the efficiency of which is ~3%.
resulting from HIV infection fell after 1999, age-adjusted mortality
Infection of household contacts is rare as well.
associated with HCV infection surpassed that of HIV infection in 2007;
Besides persons born between 1945 and 1965, other groups with
>70% of HCV-associated deaths occurred in the “baby boomer” cohort
an increased frequency of HCV infection are listed in Table 332-4. In
born between 1945 and 1965. By 2012, HCV mortality had surpassed
immunosuppressed individuals, levels of anti-HCV may be undetect-
PART 10
deaths from HIV, tuberculosis, hepatitis B, and 57 other notifiable

able, and a diagnosis may require testing for HCV RNA. Although
infectious diseases (i.e., all infectious diseases) reported to the Centers
new acute cases of hepatitis C are rare outside of the injection-drug
for Disease Control and Prevention. In NHANES 1999–2002, compared
using community, newly diagnosed cases are common among other-
to the 1.6% prevalence of HCV infection in the population at large,
wise healthy persons who experimented briefly with injection drugs,
the prevalence in the 1945–1965 birth cohort was 3.2%, representing
as noted above, three or four decades earlier. Such instances usually

three-quarters of all infected persons. Therefore, in 2012, the Centers
remain unrecognized for years, until unearthed by laboratory screen-
for Disease Control and Prevention recommended that all persons born
ing for routine medical examinations, insurance applications, and
between 1945 and 1965 be screened for hepatitis C, without ascertain-
attempted blood donation. Although, overall, the annual incidence of
ment of risk, a recommendation shown to be cost-effective and pre-
new HCV infections has continued to fall, the rate of new infections
dicted to identify 800,000 infected persons. Because of the availability of
has been increasing since 2002, amplified by the recent epidemic of
highly effective antiviral therapy, such screening would have the poten-
opioid use, in a new cohort of young injection drug users, age 15–24
tial to avert 200,000 cases of cirrhosis and 47,000 cases of hepatocellular
years (accounting for more than two-thirds of all acute cases), who,
carcinoma and to prevent 120,000 hepatitis-related deaths; with the
unlike older cohorts, had not learned to take precautions to prevent
availability of the new generation of direct-acting antivirals (efficacy
bloodborne infections.
>95%, see Chap 334), screening baby boomers and treating those with
hepatitis C have been predicted to reduce the HCV-associated disease Hepatitis E This type of hepatitis, identified in India, Asia, Africa,
burden by 50–70% through 2050. the Middle East, and Central America, resembles hepatitis A in its pri-
Hepatitis C accounts for 40% of chronic liver disease, is the most marily enteric mode of spread. The commonly recognized cases occur
frequent indication for liver transplantation, and is estimated to after contamination of water supplies such as after monsoon flooding,
account for 8000–10,000 deaths per year in the United States. The but sporadic, isolated cases occur. An epidemiologic feature that dis-
distribution of HCV genotypes varies in different parts of the world. tinguishes HEV from other enteric agents is the rarity of secondary
Worldwide, genotype 1 is the most common. In the United States, person-to-person spread from infected persons to their close contacts.
genotype 1 accounts for 70% of HCV infections, whereas genotypes 2 Large waterborne outbreaks in endemic areas are linked to genotypes
and 3 account for the remaining 30%; among African Americans, the 1 and 2, arise in populations that are immune to HAV, favor young
frequency of genotype 1 is even higher (i.e., 90%). Genotype 4 predom- adults, and account for antibody prevalences of 30–80%. In nonendemic
inates in Egypt; genotype 5 is localized to South Africa, genotype 6 to areas of the world, such as the United States, clinically apparent acute
Hong Kong, and genotype 7 to Central Africa. Most asymptomatic hepatitis E is extremely rare; however, during the 1988–1994 NHANES
blood donors found to have anti-HCV and ~20–30% of persons with survey conducted by the U.S. Public Health Service, the prevalence
reported cases of acute hepatitis C do not fall into a recognized risk of anti-HEV was 21%, reflecting subclinical infections, infection with
group; however, many such blood donors do recall risk-associated genotypes 3 and 4, predominantly in older males (>60 years). In non-
behaviors when questioned carefully. endemic areas, HEV accounts hardly at all for cases of sporadic (labeled
As a bloodborne infection, HCV potentially can be transmitted sex- “autochthonous” or indigenous) hepatitis; however, cases imported
ually and perinatally; however, both of these modes of transmission from endemic areas have been found in the United States. Evidence
are inefficient for hepatitis C. Although 10–15% of patients with acute supports a zoonotic reservoir for HEV primarily in swine, which may
hepatitis C report having potential sexual sources of infection, most account for the mostly subclinical infections in nonendemic areas. A
studies have failed to identify sexual transmission of this agent. The previously unrecognized high distribution of HEV infection, linked to
chances of sexual and perinatal transmission have been estimated to be pork-product ingestion, has been discovered in western Europe (e.g.,
~5% but shown in a prospective study to be only 1% between monog- in Germany, an estimated annual incidence of 300,000 cases and a 17%
amous sexual partners, well below comparable rates for HIV and HBV prevalence of anti-HEV among adults; in France, a 22% prevalence of
infections. Moreover, sexual transmission appears to be confined to anti-HEV in healthy blood donors).

■■CLINICAL AND LABORATORY FEATURES Laboratory Features The serum aminotransferases aspartate 2359
aminotransferase (AST) and ALT (previously designated SGOT and
Symptoms and Signs Acute viral hepatitis occurs after an incu- SGPT) increase to a variable degree during the prodromal phase of
bation period that varies according to the responsible agent. Generally,
acute viral hepatitis and precede the rise in bilirubin level (Figs. 332-2
incubation periods for hepatitis A range from 15 to 45 days (mean,
and 332-4). The level of these enzymes, however, does not correlate
4 weeks), for hepatitis B and D from 30 to 180 days (mean, 8–12 weeks),
well with the degree of liver cell damage. Peak levels vary from ~400
for hepatitis C from 15 to 160 days (mean, 7 weeks), and for hepatitis E
to ~4000 IU or more; these levels are usually reached at the time the
from 14 to 60 days (mean, 5–6 weeks). The prodromal symptoms of acute
patient is clinically icteric and diminish progressively during the recov-
viral hepatitis are systemic and quite variable. Constitutional symp-
ery phase of acute hepatitis. The diagnosis of anicteric hepatitis is based
toms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias,
on clinical features and on aminotransferase elevations.
myalgias, headache, photophobia, pharyngitis, cough, and coryza may
Jaundice is usually visible in the sclera or skin when the serum bil-
precede the onset of jaundice by 1–2 weeks. The nausea, vomiting, and
irubin value is >43 μmol/L (2.5 mg/dL). When jaundice appears, the
anorexia are frequently associated with alterations in olfaction and
serum bilirubin typically rises to levels ranging from 85 to 340 μmol/L
taste. A low-grade fever between 38° and 39°C (100°–102°F) is more
(5–20 mg/dL). The serum bilirubin may continue to rise despite falling
often present in hepatitis A and E than in hepatitis B or C, except when
serum aminotransferase levels. In most instances, the total bilirubin is
hepatitis B is heralded by a serum sickness–like syndrome; rarely, a
equally divided between the conjugated and unconjugated fractions. Bil-
fever of 39.5°–40°C (103°–104°F) may accompany the constitutional
irubin levels >340 μmol/L (20 mg/dL) extending and persisting late into
symptoms. Dark urine and clay-colored stools may be noticed by the
the course of viral hepatitis are more likely to be associated with severe
patient from 1–5 days before the onset of clinical jaundice.
disease. In certain patients with underlying hemolytic anemia, how-
With the onset of clinical jaundice, the constitutional prodromal
ever, such as glucose-6-phosphate dehydrogenase deficiency and sickle
symptoms usually diminish, but in some patients, mild weight loss
(2.5–5 kg) is common and may continue during the entire icteric cell anemia, a high serum bilirubin level is common, resulting from
phase. The liver becomes enlarged and tender and may be associ- superimposed hemolysis. In such patients, bilirubin levels >513 μmol/L
ated with right upper quadrant pain and discomfort. Infrequently, (30 mg/dL) have been observed and are not necessarily associated with
patients present with a cholestatic picture, suggesting extrahepatic a poor prognosis.
biliary obstruction. Splenomegaly and cervical adenopathy are pres- Neutropenia and lymphopenia are transient and are followed by a
ent in 10–20% of patients with acute hepatitis. Rarely, a few spider relative lymphocytosis. Atypical lymphocytes (varying between 2 and
angiomas appear during the icteric phase and disappear during 20%) are common during the acute phase. Measurement of the proth-
convalescence. During the recovery phase, constitutional symptoms rombin time (PT) is important in patients with acute viral hepatitis,

disappear, but usually some liver enlargement and abnormalities because a prolonged value may reflect a severe hepatic synthetic defect,
in liver biochemical tests are still evident. The duration of the signify extensive hepatocellular necrosis, and indicate a worse progno-
posticteric phase is variable, ranging from 2 to 12 weeks, and is sis. Occasionally, a prolonged PT may occur with only mild increases
usually more prolonged in acute hepatitis B and C. Complete clin- in the serum bilirubin and aminotransferase levels. Prolonged nausea
ical and biochemical recovery is to be expected 1–2 months after and vomiting, inadequate carbohydrate intake, and poor hepatic gly-
all cases of hepatitis A and E and 3–4 months after the onset of cogen reserves may contribute to hypoglycemia noted occasionally in
jaundice in three-quarters of uncomplicated, self-limited cases of patients with severe viral hepatitis. Serum alkaline phosphatase may
hepatitis B and C (among healthy adults, acute hepatitis B is self- be normal or only mildly elevated, whereas a fall in serum albumin is
limited in 95–99%, whereas hepatitis C is self-limited in only ~15– uncommon in uncomplicated acute viral hepatitis. In some patients,
20%). In the remainder, biochemical recovery may be delayed. A mild and transient steatorrhea has been noted, as well as slight micro-
substantial proportion of patients with viral hepatitis never become scopic hematuria and minimal proteinuria.
icteric. A diffuse but mild elevation of the γ globulin fraction is common
Infection with HDV can occur in the presence of acute or chronic during acute viral hepatitis. Serum IgG and IgM levels are elevated in
HBV infection; the duration of HBV infection determines the duration about one-third of patients during the acute phase of viral hepatitis, but
of HDV infection. When acute HDV and HBV infections occur simul- the serum IgM level is elevated more characteristically during acute hep-
taneously, clinical and biochemical features may be indistinguishable atitis A. During the acute phase of viral hepatitis, antibodies to smooth
from those of HBV infection alone, although occasionally they are muscle and other cell constituents may be present, and low titers of rheu-
more severe. As opposed to patients with acute HBV infection, patients matoid factor, nuclear antibody, and heterophile antibody can also be
with chronic HBV infection can support HDV replication indefinitely, found occasionally. In hepatitis C and D, antibodies to LKM may occur;
as when acute HDV infection occurs in the presence of a nonresolv- however, the species of LKM antibodies in the two types of hepatitis
ing acute HBV infection or, more commonly, when acute hepatitis D are different from each other as well as from the LKM antibody species
is superimposed on underlying chronic hepatitis B. In such cases, characteristic of autoimmune hepatitis type 2 (Chap. 334). The autoanti-
the HDV superinfection appears as a clinical exacerbation or an epi- bodies in viral hepatitis are nonspecific and can also be associated with
sode resembling acute viral hepatitis in someone already chronically other viral and systemic diseases. In contrast, virus-specific antibodies,
infected with HBV. Superinfection with HDV in a patient with chronic which appear during and after hepatitis virus infection, are serologic
hepatitis B often leads to clinical deterioration (see below). markers of diagnostic importance.
In addition to superinfections with other hepatitis agents, acute As described above, serologic tests are available routinely with which
hepatitis-like clinical events in persons with chronic hepatitis B may to establish a diagnosis of hepatitis A, B, D, and C. Tests for fecal or serum
accompany spontaneous HBeAg to anti-HBe seroconversion or spon- HAV are not routinely available. Therefore, a diagnosis of hepatitis A is
taneous reactivation (i.e., reversion from relatively nonreplicative to based on detection of IgM anti-HAV during acute illness (Fig. 332-2).
replicative infection). Such reactivations can occur as well in therapeu- Rheumatoid factor can give rise to false-positive results in this test.
tically immunosuppressed patients with chronic HBV infection when A diagnosis of HBV infection can usually be made by detection
cytotoxic/immunosuppressive drugs are withdrawn; in these cases, of HBsAg in serum. Infrequently, levels of HBsAg are too low to be
restoration of immune competence is thought to allow resumption of detected during acute HBV infection, even with contemporary, highly
previously checked cell-mediated immune cytolysis of HBV-infected sensitive immunoassays. In such cases, the diagnosis can be established
hepatocytes. Occasionally, acute clinical exacerbations of chronic hepa- by the presence of IgM anti-HBc.
titis B may represent the emergence of a precore mutant (see “Virology The titer of HBsAg bears little relation to the severity of clinical
and Etiology”), and the subsequent course in such patients may be disease. Indeed, an inverse correlation exists between the serum con-
characterized by periodic exacerbations. Cytotoxic chemotherapy can centration of HBsAg and the degree of liver cell damage. For example,
lead to reactivation of chronic hepatitis C as well, and anti-TNF-α ther- titers are highest in immunosuppressed patients, lower in patients with
apy can lead to reactivation of both hepatitis B and C. chronic liver disease (but higher in mild chronic than in severe chronic

2360 hepatitis), and very low in patients with acute fulminant hepatitis. those with the highest sensitivity (5–10 IU/mL) and the largest dynamic
These observations suggest that in hepatitis B the degree of liver cell range (100–109 IU/mL). With increased sensitivity, amplification assays
damage and the clinical course are related to variations in the patient’s remain reactive well below the current 103–104 IU/mL threshold for
immune response to HBV rather than to the amount of circulating infectivity and liver injury. These markers are useful in following the
HBsAg. In immunocompetent persons, however, a correlation exists course of HBV replication in patients with chronic hepatitis B receiving
between markers of HBV replication and liver injury (see below). antiviral chemotherapy (Chap. 334). Except for the early decades of
Another important serologic marker in patients with hepatitis B is life after perinatally acquired HBV infection (see above), in immuno-
HBeAg. Its principal clinical usefulness is as an indicator of relative competent adults with chronic hepatitis B, a general correlation exists
infectivity. Because HBeAg is invariably present during early acute between the level of HBV replication, as reflected by the level of serum
hepatitis B, HBeAg testing is indicated primarily in chronic infection. HBV DNA, and the degree of liver injury. High-serum HBV DNA
In patients with hepatitis B surface antigenemia of unknown dura- levels, increased expression of viral antigens, and necroinflammatory
tion (e.g., blood donors found to be HBsAg-positive) testing for IgM activity in the liver go hand in hand unless immunosuppression inter-
anti-HBc may be useful to distinguish between acute or recent infection feres with cytolytic T cell responses to virus-infected cells; reduction of
(IgM anti-HBc-positive) and chronic HBV infection (IgM anti-HBc- HBV replication with antiviral drugs tends to be accompanied by an
negative, IgG anti-HBc-positive). A false-positive test for IgM anti-HBc improvement in liver histology. Among patients with chronic hepatitis
may be encountered in patients with high-titer rheumatoid factor. Also, B, high levels of HBV DNA increase the risk of cirrhosis, hepatic dec-
IgM anti-HBc may be reexpressed during acute reactivation of chronic ompensation, and hepatocellular carcinoma (see “Complications and
hepatitis B. Sequelae”).
Anti-HBs is rarely detectable in the presence of HBsAg in patients In patients with hepatitis C, an episodic pattern of aminotransferase
with acute hepatitis B, but 10–20% of persons with chronic HBV infec- elevation is common. A specific serologic diagnosis of hepatitis C can
tion may harbor low-level anti-HBs. This antibody is directed not be made by demonstrating the presence in serum of anti-HCV. When
against the common group determinant, a, but against the heterotypic contemporary immunoassays are used, anti-HCV can be detected in
subtype determinant (e.g., HBsAg of subtype ad with anti-HBs of acute hepatitis C during the initial phase of elevated aminotransferase
subtype y). In most cases, this serologic pattern cannot be attributed activity and remains detectable after recovery (rare) and during chronic
to infection with two different HBV subtypes but, instead, is thought infection (common). Nonspecificity can confound immunoassays for
(based on the clonal selection theory of antibody diversity) to reflect anti-HCV, especially in persons with a low prior probability of infec-
the stimulation of a related clone of antibody-forming cells and is tion, such as volunteer blood donors, or in persons with circulating
not a harbinger of imminent HBsAg clearance. When such antibody rheumatoid factor, which can bind nonspecifically to assay reagents;
is detected, its presence is of no recognized clinical significance (see testing for HCV RNA can be used in such settings to distinguish
PART 10
“Virology and Etiology”). between true-positive and false-positive anti-HCV determinations.

After immunization with hepatitis B vaccine, which consists of Assays for HCV RNA are the most sensitive tests for HCV infection
HBsAg alone, anti-HBs is the only serologic marker to appear. The and represent the “gold standard” in establishing a diagnosis of
commonly encountered serologic patterns of hepatitis B and their hepatitis C. HCV RNA can be detected even before acute elevation of
interpretations are summarized in Table 332-5. Tests for the detection aminotransferase activity and before the appearance of anti-HCV in
of HBV DNA in liver and serum are now available. Like HBeAg, serum patients with acute hepatitis C. In addition, HCV RNA remains detect-
HBV DNA is an indicator of HBV replication, but tests for HBV DNA able indefinitely, continuously in most but intermittently in some, in
are more sensitive and quantitative. First-generation hybridization patients with chronic hepatitis C (detectable as well in some persons
assays for HBV DNA had a sensitivity of 105−106 virions/mL, a rela- with normal liver tests, i.e., inactive carriers). In the very small minor-
tive threshold below which infectivity and liver injury are limited and ity of patients with hepatitis C who lack anti-HCV, a diagnosis can be
HBeAg is usually undetectable. Currently, testing for HBV DNA has supported by detection of HCV RNA. If all these tests are negative and
shifted from insensitive hybridization assays to amplification assays the patient has a well-characterized case of hepatitis after percutaneous
(e.g., the PCR-based assay, which can detect as few as 10 or 100 virions/ exposure to blood or blood products, a diagnosis of hepatitis caused by
mL); among the commercially available PCR assays, the most useful are an unidentified agent can be entertained.
Amplification techniques are required to
detect HCV RNA. Currently, such target
TABLE 332-5 Commonly Encountered Serologic Patterns of Hepatitis B Infection amplification (i.e., synthesis of multiple cop-
HBsAg ANTI-HBs ANTI-HBc HBeAg ANTI-HBe INTERPRETATION ies of the viral genome) is achieved by PCR,
+ − IgM + − Acute hepatitis B, high infectivitya in which the viral RNA is reverse transcribed
+ − IgG + − Chronic hepatitis B, high infectivity to complementary DNA and then amplified
+ − IgG − + 1. Late acute or chronic hepatitis B, low by repeated cycles of DNA synthesis. Quan-
infectivity titative PCR assays provide a measurement
2. HBeAg-negative (“precore-mutant”) of relative “viral load”; current PCR assays
hepatitis B (chronic or, rarely, acute) have a sensitivity of 10 (lower limit of detec-
+ + + +/− +/− 1. HBsAg of one subtype and tion)-25 (lower limit of quantitation) IU/
heterotypic anti-HBs (common) mL and a wide dynamic range (10–107 IU/
2. Process of seroconversion from mL). Determination of HCV RNA level is
HBsAg to anti-HBs (rare) not a reliable marker of disease severity or
− − IgM +/− +/− 1. Acute hepatitis Ba prognosis but is helpful in predicting relative
2. Anti-HBc “window” responsiveness to antiviral therapy. The same
− − IgG − +/− 1. Low-level hepatitis B carrier is true for determinations of HCV genotype
2. Hepatitis B in remote past
(Chap. 334). Of course, HCV RNA monitor-
ing during and after antiviral therapy is the
− + IgG − +/− Recovery from hepatitis B
sine qua non for determining on-treatment
− + − − − 1. Immunization with HBsAg (after
and durable responsiveness.
vaccination)
A proportion of patients with hepatitis C
2. Hepatitis B in the remote past (?)
have isolated anti-HBc in their blood, a reflec-
3. False-positive tion of a common risk in certain populations
a
IgM anti-HBc may reappear during acute reactivation of chronic hepatitis B. of exposure to multiple bloodborne hepatitis
Note: See text for abbreviations. agents. The anti-HBc in such cases is almost

invariably of the IgG class and usually represents HBV infection in the and if IgM anti-HBc is undetectable, the patient has acute hepatitis A 2361
remote past (HBV DNA undetectable); it rarely represents current HBV superimposed on chronic HBV infection. The presence of anti-HCV
infection with low-level virus carriage. Detectable anti-HCV in the supports a diagnosis of acute hepatitis C. Occasionally, testing for HCV
absence of HCV RNA signifies spontaneous or therapeutically induced RNA or repeat anti-HCV testing later during the illness is necessary to
recovery from (“cured”) hepatitis C. establish the diagnosis. Absence of all serologic markers is consistent
The presence of HDV infection can be identified by demonstrating with a diagnosis of “non-A, non-B, non-C” hepatitis (no other proven
intrahepatic HDV antigen or, more practically, an anti-HDV serocon- human hepatitis viruses have been identified), if the epidemiologic
version (a rise in titer of anti-HDV or de novo appearance of anti- setting is appropriate.
HDV). Circulating HDV antigen, also diagnostic of acute infection, is In patients with chronic hepatitis, initial testing should consist of
detectable only briefly, if at all. Because anti-HDV is often undetectable HBsAg and anti-HCV. Anti-HCV supports and HCV RNA testing
once HBsAg disappears, retrospective serodiagnosis of acute self- establishes the diagnosis of chronic hepatitis C. If a serologic diagno-
limited, simultaneous HBV and HDV infection is difficult. Early diag- sis of chronic hepatitis B is made, testing for HBeAg and anti-HBe is
nosis of acute infection may be hampered by a delay of up to 30–40 indicated to evaluate relative infectivity. Testing for HBV DNA in such
days in the appearance of anti-HDV. patients provides a more quantitative and sensitive measure of the
When a patient presents with acute hepatitis and has HBsAg and level of virus replication, and therefore is very helpful during antiviral
anti-HDV in serum, determination of the class of anti-HBc is helpful therapy (Chap. 334). In patients with chronic hepatitis B and normal
in establishing the relationship between infection with HBV and HDV. aminotransferase activity in the absence of HBeAg, serial testing over
Although IgM anti-HBc does not distinguish absolutely between acute time is often required to distinguish between inactive carriage and
and chronic HBV infection, its presence is a reliable indicator of recent HBeAg-negative chronic hepatitis B with fluctuating virologic and
infection and its absence a reliable indicator of infection in the remote necroinflammatory activity. In persons with hepatitis B, testing for
past. In simultaneous acute HBV and HDV infections, IgM anti-HBc anti-HDV is useful in those with severe and fulminant disease, with
will be detectable, whereas in acute HDV infection superimposed on severe chronic disease, with chronic hepatitis B and acute hepatitis-like
chronic HBV infection, anti-HBc will be of the IgG class. Assays for exacerbations, with frequent percutaneous exposures, and from areas
HDV RNA, available in specialized laboratories and yet to be standard- where HDV infection is endemic.
ized, can be used to confirm HDV infection and to monitor treatment
during chronic infection. ■■PROGNOSIS
The serologic/virologic course of events during acute hepatitis E is Virtually all previously healthy patients with hepatitis A recover com-
entirely analogous to that of acute hepatitis A, with brief fecal shedding pletely with no clinical sequelae. Similarly, in acute hepatitis B, 95–99%

of virus and viremia and an early IgM anti-HEV response that predom- of previously healthy adults have a favorable course and recover
inates during approximately the first 3 months, but is eclipsed thereaf- completely. Certain clinical and laboratory features, however, suggest
ter by long-lasting IgG anti-HEV. Diagnostic tests of varying reliability a more complicated and protracted course. Patients of advanced age
for hepatitis E are commercially available but used routinely primarily and with serious underlying medical disorders may have a prolonged
outside the United States; in the United States, diagnostic serologic/ course and are more likely to experience severe hepatitis. Initial pre-
virologic assays can be performed at the Centers for Disease Control senting features such as ascites, peripheral edema, and symptoms
and Prevention or other specialized reference laboratories. of hepatic encephalopathy suggest a poorer prognosis. In addition,
Liver biopsy is rarely necessary or indicated in acute viral hepatitis, a prolonged PT, low serum albumin level, hypoglycemia, and very
except when the diagnosis is questionable or when clinical evidence high serum bilirubin values suggest severe hepatocellular disease.
suggests a diagnosis of chronic hepatitis. Patients with these clinical and laboratory features deserve prompt
A diagnostic algorithm can be applied in the evaluation of cases of hospital admission. The case fatality rate in hepatitis A and B is very
acute viral hepatitis. A patient with acute hepatitis should undergo four low (~0.1%) but is increased by advanced age and underlying debili-
serologic tests: HBsAg, IgM anti-HAV, IgM anti-HBc, and anti-HCV tating disorders. Among patients ill enough to be hospitalized for acute
(Table 332-6). The presence of HBsAg, with or without IgM anti-HBc, hepatitis B, the fatality rate is 1%. Hepatitis C is less severe during the
represents HBV infection. If IgM anti-HBc is present, the HBV infec- acute phase than hepatitis B and is more likely to be anicteric; fatalities
tion is considered acute; if IgM anti-HBc is absent, the HBV infection are rare, but the precise case fatality rate is not known. In outbreaks of
is considered chronic. A diagnosis of acute hepatitis B can be made in waterborne hepatitis E in India and Asia, the case fatality rate is 1–2%
the absence of HBsAg when IgM anti-HBc is detectable. A diagnosis and up to 10–20% in pregnant women. Contributing to fulminant
of acute hepatitis A is based on the presence of IgM anti-HAV. If IgM hepatitis E in endemic countries (but only very rarely or not at all in
anti-HAV coexists with HBsAg, a diagnosis of simultaneous HAV and nonendemic countries) are instances of acute hepatitis E superimposed
HBV infections can be made; if IgM anti-HBc (with or without HBsAg) on underlying chronic liver disease (“acute-on-chronic” liver disease).
is detectable, the patient has simultaneous acute hepatitis A and B, Patients with simultaneous acute hepatitis B and D do not necessarily
experience a higher mortality rate than do patients
with acute hepatitis B alone; however, in several
TABLE 332-6 Simplified Diagnostic Approach in Patients Presenting with Acute outbreaks of acute simultaneous HBV and HDV
Hepatitis infection among injection drug users, the case fatality
SEROLOGIC TESTS OF PATIENT’S SERUM rate was ~5%. When HDV superinfection occurs in
HBsAg IgM ANTI-HAV IgM ANTI-HBc ANTI-HCV DIAGNOSTIC INTERPRETATION a person with chronic hepatitis B, the likelihood of
+ − + − Acute hepatitis B
fulminant hepatitis and death is increased substan-
tially. Although the case fatality rate for hepatitis D is
+ − − − Chronic hepatitis B
not known definitively, in outbreaks of severe HDV
+ + − − Acute hepatitis A superimposed on
chronic hepatitis B
superinfection in isolated populations with a high
hepatitis B carrier rate, a mortality rate >20% has
+ + + − Acute hepatitis A and B
been recorded.
− + − − Acute hepatitis A
− + + − Acute hepatitis A and B (HBsAg ■■COMPLICATIONS AND SEQUELAE
below detection threshold)
A small proportion of patients with hepatitis A
− − + − Acute hepatitis B (HBsAg below experience relapsing hepatitis weeks to months after
detection threshold)
apparent recovery from acute hepatitis. Relapses
− − − + Acute hepatitis C are characterized by recurrence of symptoms,
Note: See text for abbreviations. aminotransferase elevations, occasional jaundice, and

2362 fecal excretion of HAV. Another unusual variant of acute hepatitis A is (2) have low-grade, mild chronic hepatitis; or (3) have moderate to
cholestatic hepatitis, characterized by protracted cholestatic jaundice and severe chronic hepatitis with or without cirrhosis. The likelihood of
pruritus. Rarely, liver test abnormalities persist for many months, even remaining chronically infected after acute HBV infection is especially
up to 1 year. Even when these complications occur, hepatitis A remains high among neonates, persons with Down’s syndrome, chronically
self-limited and does not progress to chronic liver disease. During the hemodialyzed patients, and immunosuppressed patients, including
prodromal phase of acute hepatitis B, a serum sickness–like syndrome persons with HIV infection.
characterized by arthralgia or arthritis, rash, angioedema, and, rarely, Chronic hepatitis is an important late complication of acute hepatitis B
hematuria and proteinuria may develop in 5–10% of patients. This syn- occurring in a small proportion of patients with acute disease but
drome occurs before the onset of clinical jaundice, and these patients more common in those who present with chronic infection without
are often diagnosed erroneously as having rheumatologic diseases. The having experienced an acute illness, as occurs typically after neonatal
diagnosis can be established by measuring serum aminotransferase infection or after infection in an immunosuppressed host (Chap. 334).
levels, which are almost invariably elevated, and serum HBsAg. As The following clinical and laboratory features suggest progression of
noted above, EMC is an immune-complex disease that can complicate acute hepatitis to chronic hepatitis: (1) lack of complete resolution of
chronic hepatitis C and is part of a spectrum of B cell lymphoprolifera- clinical symptoms of anorexia, weight loss, fatigue, and the persistence
tive disorders, which, in rare instances, can evolve to B cell lymphoma of hepatomegaly; (2) the presence of bridging/interface or multilob-
(Chap. 104). Attention has been drawn as well to associations between ular hepatic necrosis on liver biopsy during protracted, severe acute
hepatitis C and such cutaneous disorders as porphyria cutanea tarda viral hepatitis; (3) failure of the serum aminotransferase, bilirubin, and
and lichen planus. A mechanism for these associations is unknown. globulin levels to return to normal within 6–12 months after the acute
Finally, related to the reliance of HCV on lipoprotein secretion illness; and (4) the persistence of HBeAg for >3 months or HBsAg for
and assembly pathways and on interactions of HCV with glucose >6 months after acute hepatitis.
metabolism, HCV infection may be complicated by hepatic steatosis, Although acute hepatitis D infection does not increase the likelihood
hypercholesterolemia, insulin resistance (and other manifestations of of chronicity of simultaneous acute hepatitis B, hepatitis D has the poten-
the metabolic syndrome), and type 2 diabetes mellitus; both hepatic tial for contributing to the severity of chronic hepatitis B. Hepatitis D
steatosis and insulin resistance appear to accelerate hepatic fibrosis and superinfection can transform inactive or mild chronic hepatitis B into
blunt responsiveness to interferon-based antiviral therapy (Chap. 334). severe, progressive chronic hepatitis and cirrhosis; it also can accelerate
The most feared complication of viral hepatitis is fulminant hepatitis the course of chronic hepatitis B. Some HDV superinfections in patients
(massive hepatic necrosis); fortunately, this is a rare event. Fulminant with chronic hepatitis B lead to fulminant hepatitis. As defined in
hepatitis is seen primarily in hepatitis B, D, and E, but rare fulminant longitudinal studies over three decades, the annual rate of cirrhosis in
cases of hepatitis A occur primarily in older adults and in persons patients with chronic hepatitis D is 4%. Although HDV and HBV infec-
PART 10
with underlying chronic liver disease, including, according to some tions are associated with severe liver disease, mild hepatitis and even
reports, chronic hepatitis B and C. Hepatitis B accounts for >50% of inactive carriage have been identified in some patients, and the disease
fulminant cases of viral hepatitis, a sizable proportion of which are may become indolent beyond the early years of infection.
associated with HDV infection and another proportion with under- After acute HCV infection, the likelihood of remaining chronically
lying chronic hepatitis C. Fulminant hepatitis is hardly ever seen in infected approaches 85–90%. Although many patients with chronic
hepatitis C, but hepatitis E, as noted above, can be complicated by fatal hepatitis C have no symptoms, cirrhosis may develop in as many
fulminant hepatitis in 1–2% of all cases and in up to 20% of cases in as 20% within 10–20 years of acute illness; in some series of cases
pregnant women. Patients usually present with signs and symptoms reported by referral centers, cirrhosis has been reported in as many
of encephalopathy that may evolve to deep coma. The liver is usually as 50% of patients with chronic hepatitis C. Among cirrhotic patients
small and the PT excessively prolonged. The combination of rapidly with chronic hepatitis C, the annual risk of hepatic decompensation is
shrinking liver size, rapidly rising bilirubin level, and marked prolon- ~4%. Although chronic hepatitis C accounts for at least 40% of cases of
gation of the PT, even as aminotransferase levels fall, together with chronic liver disease and of patients undergoing liver transplantation
clinical signs of confusion, disorientation, somnolence, ascites, and for end-stage liver disease in the United States and Europe, in the
edema, indicates that the patient has hepatic failure with encephalop- majority of patients with chronic hepatitis C, morbidity and mortality
athy. Cerebral edema is common; brainstem compression, gastrointes- are limited during the initial 20 years after the onset of infection. Pro-
tinal bleeding, sepsis, respiratory failure, cardiovascular collapse, and gression of chronic hepatitis C may be influenced by advanced age of
renal failure are terminal events. The mortality rate is exceedingly high acquisition, long duration of infection, immunosuppression, coexisting
(>80% in patients with deep coma), but patients who survive may have excessive alcohol use, concomitant hepatic steatosis, other hepatitis
a complete biochemical and histologic recovery. If a donor liver can be virus infection, or HIV co-infection. In fact, instances of severe and rap-
located in time, liver transplantation may be lifesaving in patients with idly progressive chronic hepatitis B and C are being recognized with
fulminant hepatitis (Chap. 338). increasing frequency in patients with HIV infection (Chap. 197). In
Documenting the disappearance of HBsAg after apparent clinical contrast, neither HAV nor HEV causes chronic liver disease in immu-
recovery from acute hepatitis B is particularly important. Before labo- nocompetent hosts; however, cases of chronic hepatitis E (including
ratory methods were available to distinguish between acute hepatitis cirrhosis and end-stage liver disease) have been observed in immu-
and acute hepatitis-like exacerbations (spontaneous reactivations) of nosuppressed organ-transplant recipients, persons receiving cytotoxic
chronic hepatitis B, observations suggested that ~10% of previously chemotherapy, and persons with HIV infection. Among patients with
healthy patients remained HBsAg-positive for >6 months after the chronic hepatitis (e.g., caused by hepatitis B or C, alcohol, etc.) in
onset of clinically apparent acute hepatitis B. One-half of these persons endemic countries, hepatitis E has been reported as the cause of acute-
cleared the antigen from their circulations during the next several on-chronic liver failure; however, in most experiences among patients
years, but the other 5% remained chronically HBsAg-positive. More from nonendemic countries, HEV has not been found to contribute to
recent observations suggest that the true rate of chronic infection after hepatic decompensation in patients with chronic hepatitis.
clinically apparent acute hepatitis B is as low as 1% in normal, immu- Persons with chronic hepatitis B, particularly those infected in
nocompetent, young adults. Earlier, higher estimates may have been infancy or early childhood and especially those with HBeAg and/or
confounded by inadvertent inclusion of acute exacerbations in chron- high-level HBV DNA, have an enhanced risk of hepatocellular car-
ically infected patients; these patients, chronically HBsAg-positive cinoma. The risks of cirrhosis and hepatocellular carcinoma increase
before exacerbation, were unlikely to seroconvert to HBsAg-negative with the level of HBV replication. The annual rate of hepatocellular
thereafter. Whether the rate of chronicity is 10% or 1%, such patients carcinoma in patients with chronic hepatitis D and cirrhosis is ~3%. The
have IgG anti-HBc in serum; anti-HBs is either undetected or detected risk of hepatocellular carcinoma is increased as well in patients with
at low titer against the opposite subtype specificity of the antigen (see chronic hepatitis C, almost exclusively in patients with cirrhosis, and
“Laboratory Features”). These patients may (1) be inactive carriers; almost always after at least several decades, usually after three decades

of disease (Chap. 78). Among such cirrhotic patients with chronic clinically apparent acute hepatitis, recovery occurs in ~99%; there- 2363
hepatitis C, the annual risk of hepatocellular carcinoma is ~1–4%. fore, antiviral therapy is not likely to improve the rate of recovery
Rare complications of viral hepatitis include pancreatitis, myocar- and is not required. In rare instances of severe acute hepatitis B,
ditis, atypical pneumonia, aplastic anemia, transverse myelitis, and treatment with a nucleoside analogue at oral doses used to treat
peripheral neuropathy. In children, hepatitis B may present rarely with chronic hepatitis B (Chap. 334) has been attempted successfully.
anicteric hepatitis, a nonpruritic papular rash of the face, buttocks, and Although clinical trials have not been done to establish the efficacy
limbs, and lymphadenopathy (papular acrodermatitis of childhood or or duration of this approach, most authorities would recommend
Gianotti-Crosti syndrome). institution of antiviral therapy with a nucleoside analogue (entecavir
Rarely, autoimmune hepatitis (Chap. 334) can be triggered by a or tenofovir, the most potent and least resistance-prone agents) for
bout of otherwise self-limited acute hepatitis, as reported after acute severe, but not mild–moderate, acute hepatitis B. Treatment should
hepatitis A, B, and C. continue until 3 months after HBsAg seroconversion or 6 months
after HBeAg seroconversion.
■■DIFFERENTIAL DIAGNOSIS In typical cases of acute hepatitis C, recovery is rare (~15–20%
Viral diseases such as infectious mononucleosis; those due to cytomeg- in most experiences), progression to chronic hepatitis is the rule,
alovirus, herpes simplex, and coxsackieviruses; and toxoplasmosis may and small clinical trials during the era of interferon-based regimens
share certain clinical features with viral hepatitis and cause elevations suggested that antiviral therapy with courses (usually 24 weeks)
in serum aminotransferase and, less commonly, in serum bilirubin of standard or pegylated interferon α monotherapy reduced the
levels. Tests such as the differential heterophile and serologic tests for rate of chronicity considerably by inducing sustained responses
these agents may be helpful in the differential diagnosis if HBsAg, in 30–70% of patients (according to a meta-analyses of published
anti-HBc, IgM anti-HAV, and anti-HCV determinations are negative. studies) and in up to 98% in a small German multicenter study
Aminotransferase elevations can accompany almost any systemic viral (treatment initiated an average of 3 months after infection). In the
infection; other rare causes of liver injury confused with viral hepati- current interferon-free therapy era, as of 2016, six different all-oral,
tis are infections with Leptospira, Candida, Brucella, Mycobacteria, and brief-duration (most lasting 12 weeks), very well-tolerated, highly
Pneumocystis. A complete drug history is particularly important because effective (sustained virologic response rates exceeding 90–95%) com-
many drugs and certain anesthetic agents can produce a picture of bination regimens (of polymerase inhibitors, protease inhibitors,
either acute hepatitis or cholestasis (Chap. 333). Equally important and/or NS5A inhibitors) are available to treat patients with chronic
is a past history of unexplained “repeated episodes” of acute hepati- hepatitis C (see Chap. 334); the same regimens are available and
tis. This history should alert the physician to the possibility that the recommended to treat patients with acute hepatitis C. Although the

underlying disorder is chronic hepatitis, for example autoimmune duration of therapy for acute hepatitis C has not been determined
hepatitis (Chap. 334). Alcoholic hepatitis must also be considered, definitively, in a study of 20 patients, acute hepatitis C resolved after
but usually the serum aminotransferase levels are not as markedly treatment lasting only 6 weeks. In 2016, the European Association for
elevated, and other stigmata of alcoholism may be present. The finding the Study of the Liver (EASL) recommended 8 weeks of treatment
on liver biopsy of fatty infiltration, a neutrophilic inflammatory reac- for acute hepatitis C with a genotype-appropriate (see Chap. 334)
tion, and “alcoholic hyaline” would be consistent with alcohol-induced direct-acting antiviral regimen consisting of sofosbuvir plus one of
rather than viral liver injury. Because acute hepatitis may present with the three approved NS5A inhibitors without ribavirin (12 weeks
right upper quadrant abdominal pain, nausea and vomiting, fever, and for patients with acute hepatitis C and either a baseline HCV RNA
icterus, it is often confused with acute cholecystitis, common duct stone, level >1 million IU/mL or HIV co-infection).
or ascending cholangitis. Patients with acute viral hepatitis may toler- Because spontaneous recovery can occur and because most cases
ate surgery poorly; therefore, it is important to exclude this diagnosis, of acute hepatitis C are not clinically severe or rapidly progressive,
and in confusing cases, a percutaneous liver biopsy may be necessary delaying antiviral therapy of acute hepatitis C for at least 12–16
before laparotomy. Viral hepatitis in the elderly is often misdiagnosed weeks and even up to 6 months (after which recovery is unlikely) is
as obstructive jaundice resulting from a common duct stone or carci- a recommended approach. Patients with jaundice, those with HCV
noma of the pancreas. Because acute hepatitis in the elderly may be genotype 1, women, earlier age of infection, lower level of HCV
quite severe and the operative mortality high, a thorough evaluation RNA, HBV co-infection, and absence of current injection-drug use
including biochemical tests, radiographic studies of the biliary tree, are more likely to recover from acute hepatitis C, as are persons who
and even liver biopsy may be necessary to exclude primary parenchy- have genetic markers associated with spontaneous recovery (IL28B
mal liver disease. Another clinical constellation that may mimic acute CC haplotype). Because of the marked reduction over the past
hepatitis is right ventricular failure with passive hepatic congestion or three decades in the frequency of acute hepatitis C, opportunities to
hypoperfusion syndromes, such as those associated with shock, severe identify and treat patients with acute hepatitis C are rare, except in
hypotension, and severe left ventricular failure. Also included in this two population subsets: (1) In health workers who sustain hepatitis
general category is any disorder that interferes with venous return to C–contaminated needle sticks (occupational accidents), monitoring
the heart, such as right atrial myxoma, constrictive pericarditis, hepatic for ALT elevations and the presence of HCV RNA identify acute
vein occlusion (Budd-Chiari syndrome), or venoocclusive disease. Clin- hepatitis C in ~3%, and this group should be treated; (2) in injec-
ical features are usually sufficient to distinguish among these vascular tion-drug users, the risk of acute hepatitis C has been on the rise,
disorders and viral hepatitis. Acute fatty liver of pregnancy, cholestasis and the epidemic of opioid use has contributed to an amplification
of pregnancy, eclampsia, and the HELLP (hemolysis, elevated liver tests, of HCV infection among drug users. Such patients are candidates
and low platelets) syndrome can be confused with viral hepatitis during for antiviral therapy, and efforts to combine antiviral therapy with
pregnancy. Very rarely, malignancies metastatic to the liver can mimic drug-rehabilitation therapy have been very successful.
acute or even fulminant viral hepatitis. Occasionally, genetic or meta- Notwithstanding these specific therapeutic considerations, in
bolic liver disorders (e.g., Wilson’s disease, α1 antitrypsin deficiency) and most cases of typical acute viral hepatitis, specific treatment gen-
nonalcoholic fatty liver disease are confused with acute viral hepatitis. erally is not necessary. Although hospitalization may be required
for clinically severe illness, most patients do not require hospital
care. Forced and prolonged bed rest is not essential for full recovery,
TREATMENT but many patients will feel better with restricted physical activity.
Acute Viral Hepatitis A high-calorie diet is desirable, and because many patients may
experience nausea late in the day, the major caloric intake is best tol-
Most persons with acute hepatitis (especially hepatitis A, B, and E) erated in the morning. Intravenous feeding is necessary in the acute
recover spontaneously and do not require specific antiviral therapy. stage if the patient has persistent vomiting and cannot maintain
In hepatitis B, among previously healthy adults who present with oral intake. Drugs capable of producing adverse reactions such as

2364 cholestasis and drugs metabolized by the liver should be avoided. If is recommended as early after exposure as possible; it may be effective
severe pruritus is present, the use of the bile salt-sequestering resin even when administered as late as 2 weeks after exposure. Prophylaxis
cholestyramine is helpful. Glucocorticoid therapy has no value in is not necessary for those who have already received hepatitis A vac-
acute viral hepatitis, even in severe cases, and may be deleterious, cine, for casual contacts (office, factory, school, or hospital), for most
even increasing the risk of chronicity (e.g., of acute hepatitis B). elderly persons, who are very likely to be immune, or for those known
Physical isolation of patients with hepatitis to a single room and to have anti-HAV in their serum. In day care centers, recognition of
bathroom is rarely necessary except in the case of fecal incontinence hepatitis A in children or staff should provide a stimulus for immuno-
for hepatitis A and E or uncontrolled, voluminous bleeding for hep- prophylaxis in the center and in the children’s family members. By the
atitis B (with or without concomitant hepatitis D) and C. Because time most common-source outbreaks of hepatitis A are recognized, it is
most patients hospitalized with hepatitis A excrete little, if any, HAV, usually too late in the incubation period for IG to be effective; however,
the likelihood of HAV transmission from these patients during their prophylaxis may limit the frequency of secondary cases. For travelers
hospitalization is low. Therefore, burdensome enteric precautions are no to tropical countries, developing countries, and other areas outside
longer recommended. Although gloves should be worn when the bed standard tourist routes, IG prophylaxis had been recommended before
pans or fecal material of patients with hepatitis A are handled, these a vaccine became available. When such travel lasted <3 months, 0.02
precautions do not represent a departure from sensible procedure mL/kg was given; for longer travel or residence in these areas, a dose
and contemporary universal precautions for all hospitalized patients. of 0.06 mL/kg every 4–6 months was recommended. Administration
For patients with hepatitis B and C, emphasis should be placed of plasma-derived globulin is safe; all contemporary lots of IG are
on blood precautions (i.e., avoiding direct, ungloved hand contact subjected to viral inactivation steps and must be free of HCV RNA as
with blood and other body fluids). Enteric precautions are unneces- determined by PCR testing. Administration of IM lots of IG has not
sary. The importance of simple hygienic precautions such as hand been associated with transmission of HBV, HCV, or HIV.
washing cannot be overemphasized. Universal precautions that have Formalin-inactivated vaccines made from strains of HAV attenu-
been adopted for all patients apply to patients with viral hepatitis. ated in tissue culture have been shown to be safe, immunogenic, and
Hospitalized patients may be discharged following substantial effective in preventing hepatitis A. Hepatitis A vaccines are approved
symptomatic improvement, a significant downward trend in the for use in persons who are at least 1 year old and appear to provide
serum aminotransferase and bilirubin values, and a return to normal adequate protection beginning 4 weeks after a primary inoculation.
of the PT. Mild aminotransferase elevations should not be considered If it can be given within 4 weeks of an expected exposure, such as
contraindications to the gradual resumption of normal activity. by travel to an endemic area, hepatitis A vaccine is the preferred
In fulminant hepatitis, the goal of therapy is to support the patient approach to preexposure immunoprophylaxis. If travel is more immi-
by maintenance of fluid balance, support of circulation and respira- nent, IG (0.02 mL/kg) should be administered at a different injection
PART 10
tion, control of bleeding, correction of hypoglycemia, and treatment site, along with the first dose of vaccine. Because vaccination provides
of other complications of the comatose state in anticipation of liver long-lasting protection (protective levels of anti-HAV should last 20
regeneration and repair. Protein intake should be restricted, and years after vaccination), persons whose risk will be sustained (e.g.,
oral lactulose administered. Glucocorticoid therapy has been shown frequent travelers or those remaining in endemic areas for prolonged
in controlled trials to be ineffective. Likewise, exchange transfu- periods) should be vaccinated, and vaccine should supplant the need
sion, plasmapheresis, human cross-circulation, porcine liver cross- for repeated IG injections. Shortly after its introduction, hepatitis A
perfusion, hemoperfusion, and extracorporeal liver-assist devices vaccine was recommended for children living in communities with a
have not been proven to enhance survival. Meticulous intensive high incidence of HAV infection; in 1999, this recommendation was
care that includes prophylactic antibiotic coverage is the one factor extended to include all children living in states, counties, and com-
that appears to improve survival. Orthotopic liver transplantation munities with high rates of HAV infection. As of 2006, the Advisory
is resorted to with increasing frequency, with excellent results, in Committee on Immunization Practices of the U.S. Public Health Ser-
patients with fulminant hepatitis (Chap. 338). Fulminant hepatitis C vice recommended routine hepatitis A vaccination of all children. Other
is very rare; however, in fulminant hepatitis B, oral antiviral therapy groups considered being at increased risk for HAV infection and who
has been used successfully, as reported anecdotally. In clinically are candidates for hepatitis A vaccination include military personnel,
severe hepatitis E (with jaundice and coagulopathy), successful populations with cyclic outbreaks of hepatitis A (e.g., Alaskan natives),
therapy with ribavirin (600 mg twice daily, 15 mg/kg) has been employees of day care centers, primate handlers, laboratory workers
reported anecdotally. Unfortunately, when fulminant hepatitis E exposed to hepatitis A or fecal specimens, and patients with chronic
occurs in pregnant women (as it does in up to 20% of pregnant liver disease. Because of an increased risk of fulminant hepatitis A—
women with acute hepatitis E), ribavirin, which is teratogenic, is observed in some experiences but not confirmed in others—among
contraindicated. patients with chronic hepatitis C, patients with chronic hepatitis C
are candidates for hepatitis A vaccination, as are persons with chronic
hepatitis B. Other populations whose recognized risk of hepatitis A
■■PROPHYLAXIS
is increased should be vaccinated, including men who have sex with
Because application of therapy for acute viral hepatitis is limited and
men, injection drug users, persons with clotting disorders who require
because antiviral therapy for chronic viral hepatitis is cumbersome,
frequent administration of clotting-factor concentrates, persons travel-
costly, and not effective in all patients (Chap. 334), emphasis is placed
ing from the United States to countries with high or intermediate hep-
on prevention through immunization. The prophylactic approach
atitis A endemicity, postexposure prophylaxis for contacts of persons
differs for each of the types of viral hepatitis. In the past, immunopro-
with hepatitis A, and household members and other close contacts of
phylaxis relied exclusively on passive immunization with antibody-
adopted children arriving from countries with high and moderate hep-
containing globulin preparations purified by cold ethanol fractionation
atitis A endemicity. Recommendations for dose and frequency differ
from the plasma of hundreds of normal donors. Currently, for hepa-
for the two approved vaccine preparations (Table 332-7); all injections
titis A, B, and E, active immunization with vaccines is the preferable
are IM. Hepatitis A vaccine has been reported to be effective in pre-
approach to prevention.
venting secondary household and day care center–associated cases of
Hepatitis A Both passive immunization with IG and active immu- acute hepatitis A. Because the vaccine provides long-lasting protection
nization with killed vaccines are available. All preparations of IG and is simpler to use, in 2006, the Immunization Practices Advisory
contain anti-HAV concentrations sufficient to be protective. When Committee of the U.S. Public Health Service favored hepatitis A vaccine
administered before exposure or during the early incubation period, to IG for postexposure prophylaxis of healthy persons age 2–40 years;
IG is effective in preventing clinically apparent hepatitis A. For pos- for younger or older persons, for immunosuppressed patients, and
texposure prophylaxis of intimate contacts (household, sexual, institu- for patients with chronic liver disease, IG should continue to be used.
tional) of persons with hepatitis A, the administration of 0.02 mL/kg In the United States, reported mortality resulting from hepatitis A

TABLE 332-7 Hepatitis A Vaccination Schedules groups was not effective. The incidence of new hepatitis B cases contin- 2365
ued to increase in the United States after the introduction of vaccines;
SCHEDULE,
AGE, YEARS NO. OF DOSES DOSE MONTHS <10% of all targeted persons in high-risk groups were actually vacci-
nated, and ~30% of persons with sporadic acute hepatitis B did not fall
HAVRIX (GlaxoSmithKline)a
into any high-risk-group category. Therefore, to have an impact on the
1–18 2 720 ELUb (0.5 mL) 0, 6–12 frequency of HBV infection in an area of low endemicity such as the
≥19 2 1440 ELU (1 mL) 0, 6–12 United States, universal hepatitis B vaccination in childhood has been
VAQTA (Merck) recommended. For unvaccinated children born after the implementa-
1–18 2 25 units (0.5 mL) 0, 6–18 tion of universal infant vaccination, vaccination during early adoles-
≥19 2 50 units (1 mL) 0, 6–18 cence, at age 11–12 years, was recommended, and this recommendation
has been extended to include all unvaccinated children age 0–19 years.
a
A combination of this hepatitis A vaccine and hepatitis B vaccine, TWINRIX, is
licensed for simultaneous protection against both of these viruses among adults In HBV-hyperendemic areas (e.g., Asia), universal vaccination of chil-
(age ≥18 years). Each 1-mL dose contains 720 ELU of hepatitis A vaccine and dren has resulted in a marked (~70–90%) 30-year decline in complica-
20 μg of hepatitis B vaccine. These doses are recommended at months 0, 1, tions of hepatitis B, including liver-related mortality and hepatocellular
and 6. bEnzyme-linked immunoassay units.
carcinoma.
The two available recombinant hepatitis B vaccines are comparable,
declined in parallel with hepatitis A vaccine–associated reductions in one containing 10 μg of HBsAg (Recombivax-HB) and the other con-
the annual incidence of new infections. taining 20 μg of HBsAg (Engerix-B), and recommended doses for each
injection vary for the two preparations (Table 332-8). Combinations of
Hepatitis B Until 1982, prevention of hepatitis B was based on hepatitis B vaccine with other childhood vaccines are available as well
passive immunoprophylaxis either with standard immunoglobulin, (Table 332-8).
containing modest levels of anti-HBs, or hepatitis B immunoglobulin For unvaccinated persons sustaining an exposure to HBV, postexpo-
(HBIG), containing high-titer anti-HBs. The efficacy of standard IG sure prophylaxis with a combination of HBIG (for rapid achievement
has never been established and remains questionable; even the effi- of high-titer circulating anti-HBs) and hepatitis B vaccine (for achieve-
cacy of HBIG, demonstrated in several clinical trials, has been chal- ment of long-lasting immunity as well as its apparent efficacy in atten-
lenged, and its contribution appears to be in reducing the frequency uating clinical illness after exposure) is recommended. For perinatal
of clinical illness, not in preventing infection. The first vaccine for active exposure of infants born to HBsAg-positive mothers, a single dose of
immunization, introduced in 1982, was prepared from purified, non- HBIG, 0.5 mL, should be administered IM in the thigh immediately after

infectious 22-nm spherical HBsAg particles derived from the plasma birth, followed by a complete course of three injections of recombinant
of healthy HBsAg carriers. In 1987, the plasma-derived vaccine was hepatitis B vaccine (see doses above) to be started within the first 12
supplanted by a genetically engineered vaccine derived from recom- h of life. For those experiencing a direct percutaneous inoculation or
binant yeast. The latter vaccine consists of HBsAg particles that are transmucosal exposure to HBsAg-positive blood or body fluids (e.g.,
nonglycosylated but are otherwise indistinguishable from natural accidental needle stick, other mucosal penetration, or ingestion), a single
HBsAg; two recombinant vaccines are licensed for use in the United IM dose of HBIG, 0.06 mL/kg, administered as soon after exposure
States. Current recommendations can be divided into those for preex- as possible, is followed by a complete course of hepatitis B vaccine
posure and postexposure prophylaxis. to begin within the first week. For pregnant mothers with high-level
For preexposure prophylaxis against hepatitis B in settings of frequent HBV DNA (>2 × 105 IU/mL), adding antiviral nucleoside analogues (e.g.,
exposure (health workers exposed to blood; first-responder public pregnancy class B tenofovir, see Chap 334) during the third trimester
safety workers; hemodialysis patients and staff; residents and staff of pregnancy reduces perinatal transmission even further. For persons
of custodial institutions for the developmentally handicapped; injec- exposed by sexual contact to a patient with acute hepatitis B, a single IM
tion drug users; inmates of long-term correctional facilities; persons dose of HBIG, 0.06 mL/kg, should be given within 14 days of exposure,
with multiple sexual partners or who have
had a sexually transmitted disease; men
who have sex with men; persons such TABLE 332-8 Preexposure Hepatitis B Vaccination Schedules
as hemophiliacs who require long-term, TARGET GROUP NO. OF DOSES DOSE SCHEDULE, MONTHS
high-volume therapy with blood deriv- RECOMBIVAX-HB (Merck)a
atives; household and sexual contacts of Infants, children (<1–10 years) 3 5 μg (0.5 mL) 0, 1–2, 4–6
persons with chronic HBV infection; per- Adolescents (11–19 years) 3 or 4 5 μg (0.5 mL) 0–2, 1–4, 4–6 or 0, 12, 24 or 0, 1, 2, 12
sons living in or traveling extensively in
Or
endemic areas; unvaccinated children aged
Adults (≥20 years) 2 10 μg (1 mL) 0, 4–6 (age 11–15)
<18; unvaccinated children who are Alas-
kan natives, Pacific Islanders, or residents Hemodialysis patients b
3 10 μg (1 mL) 0–2, 1–4, 4–6
in households of first-generation immi- <20 years 3 5 μg (0.5 mL) 0, 1, 6
grants from endemic countries; persons ≥20 years 3 40 μg (4 mL) 0, 1, 6
born in countries with a prevalence of HBV ENGERIX-B (GlaxoSmithKline) c
infection ≥2%; patients with chronic liver Infants, children (<1–10 years) 3 or 4 10 μg (0.5 mL) 0, 1–2, 4–6 or 0, 1, 2, 12
disease; persons <age 60 with diabetes Adolescents (10–19 years) 3 or 4 10 μg (0.5 mL) 0, 1–2, 4–6 or 0, 12, 24 or 0, 1, 2, 12
mellitus [those ≥60 at the discretion of their Adults (≥20 years) 3 or 4 20 μg (1 mL) 0–2, 1–4, 4–6 or 0, 1, 2, 12
physicians]; persons with end-stage renal
Hemodialysis patientsb
disease; and persons with HIV infection),
<20 years 4 10 μg (0.5 mL) 0, 1, 2, 6
three IM (deltoid, not gluteal) injections of
≥20 years 4 40 μg (2 mL) 0, 1, 2, 6
hepatitis B vaccine are recommended at 0,
1, and 6 months (other, optional schedules a
This manufacturer produces a licensed combination of hepatitis B vaccine and vaccines against Haemophilus
are summarized in Table 332-8). Pregnancy influenzae type b and Neisseria meningitides, Comvax, for use in infants and young children. Please consult
product insert for dose and schedule. bThis group also includes other immunocompromised persons. cThis
is not a contraindication to vaccination. In manufacturer produces two licensed combination hepatitis B vaccines: (1) Twinrix, recombinant hepatitis B
areas of low HBV endemicity such as the vaccine plus inactivated hepatitis A vaccine, is licensed for simultaneous protection against both of these viruses
United States, despite the availability of among adults (age ≥18 years). Each 1-mL dose contains 720 ELU of hepatitis A vaccine and 20 μg of hepatitis
B vaccine. These doses are recommended at months 0, 1, and 6. (2) Pediarix, recombinant hepatitis B vaccine
safe and effective hepatitis B vaccines, a plus diphtheria and tetanus toxoid, pertussis, and inactivated poliovirus, is licensed for use in infants and young
strategy of vaccinating persons in high-risk children. Please consult product insert for doses and schedules.

2366 to be followed by a complete course of hepatitis B vaccine. When both For stable, monogamous sexual partners, sexual transmission of
HBIG and hepatitis B vaccine are recommended, they may be given at hepatitis C is unlikely, and sexual barrier precautions are not recom-
the same time but at separate sites. Testing adults for anti-HBs after a mended. For persons with multiple sexual partners or with sexually
course of vaccine is advisable to document the acquisition of immunity, transmitted diseases, the risk of sexual transmission of hepatitis C is
but, because hepatitis B vaccine immunogenicity is nearly universal in increased, and barrier precautions (latex condoms) are recommended.
infants, postvaccination anti-HBs testing of children is not recommended. A person with hepatitis C should avoid sharing such items as razors,
The precise duration of protection afforded by hepatitis B vaccine toothbrushes, and nail clippers with sexual partners and family mem-
is unknown; however, ~80–90% of immunocompetent adult vaccinees bers. No special precautions are recommended for babies born to moth-
retain protective levels of anti-HBs for at least 5 years, and 60–80% ers with hepatitis C, and breast-feeding does not have to be restricted.
for 10 years, and protective antibody has been documented to last
for at least two decades after vaccination in infancy. Thereafter and
Hepatitis E Whether IG prevents hepatitis E remains undeter-
mined. Safe and effective recombinant genotype 1 vaccines, which
even after anti-HBs becomes undetectable, protection persists against
protect against other genotypes as well, have been developed and
clinical hepatitis B, hepatitis B surface antigenemia, and chronic HBV
are available in endemic areas but not in the United States. Protection
infection. Currently, booster immunizations are not recommended rou-
provided by the Chinese hepatitis E vaccine is long-lasting, docu-
tinely, except in immunosuppressed persons who have lost detectable
mented in a clinical trial up to 4.5 years.
anti-HBs or immunocompetent persons who sustain percutaneous
HBsAg-positive inoculations after losing detectable antibody. Spe- ■■FURTHER READING
cifically, for hemodialysis patients, annual anti-HBs testing is rec- Buckley GJ, Strom BL (eds): Eliminating the Public Health Problem of
ommended after vaccination; booster doses are recommended when Hepatitis B and C in the United States: Phase One Report. Washington
anti-HBs levels fall to <10 mIU/mL. As noted above, for persons at risk DC, National Academies Press, 2016. Available from http://www
of both hepatitis A and B, a combined vaccine is available containing .nap.edu/23407. Accessed September 22, 2016.
720 enzyme-linked immunoassay units (ELUs) of inactivated HAV and Centers for Disease Control and Prevention: Recommendations
20 μg of recombinant HBsAg (at 0, 1, and 6 months). for the identification of chronic hepatitis C virus infection among
Hepatitis D Infection with hepatitis D can be prevented by vac- persons born during 1945–1965. MMWR 61(RR-4):1, 2012.
cinating susceptible persons with hepatitis B vaccine. No product is Debing Y et al: Update on hepatitis E virology: Implications for clinical
available for immunoprophylaxis to prevent HDV superinfection in practice. J Hepatol 65:200, 2016.
persons with chronic HBV infection; for them, avoidance of percuta- Denniston MM et al: Chronic hepatitis C virus infection in the United
neous exposures and limitation of intimate contact with persons who States, National Health and Nutrition Examination Survey 2003–
have HDV infection are recommended. 2010. Ann Intern Med 160:293, 2014.
PART 10
Douam F et al: The mechanism of HCV entry into host cells. Prog Mol
Hepatitis C IG is ineffective in preventing hepatitis C and is no Biol Transl Sci 129:63, 2015.
longer recommended for postexposure prophylaxis in cases of perina- Joy JB et al: The spread of hepatitis C virus genotype 1a in North
tal, needle stick, or sexual exposure. Although prototype vaccines that America: A retrospective phylogenetic study. Lancet Infect Dis 16:698,
induce antibodies to HCV envelope proteins have been developed, 2016.
currently, hepatitis C vaccination is not feasible practically. Genotype Lin H-H et al: Changing hepatitis D virus epidemiology in a hepatitis B
and quasispecies viral heterogeneity, as well as rapid evasion of neu- virus endemic area with a national vaccination program. Hepatology
tralizing antibodies by this rapidly mutating virus, conspire to render 61:1870, 2016.
HCV a difficult target for immunoprophylaxis with a vaccine. Pre- Pan CQ et al: Tenofovir to prevent hepatitis B transmission in mothers
vention of transfusion-associated hepatitis C has been accomplished with high viral load. N Engl J Med 374:2324, 2016.
by the following successively introduced measures: exclusion of Roberts H et al: Prevalence of chronic hepatitis B virus (HBV) infec-
commercial blood donors and reliance on a volunteer blood supply; tion in U.S. households: National Health and Nutrition Examination
screening donor blood with surrogate markers such as ALT (no longer Survey (NHANES), 1988–2012. Hepatology 63:388, 2016.
recommended) and anti-HBc, markers that identify segments of the Trépo C et al: Hepatitis B virus infection. Lancet 384:2053, 2014.
blood donor population with an increased risk of bloodborne infec-
tions; exclusion of blood donors in high-risk groups for AIDS and the
introduction of anti-HIV screening tests; and progressively sensitive
serologic and virologic screening tests for HCV infection.
In the absence of active or passive immunization, prevention of
333 Toxic
hepatitis C includes behavior changes and precautions to limit expo-
sures to infected persons. Recommendations designed to identify and Drug-Induced
patients with clinically inapparent hepatitis as candidates for medical
management have as a secondary benefit the identification of persons Hepatitis
whose contacts could be at risk of becoming infected. A so-called look-
back program has been recommended to identify persons who were William M. Lee, Jules L. Dienstag
transfused before 1992 with blood from a donor found subsequently
to have hepatitis C. In addition, anti-HCV testing is recommended for
persons born between 1945 and 1965, anyone who received a blood Liver injury is a possible consequence of ingestion of any xenobiotic,
transfusion or a transplanted organ before the introduction of sec- including industrial toxins, pharmacologic agents, and complementary
ond-generation screening tests in 1992, those who ever used injection and alternative medications (CAMs). Among patients with acute liver
drugs (or took other illicit drugs by noninjection routes), chronically failure, drug-induced liver injury (DILI) is the most common cause,
hemodialyzed patients, persons with clotting disorders who received and evidence for hepatotoxicity detected during clinical trials for drug
clotting factors made before 1987 from pooled blood products, per- development is the most common reason for failure of compounds to
sons with elevated aminotransferase levels, health workers exposed reach approval status. DILI requires careful history taking to identify
to HCV-positive blood or contaminated needles, recipients of blood unrecognized exposure to chemicals used in work or at home, drugs
or organs from a donor found to be positive for hepatitis C, persons taken by prescription or bought over the counter, and herbal or dietary
with HIV infection, health care and public safety personnel following supplement medicines. Hepatotoxic drugs can injure the hepatocyte
a needle stick or other nonpercutaneous exposure to HCV-infected directly, for example, via a free-radical or metabolic intermediate that
material, sexual partners of persons with hepatitis C, and children born causes peroxidation of membrane lipids and that results in liver cell
to HCV-positive mothers (Table 332-4). injury. Alternatively, a drug or its metabolite may activate components

of the innate or adaptive immune system, stimulate apoptotic path- metabolites have been invoked to explain idiosyncratic drug reactions. 2367
ways, or initiate damage to bile excretory pathways (Fig. 333-1). Inter- The most current data appear to implicate the adaptive immune system
ference with bile canalicular pumps can allow endogenous bile acids, responding to the formation of immune stimulatory compounds result-
which can injure the liver, to accumulate. Such secondary injury, in turn, ing from phase I metabolic activation of the offending drug. Differences
may lead to necrosis of hepatocytes; injure bile ducts, producing choles- in host susceptibility may result from varying kinetics of toxic metab-
tasis; or block pathways of lipid movement, inhibit protein synthesis, or olite generation and genetic polymorphisms in downstream drug-
impair mitochondrial oxidation of fatty acids, resulting in lactic acidosis metabolizing pathways or cytokine activation; in addition, certain
and intracellular triglyceride accumulation (expressed histologically as HLA haplotypes have been associated with hepatotoxicity of certain
microvesicular steatosis). In other instances, drug metabolites sensi- drugs such as amoxicillin-clavulanate and flucloxacillin. Occasionally,
tize hepatocytes to toxic cytokines. The differences observed between however, the clinical features of an allergic reaction (prominent tissue
susceptible and nonsusceptible drug recipients may be attributable to eosinophilia, autoantibodies, etc.) are difficult to ignore and suggest
human leukocyte antigens (HLA) haplotypes that determine binding of activation of IgE pathways. A few instances of drug hepatotoxicity
drug-related haptens on the cell surface as well as to polymorphisms in are observed to be associated with autoantibodies, including a class of
elaboration of competing, protective cytokines, as has been suggested antibodies to liver-kidney microsomes, anti-LKM2, directed against a
for acetaminophen hepatotoxicity (see below). Immune mechanisms cytochrome P450 enzyme.
may include cytotoxic lymphocytes or antibody-mediated cellular Idiosyncratic reactions lead to a morphologic pattern that is more
cytotoxicity. In addition, a role has been shown for activation of nuclear variable than those produced by direct toxins; a single agent is often
transporters, such as the constitutive androstane receptor (CAR) or, capable of causing a variety of lesions, although certain patterns tend
more recently, the pregnane X receptor (PXR), in the induction of drug to predominate. Depending on the agent involved, idiosyncratic hepa-
hepatotoxicity. titis may result in a clinical and morphologic picture indistinguishable
from that of viral hepatitis (e.g., INH or ciprofloxacin). So-called hepa-
■■DRUG METABOLISM tocellular injury is the most common form, featuring spotty necro-
Most drugs, which are water-insoluble, undergo a series of metabolic sis in the liver lobule with a predominantly lymphocytic infiltrate
steps, culminating in a water-soluble form appropriate for renal or resembling that observed in acute hepatitis A, B, or C. Drug-induced
biliary excretion. This process begins with oxidation or methylation cholestasis ranges from mild to increasingly severe: (1) bland cholesta-
mediated initially by the microsomal mixed-function oxygenases, sis with limited hepatocellular injury (e.g., estrogens, 17,α-substituted
cytochrome P450 (phase I reaction), followed by glucuronidation or androgens); (2) inflammatory cholestasis (e.g., amoxicillin-clavulanic
sulfation (phase II reaction) or inactivation by glutathione. Most drug acid [the most frequently implicated antibiotic among cases of DILI],
CHAPTER 333 Toxic and Drug-Induced Hepatitis

hepatotoxicity is mediated by a phase I toxic metabolite, but gluta- oxacillin, erythromycin estolate); (3) sclerosing cholangitis (e.g., after
thione depletion, precluding inactivation of harmful compounds by intrahepatic infusion of the chemotherapeutic agent floxuridine for
glutathione S-transferase, can contribute as well. hepatic metastases from a primary colonic carcinoma); and (4) dis-
appearance of bile ducts, “ductopenic” cholestasis, similar to that
■■LIVER INJURY CAUSED BY DRUGS observed in chronic rejection (Chap. 338) following liver transplanta-
In general, two major types of chemical hepatotoxicity have been rec- tion (e.g., carbamazepine, levofloxacin). Cholestasis may result from
ognized: (1) direct toxic and (2) idiosyncratic. As shown in Table 333-1, binding of drugs to canalicular membrane transporters, accumulation
direct toxic hepatitis occurs with predictable regularity in individuals of toxic bile acids resulting from canalicular pump failure, or genetic
exposed to the offending agent and is dose-dependent. The latent defects in canalicular transporter proteins. Clinically, the distinction
period between exposure and liver injury is usually short (often several between a hepatocellular and a cholestatic reaction is indicated by
hours), although clinical manifestations may be delayed for 24–48 h. the R value, the ratio of alanine aminotransferase (ALT) to alkaline
Agents producing toxic hepatitis are generally systemic poisons or phosphatase values, both expressed as multiples of the upper limit of
are converted in the liver to toxic metabolites. The direct hepatotoxins normal. An R value of >5.0 is associated with hepatocellular injury,
result in morphologic abnormalities that are reasonably characteristic R <2.0 with cholestatic injury, and R between 2.0 and 5.0 with mixed
and reproducible for each toxin. For example, carbon tetrachloride hepatocellular-cholestatic injury.
and trichloroethylene characteristically produce a centrilobular zonal Morphologic alterations may also include bridging hepatic necrosis
necrosis, whereas yellow phosphorus poisoning typically results in (e.g., methyldopa) or, infrequently, hepatic granulomas (e.g., sul-
periportal injury. The hepatotoxic octapeptides of Amanita phalloides fonamides). Some drugs result in macrovesicular or microvesicular
usually produce massive hepatic necrosis; the lethal dose of the toxin steatosis or steatohepatitis, which, in some cases, has been linked to
is ~10 mg, the amount found in a single deathcap mushroom. Liver mitochondrial dysfunction and lipid peroxidation. Severe hepatotox-
injury, which is often only one facet of the toxicity produced by the icity associated with steatohepatitis, most likely a result of mitochon-
direct hepatotoxins, may go unrecognized until jaundice appears. drial toxicity, is being recognized with increasing frequency among
In idiosyncratic drug reactions, the occurrence of hepatitis is usually patients receiving antiretroviral therapy with reverse transcriptase
infrequent (1 in 103–105 patients) and unpredictable; the response is not inhibitors for HIV infection (e.g., zidovudine, didanosine), although
as clearly dose-dependent as is injury associated with direct hepato- many of these drugs have been withdrawn because of such hepato-
toxins, and liver injury may occur at any time during or shortly after toxicity (Chap. 197). Generally, such mitochondrial hepatotoxicity of
exposure to the drug. That said, recent data suggest that most agents these antiretroviral agents is reversible, but dramatic, nonreversible
causing idiosyncratic toxicity are given at a daily dose exceeding 100 mg, hepatotoxicity associated with mitochondrial injury (inhibition of
suggesting a role for dose—drugs with low potency must be given DNA polymerase γ) was the cause of acute liver failure encountered
in higher doses that engender greater chances for “off-target” effects. during early clinical trials of now-abandoned fialuridine, a fluorinated
Adding to the difficulty of predicting or identifying idiosyncratic drug pyrimidine analogue with potent antiviral activity against hepatitis B
hepatotoxicity is the occurrence of mild, transient, nonprogressive virus. Another potential target for idiosyncratic drug hepatotoxicity is
serum aminotransferase elevations that resolve with continued drug sinusoidal lining cells; when these are injured, such as by high-dose
use. Such “adaptation,” the mechanism of which is unknown, is well chemotherapeutic agents (e.g., cyclophosphamide, melphalan, busul-
recognized for drugs such as isoniazid (INH), valproate, phenytoin, fan) administered prior to bone marrow transplantation, venoocclusive
and HMG-CoA reductase inhibitors (statins). Extrahepatic manifesta- disease can result. Nodular regenerative hyperplasia, a subtle form
tions of hypersensitivity, such as rash, arthralgias, fever, leukocytosis, of portal hypertension, may also result from vascular injury to portal
and eosinophilia, occur in about one-quarter of patients with idio- venous endothelium following systemic chemotherapy, such as with
syncratic hepatotoxic drug reactions but are characteristic for certain oxaliplatin, as part of adjuvant treatment for colon cancer.
drugs and not others. Both primary immunologic injury and direct Not all adverse hepatic drug reactions can be classified as either
hepatotoxicity related to idiosyncratic differences in generation of toxic toxic or idiosyncratic. For example, oral contraceptives, which

2368 Six Mechanisms of Liver Injury
B
Membrane
Transport
Hepatocyte pumps (MRP3)
Canaliculus
Heme
P-450 Drug
Endoplasmic
reticulum
PART 10
F
Triglycerides
Free fatty
Vesicle
acid
D Enzyme-drug
E Cell death adduct
Other Other Cytokines

caspases caspases
Inhibition of
β-oxidation, respiration, Caspase
or both
Caspase Caspase
DD DD
DD DD
Cytolytic
Mitochondrion TNF-α receptor, T cell
Fas
Lactate
A. Rupture of cell membrane. D. Drug adducts targeted by CTLs/cytokines.

B. Injury of bile canaliculus (disruption of transport pumps). E. Activation of apoptotic pathway by TNFα/Fas.
C. P-450-drug covalent binding (drug adducts). F. Inhibition of mitochondrial function.
FIGURE 333-1 Potential mechanisms of drug-induced liver injury. The normal hepatocyte may be affected adversely by drugs through (A) disruption of intracellular
calcium homeostasis that leads to the disassembly of actin fibrils at the surface of the hepatocyte, resulting in blebbing of the cell membrane, rupture, and cell
lysis; (B) disruption of actin filaments next to the canaliculus (the specialized portion of the cell responsible for bile excretion), leading to loss of villous processes
and interruption of transport pumps such as multidrug resistance–associated protein 3 (MRP3), which, in turn, prevents the excretion of bilirubin and other organic
compounds; (C) covalent binding of the heme-containing cytochrome P450 enzyme to the drug, thus creating nonfunctioning adducts; (D) migration of these enzyme-
drug adducts to the cell surface in vesicles to serve as target immunogens for cytolytic attack by T cells, stimulating an immune response involving cytolytic T cells and
cytokines; (E) activation of apoptotic pathways by tumor necrosis factor α (TNF-α) receptor or Fas (DD denotes death domain), triggering the cascade of intercellular
caspases, resulting in programmed cell death; or (F) inhibition of mitochondrial function by a dual effect on both β-oxidation and the respiratory-chain enzymes, leading
to failure of free fatty acid metabolism, a lack of aerobic respiration, and accumulation of lactate and reactive oxygen species (which may disrupt mitochondrial DNA).
Toxic metabolites excreted in bile may damage bile-duct epithelium (not shown). CTLs, cytolytic T lymphocytes. (Reproduced from WM Lee: Drug-induced hepatotoxicity.
N Engl J Med 349:474, 2003, with permission.)
combine estrogenic and progestational compounds, may result in oral contraceptive–induced cholestasis appears to be genetically deter-
impairment of liver tests and, occasionally, jaundice; however, they mined. Such estrogen-induced cholestasis is more common in women
do not produce necrosis or fatty change, manifestations of hypersen- with cholestasis of pregnancy, a disorder linked to genetic defects in
sitivity are generally absent, and susceptibility to the development of multidrug resistance–associated canalicular transporter proteins. A rare

TABLE 333-1 Some Features of Toxic and Drug-Induced Hepatic Injury 2369
DIRECT TOXIC EFFECT a

IDIOSYNCRATIC a
OTHER a
ESTROGENS/

CARBON AMOXICILLIN- ANDROGENIC
FEATURES TETRACHLORIDE ACETAMINOPHEN CLAVULANATE ISONIAZID CIPROFLOXACIN STEROIDS
Predictable and dose- + + 0 0 0 +
related toxicity
Latent period Short Short Delayed onset Variable May be short Variable
Arthralgia, fever, rash, 0 0 0 0 0 0
eosinophilia
Liver morphology Necrosis, fatty Centrilobular Mixed Hepatocellular injury Hepatocellular injury Cholestasis without
infiltration necrosis hepatocellular/ resembling viral resembling viral portal inflammation
cholestatic hepatitis hepatitis
The drugs listed are typical examples.
a
complication of oral contraceptive therapy is hepatic sinusoidal dilata- TREATMENT

tion localized to the periportal zone of the liver lobule.
Any idiosyncratic reaction that occurs in <1:10,000 recipients will Toxic and Drug-Induced Hepatic Disease
go unrecognized in most clinical trials, which involve only several
thousand recipients. The U.S. Food and Drug Administration (FDA) Treatment is largely supportive, except in acetaminophen hepatotox-
and pharmaceutical companies have learned to look for even subtle icity (for which N-acetylcysteine is effective, see below). In patients
with fulminant hepatitis resulting from drug hepatotoxicity, liver
indications of serious toxicity and monitor regularly the number of
transplantation may be lifesaving (Chap. 338). Withdrawal of the
trial subjects in whom any aminotransferase elevations develop, as a
suspected agent is indicated at the first sign of an adverse reaction.
possible surrogate for more serious toxicity. Even more valid as a pre-
A number of studies have suggested that lethal outcomes follow
dictor of severe hepatotoxicity is the occurrence of jaundice in patients
continued use of an agent in the face of symptoms and signs of liver
enrolled in a clinical drug trial, so-called “Hy’s Law,” named after
injury. In the case of the direct toxins, liver involvement should not
Hyman Zimmerman, one of the pioneers of the field of drug hepatotox-
divert attention from renal or other organ involvement, which may

icity. He recognized that, if jaundice occurred during a phase III trial,
also threaten survival. A number of agents are used occasionally but
more serious liver injury was likely, with a 10:1 ratio between cases of
are of questionable value: glucocorticoids for drug hepatotoxicity
jaundice and liver failure—10 patients with jaundice to 1 patient with
with allergic features, silibinin for hepatotoxic mushroom poisoning,
acute liver failure. Thus, the finding of such Hy’s Law cases during
and ursodeoxycholic acid for cholestatic drug hepatotoxicity have
drug development often portends failure of approval, particularly if
not been shown to be effective and cannot be recommended. A dou-
any of the subjects sustains a bad outcome. Troglitazone, a peroxisome
ble-blind, randomized controlled trial of the use of N-acetylcysteine
proliferator-activated receptor γ agonist, was the first in its class of
for non-acetaminophen acute liver failure, including cases of DILI
thiazolidinedione insulin-sensitizing agents. Although in retrospect,
demonstrated benefit particularly for patients with early-stage
Hy’s Law cases of jaundice had occurred during phase III trials, no hepatic encephalopathy; however, the drug is not FDA-approved
instances of liver failure were recognized until well after the drug was for this indication.
introduced, emphasizing the importance of postmarketing surveillance
in identifying toxic drugs and in leading to their withdrawal from use.
In Table 333-2, several classes of chemical agents are listed together
Fortunately, such hepatotoxicity is not characteristic of the second-
with examples of the pattern of liver injury they produce. Certain drugs
generation thiazolidinedione insulin-sensitizing agents rosiglitazone
appear to be responsible for the development of chronic as well as
and pioglitazone; in clinical trials, the frequency of aminotransferase
acute hepatic injury. For example, nitrofurantoin, minocycline, hydral-
elevations in patients treated with these medications did not differ
azine, and methyldopa have been associated with moderate to severe
from that in placebo recipients, and isolated reports of liver injury
chronic hepatitis with autoimmune features. Methotrexate, tamoxifen,
among recipients are extremely rare.
and amiodarone have been implicated in the development of cirrhosis.
Proving that an episode of liver injury is caused by a drug is dif-
Portal hypertension in the absence of cirrhosis may result from altera-
ficult in many cases. DILI is nearly always a presumptive diagnosis,
tions in hepatic architecture produced by vitamin A or arsenic intoxi-
and many other disorders produce a similar clinicopathologic picture.
cation, industrial exposure to polyvinyl chloride, or administration of
Thus, causality may be difficult to establish and requires several
thorium dioxide. The latter three agents have also been associated with
separate supportive assessment variables to lead to a high level of angiosarcoma of the liver. Oral contraceptives have been implicated in
certainty, including temporal association (time of onset, time to res- the development of hepatic adenoma and, rarely, hepatocellular car-
olution), clinical-biochemical features, type of injury (hepatocellular cinoma and hepatic vein occlusion (Budd-Chiari syndrome). Another
versus cholestatic), extrahepatic features, likelihood that a given agent unusual lesion, peliosis hepatis (blood cysts of the liver), has been
is to blame based on its past record, and exclusion of other potential observed in some patients treated with anabolic or contraceptive ste-
causes. Scoring systems such as the Roussel-Uclaf Causality Assess- roids. The existence of these hepatic disorders expands the spectrum
ment Method (RUCAM) yield residual uncertainty and have not of liver injury induced by chemical agents and emphasizes the need
been adopted widely. Currently, the U.S. Drug-Induced Liver Injury for a thorough drug history in all patients with liver dysfunction. The
Network (DILIN) relies on a structured expert opinion process requir- comprehensive, authoritative LiverTox website, which contains up-to-
ing detailed data on each case and a comprehensive review by three date information on drug-induced liver injury, is available as a valuable
experts who arrive at a consensus on a five-degree scale of likelihood reference through the National Institutes of Health and the National
(definite, highly likely, probable, possible, unlikely); however, this Library of Medicine (www.livertox.nih.gov).
approach is not practical for routine clinical application. The following are patterns of adverse hepatic reactions for some
Generally, drug hepatotoxicity is not more frequent in persons with prototypic agents.
underlying chronic liver disease, although the severity of the outcome
may be amplified. Reported exceptions include hepatotoxicity of ■■ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
aspirin, methotrexate, INH (only in certain experiences), antiretroviral Acetaminophen represents the most prevalent cause of acute liver fail-
therapy for HIV infection, and certain drugs such as conditioning reg- ure in the Western world; up to 72% of patients with acetaminophen
imens for bone marrow transplantation in the presence of hepatitis C. hepatotoxicity in Scandinavia—somewhat lower frequencies in the

2370 TABLE 333-2 Principal Alterations of Hepatic Morphology Produced by Some Commonly Used Drugs and Chemicalsa
PRINCIPAL
MORPHOLOGIC CHANGE CLASS OF AGENT EXAMPLE
Cholestasis Anabolic steroid Methyl testosterone, many other body-building supplements
Antibiotic Erythromycin estolate, nitrofurantoin, rifampin, amoxicillin-clavulanic acid, oxacillin
Anticonvulsant Carbamazepine
Antidepressant Duloxetine, mirtazapine, tricyclic antidepressants
Anti-inflammatory Sulindac
Antiplatelet Clopidogrel
Antihypertensive Irbesartan, fosinopril
Antithyroid Methimazole
Calcium channel blocker Nifedipine, verapamil
Immunosuppressive Cyclosporine
Lipid-lowering Ezetimibe
Oncotherapeutic Anabolic steroids, busulfan, tamoxifen, irinotecan, cytarabine, temozolomide
Oral contraceptive Norethynodrel with mestranol
Oral hypoglycemic Chlorpropamide
Tranquilizer Chlorpromazineb
Fatty liver Antiarrhythmic Amiodarone
Antibiotic Tetracycline (high-dose, IV)
Anticonvulsant Valproic acid
Antiviral Dideoxynucleosides (e.g., zidovudine), protease inhibitors (e.g., indinavir, ritonavir)
Oncotherapeutic Asparaginase, methotrexate, tamoxifen
Hepatitis Anesthetic Halothane, fluothane
Antiandrogen Flutamide
Antibiotic Isoniazid,c rifampicin, nitrofurantoin, telithromycin, minocycline,d pyrazinamide,
trovafloxacine
PART 10
Anticonvulsant Phenytoin, carbamazepine, valproic acid, phenobarbital

Antidepressant Iproniazid, amitriptyline, trazodone, venlafaxine, fluoxetine, paroxetine, duloxetine,
sertraline, nefazodonee
Antifungal Ketoconazole, fluconazole, itraconazole
Antihypertensive Methyldopa,c captopril, enalapril, lisinopril, losartan

Anti-inflammatory Ibuprofen, indomethacin, diclofenac, sulindac, bromfenac
Antipsychotic Risperidone
Antiviral Zidovudine, didanosine, stavudine, nevirapine, ritonavir, indinavir, tipranavir, zalcitabine
Calcium channel blocker Nifedipine, verapamil, diltiazem
Cholinesterase inhibitor Tacrine
Diuretic Chlorothiazide
Laxative Oxyphenisatinc,e
Norepinephrine-reuptake inhibitor Atomoxetine
Oral hypoglycemic Troglitazone,e acarbose
Mixed hepatitis/cholestatic Antibiotic Amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole
Antibacterial Clindamycin
Antifungal Terbinafine
Antihistamine Cyproheptadine
Immunosuppressive Azathioprine
Lipid-lowering Nicotinic acid, lovastatin, ezetimibe
Toxic (necrosis) Analgesic Acetaminophen
Hydrocarbon Carbon tetrachloride
Metal Yellow phosphorus
Mushroom Amanita phalloides
Solvent Dimethylformamide
Granulomas Antiarrhythmic Quinidine, diltiazem
Antibiotic Sulfonamides
Anticonvulsant Carbamazepine
Anti-inflammatory Phenylbutazone
Xanthine oxidase inhibitor Allopurinol
Vascular injury Chemotherapeutic Oxaliplatin, melphalan
a
Several agents cause more than one type of liver lesion and appear under more than one category. bRarely associated with primary biliary cirrhosis–like lesion.
c
Occasionally associated with chronic hepatitis or bridging hepatic necrosis or cirrhosis. dAssociated with an autoimmune hepatitis–like syndrome. eWithdrawn from use
because of severe hepatotoxicity.

United Kingdom and the United States—progress to encephalopathy and with an increased risk of acute liver injury in patients hospitalized for 2371
coagulopathy. Acetaminophen causes dose-related centrilobular hepatic acetaminophen overdose, generally, in patients with nonalcoholic liver
necrosis after single-time-point ingestions, as intentional self-harm, or disease, acetaminophen taken in recommended doses is well toler-
over extended periods, as unintentional overdoses, when multiple drug ated. Acetaminophen use in cirrhotic patients has not been associated
preparations or inappropriate drug amounts are used daily for several with hepatic decompensation. On the other hand, because of the link
days, for example, for relief of pain or fever. In these instances, 8 g/d, between acetaminophen use and liver injury, and because of the limited
twice the daily recommended maximum dose, over several days can safety margin between safe and toxic doses, the FDA has recommended
readily lead to liver failure. Use of opioid-acetaminophen combinations that the daily dose of acetaminophen be reduced from 4 g to 3 g (even
appears to be particularly harmful, because habituation to the opioid lower for persons with chronic alcohol use), that all acetaminophen-
may occur with a gradual increase in opioid-acetaminophen combina- containing products be labeled prominently as containing acetamin-
tion dosing over days or weeks. A single dose of 10–15 g, occasionally ophen, and that the potential for liver injury be prominent in the
less, may produce clinical evidence of liver injury. Fatal fulminant packaging of acetaminophen and acetaminophen-containing products.
disease is usually (although not invariably) associated with ingestion Within opioid combination products, the limit for the acetaminophen
of ≥25 g. Blood levels of acetaminophen correlate with severity of component has been lowered to 325 mg per tablet.
hepatic injury (levels >300 μg/mL 4 h after ingestion are predictive
of the development of severe damage; levels <150 μg/mL suggest
that hepatic injury is highly unlikely). Nausea, vomiting, diarrhea, TREATMENT
abdominal pain, and shock are early manifestations occurring 4–12 h Acetaminophen Overdosage
after ingestion. Then 24–48 h later, when these features are abating,
hepatic injury becomes apparent. Maximal abnormalities and hepatic Treatment includes gastric lavage, supportive measures, and oral
failure are evident 3–5 days after ingestion, and aminotransferase levels administration of activated charcoal or cholestyramine to prevent
exceeding 10,000 IU/L are not uncommon (i.e., levels far exceeding absorption of residual drug. Neither charcoal nor cholestyramine
those in patients with viral hepatitis). Renal failure and myocardial appears to be effective if given >30 min after acetaminophen inges-
injury may be present. Whether or not a clear history of overdose can tion; if they are used, the stomach lavage should be done before other
be elicited, clinical suspicion of acetaminophen hepatotoxicity should agents are administered orally. The chances of possible, probable,
be raised by the presence of the extremely high aminotransferase levels and high-risk hepatotoxicity can be derived from a nomogram plot
in association with low bilirubin levels that are characteristic of this (Fig. 333-2), readily available in emergency departments, as a func-
hyperacute injury. This biochemical signature should trigger further tion of measuring acetaminophen plasma levels 8 h after ingestion.

questioning of the subject if possible; however, denial or altered men- In patients with high acetaminophen blood levels (>200 μg/mL
tation may confound diagnostic efforts. In this setting, a presumptive measured at 4 h or >100 μg/mL at 8 h after ingestion), the adminis-
diagnosis is reasonable, and the proven antidote, N-acetylcysteine— tration of N-acetylcysteine reduces the severity of hepatic necrosis.
both safe and presumed to be effective even when injury has already This agent provides sulfhydryl donor groups to replete glutathione,
begun to evolve—should be instituted. which is required to render harmless toxic metabolites that would
Acetaminophen is metabolized predominantly by a phase II reaction otherwise bind covalently via sulfhydryl linkages to cell proteins,
to innocuous sulfate and glucuronide metabolites; however, a small resulting in the formation of drug metabolite-protein adducts. Ther-
proportion of acetaminophen is metabolized by a phase I reaction to apy should be begun within 8 h of ingestion but may be at least
a hepatotoxic metabolite formed from the parent compound by cyto- partially effective when given as late as 24–36 h after overdose.
chrome P450 CYP2E1. This metabolite, N-acetyl-p-benzoquinone-imine
(NAPQI), is detoxified by binding to “hepatoprotective” glutathione
to become harmless, water-soluble mercapturic acid, which undergoes 4000
renal excretion. When excessive amounts of NAPQI are formed, or 500 Lower limit for high-risk group
3000
when glutathione levels are low, glutathione levels are depleted and 400 Lower limit for probable-risk group
overwhelmed, permitting covalent binding to nucleophilic hepatocyte Study nomogram line
2000 300
macromolecules forming acetaminophen-protein “adducts.” These
adducts, which can be measured in serum by high-performance liquid 1300 200
Plasma acetaminophen concentration
chromatography, hold promise as diagnostic markers of acetamino-

1000 150
phen hepatotoxicity, and a point-of-care assay for acetaminophen-Cys
adducts is under development. The binding of acetaminophen to 100
hepatocyte macromolecules is believed to lead to hepatocyte necrosis;
500
the precise sequence and mechanism are unknown. Hepatic injury
may be potentiated by prior administration of alcohol, phenobarbital, 50
INH, or other drugs; by conditions that stimulate the mixed-function
oxidase system; or by conditions such as starvation (including inabil-
ity to maintain oral intake during severe febrile illnesses) that reduce
hepatic glutathione levels. Alcohol induces cytochrome P450 CYP2E1;
consequently, increased levels of the toxic metabolite NAPQI may be
produced in chronic alcoholics after acetaminophen ingestion, but 100
the role of alcohol in potentiating acute acetaminophen injury is still
debated. Alcohol also suppresses hepatic glutathione production. 10
Therefore, in chronic alcoholics, the toxic dose of acetaminophen may 50
be as low as 2 g, and alcoholic patients should be warned specifically
about the dangers of even standard doses of this commonly used drug. 30 5
In a 2006 study, aminotransferase elevations were identified in 31–44%
of normal subjects treated for 14 days with the maximal recommended
dose of acetaminophen, 4 g daily (administered alone or as part of µmol/L µg/mL 4 8 12 16 20 24 28
an acetaminophen-opioid combination); because these changes were Hours after acetaminophen ingestion
transient and never associated with bilirubin elevation, the clinical FIGURE 333-2 Nomogram to define risk of acetaminophen hepatotoxicity
relevance of these findings remains to be determined. Although under- according to initial plasma acetaminophen concentration. (After BH Rumack,
lying hepatitis C virus (HCV) infection was found to be associated H Matthew: Pediatrics 55:871, 1975.)

2372 Later administration of sulfhydryl compounds is of uncertain value. bridging hepatic necrosis, predominantly in the centrilobular zone.
Routine use of N-acetylcysteine has substantially reduced the occur- Bile duct injury may also be apparent. Most likely, sodium valproate
rence of fatal acetaminophen hepatotoxicity. N-acetylcysteine may is not directly hepatotoxic, but its metabolite, 4-pentenoic acid, may be
be given orally but is more commonly used as an IV solution, with a responsible for hepatic injury. Valproate hepatotoxicity is more com-
loading dose of 140 mg/kg over 1 h, followed by 70 mg/kg every 4 h mon in persons with mitochondrial enzyme deficiencies and may be
for 15–20 doses. Whenever a patient with potential acetaminophen ameliorated by IV administration of carnitine, which valproate therapy
hepatotoxicity is encountered, a local poison control center should can deplete. Valproate toxicity has been linked to HLA haplotypes
be contacted. Treatment can be stopped when plasma acetamino- (DR4 and B*1502) and to mutations in mitochondrial DNA polymerase
phen levels indicate that the risk of liver damage is low. If signs of gamma 1.
hepatic failure (e.g., progressive jaundice, coagulopathy, confusion)
occur despite N-acetylcysteine therapy for acetaminophen hepato- ■■NITROFURANTOIN HEPATOTOXICITY
toxicity, liver transplantation may be the only option. Early arterial (IDIOSYNCRATIC REACTION)
blood lactate levels among such patients with acute liver failure This commonly used antibiotic for urinary tract infections may cause
may distinguish patients highly likely to require liver transplan- an acute hepatitis leading to fatal outcome or, more frequently, chronic
tation (lactate levels >3.5 mmol/L) from those likely to survive hepatitis of varying severity but indistinguishable from autoimmune
without liver replacement. Acute renal injury occurs in nearly 75% hepatitis. These two scenarios may reflect the frequent use and reuse of
of patients with severe acetaminophen injury but is virtually always the drug for treatment of recurrent cystitis in women. Although most
self-limited. toxic agents manifest injury within 6 months of first ingestion, nitro-
furantoin may have a longer latency period, in part perhaps because of
Survivors of acute acetaminophen overdose rarely, if ever, have its intermittent, recurrent use. Autoantibodies to nuclear components,
ongoing liver injury or sequelae. smooth muscle, and mitochondria are seen and may subside after res-
olution of infection; however, glucocorticoid or other immunosuppres-
■■ISONIAZID HEPATOTOXICITY (TOXIC AND sive medication may be necessary to resolve the autoimmune injury,
IDIOSYNCRATIC REACTION) and cirrhosis may be seen in cases that are not recognized quickly.
INH remains central to most antituberculous prophylactic and thera- Interstitial pulmonary fibrosis presenting as chronic cough and dysp-
peutic regimens, despite its long-standing recognition as a hepatotoxin. nea may be present and resolve slowly with medication withdrawal.
In 10% of patients treated with INH, elevated serum aminotransferase Histologic findings are identical to those of autoimmune hepatitis. A
levels develop during the first few weeks of therapy; however, these ele- similar disease pattern can be observed with minocycline that is used
vations in most cases are self-limited, mild (values for ALT <200 IU/L), repeatedly for the treatment of acne in teenagers as well as with hydral-
PART 10
and resolve despite continued drug use. This adaptive response allows azine and alpha methyldopa.
continuation of the agent if symptoms and progressive enzyme eleva-
tions do not follow the initial elevations. Acute hepatocellular drug- ■■AMOXICILLIN-CLAVULANATE HEPATOTOXICITY
induced liver injury secondary to INH is evident with a variable (IDIOSYNCRATIC MIXED REACTION)
Currently, the most common agent implicated as causing drug-induced
latency period up to 6 months and is more frequent in alcoholics and
liver injury in the United States and in Europe is amoxicillin-clavulanate

patients taking certain other medications, such as barbiturates, rifam-
(most frequent brand name: Augmentin). This medication causes a very
pin, and pyrazinamide. If the clinical threshold of encephalopathy is
specific syndrome of mixed or primarily cholestatic injury. Because
reached, severe hepatic injury is likely to be fatal or to require liver
hepatotoxicity may follow amoxicillin-clavulanate therapy after a
transplantation. Liver biopsy reveals morphologic changes similar to
relatively long latency period, the liver injury may begin to manifest
those of viral hepatitis or bridging hepatic necrosis. Substantial liver
at the time of drug withdrawal or after the drug has been withdrawn.
injury appears to be age-related, increasing substantially after age 35;
The high prevalence of hepatotoxicity reflects in part the very frequent
the highest frequency is in patients over age 50, and the lowest is in
use of this drug for respiratory tract infections, including community-
patients under the age of 20. Even for patients >50 years of age moni-
acquired pneumonia. The mechanism of hepatotoxicity is unclear, but
tored carefully during therapy, hepatotoxicity occurs in only ~2%, well
the liver injury is thought to be caused by amoxicillin toxicity that is
below the risk estimate derived from earlier experiences. Fever, rash,
potentiated in some way by clavulanate, which itself appears not to be
eosinophilia, and other manifestations of drug allergy are distinctly
toxic. Symptoms include nausea, anorexia, fatigue, and jaundice—which
unusual. Antibodies to INH have been detected in INH recipients, but
may be prolonged—with pruritus. Rash is quite uncommon. On occa-
a link to causality of liver injury remains unclear. A clinical picture
sion, amoxicillin-clavulanate, like other cholestatic hepatotoxic drugs,
resembling chronic hepatitis has been observed in a few patients.
causes permanent injury to small bile ducts, leading to the so-called
Many public health programs that require INH prophylaxis for a pos- “vanishing bile duct syndrome.” In vanishing bile duct syndrome, ini-
itive tuberculin skin test or blood test (Quantiferon or T-Spot) include tially, liver injury is minimal except for severe cholestasis; however, over
monthly monitoring of aminotransferase levels, although this practice time, histologic evidence of bile duct abnormalities is replaced by a pau-
has been called into question. Even more effective in limiting serious city and eventual absence of discernible ducts on subsequent biopsies.
outcomes may be encouraging patients to be alert for symptoms such
as nausea, fatigue, or jaundice, because most fatalities occur in the set- ■■PHENYTOIN HEPATOTOXICITY (IDIOSYNCRATIC
ting of continued INH use despite clinically apparent illness. REACTION)
Phenytoin, formerly diphenylhydantoin, a mainstay in the treatment
■■SODIUM VALPROATE HEPATOTOXICITY (TOXIC AND of seizure disorders, has been associated in rare instances with the
IDIOSYNCRATIC REACTION) development of severe hepatitis-like liver injury leading to fulminant
Sodium valproate, an anticonvulsant useful in the treatment of petit hepatic failure. In many patients, the hepatitis is associated with
mal and other seizure disorders, has been associated with the devel- striking fever, lymphadenopathy, rash (Stevens-Johnson syndrome or
opment of severe hepatic toxicity and, rarely, fatalities, predominantly exfoliative dermatitis), leukocytosis, and eosinophilia, suggesting an
in children but also in adults. Among children listed as candidates immunologically mediated hypersensitivity mechanism. Despite these
for liver transplantation, valproate is the most common antiepileptic observations, evidence suggests that metabolic idiosyncrasy may be
drug implicated. Asymptomatic elevations of serum aminotransferase responsible for hepatic injury. In the liver, phenytoin is converted by
levels have been recognized in as many as 45% of treated patients. cytochrome P450 to metabolites that include the highly reactive elec-
These “adaptive” changes, however, appear to have no clinical trophilic arene oxides. These metabolites are normally metabolized
importance, because major hepatotoxicity is not seen in the majority further by epoxide hydrolases. A defect (genetic or acquired) in epox-
of patients despite continuation of drug therapy. In the rare patients ide hydrolase activity could permit covalent binding of arene oxides
in whom jaundice, encephalopathy, and evidence of hepatic failure to hepatic macromolecules, thereby leading to hepatic injury. Hepatic
are found, examination of liver tissue reveals microvesicular fat and injury is usually manifest within the first 2 months after beginning

phenytoin therapy. With the exception of an abundance of eosinophils cholestasis, portal inflammation is absent. The lesion is reversible on 2373
in the liver, the clinical, biochemical, and histologic picture resembles withdrawal of the agent. The two steroid components appear to act
that of viral hepatitis. In rare instances, bile duct injury may be the synergistically on hepatic function, although the estrogen may be pri-
salient feature of phenytoin hepatotoxicity, with striking features of marily responsible. Oral contraceptives are contraindicated in patients
intrahepatic cholestasis. Asymptomatic elevations of aminotransfer- with a history of recurrent jaundice of pregnancy. Primarily benign,
ase and alkaline phosphatase levels have been observed in a sizable but rarely malignant, neoplasms of the liver, hepatic vein occlusion,
proportion of patients receiving long-term phenytoin therapy. These and peripheral sinusoidal dilatation have also been associated with
liver changes are believed by some authorities to represent the potent oral contraceptive therapy. Focal nodular hyperplasia of the liver is not
hepatic enzyme-inducing properties of phenytoin and are accompa- more frequent among users of oral contraceptives.
nied histologically by swelling of hepatocytes in the absence of necro-
inflammatory activity or evidence of chronic liver disease. ■■ANABOLIC STEROIDS (CHOLESTATIC REACTION)
The most common form of liver injury caused by CAMs is the pro-
■■AMIODARONE HEPATOTOXICITY (TOXIC AND found cholestasis associated with anabolic steroids used by body
IDIOSYNCRATIC REACTION) builders. Unregulated agents sold in gyms and health food stores as
Therapy with this potent antiarrhythmic drug is accompanied in diet supplements, which are taken by athletes to improve their perfor-
15–50% of patients by modest elevations of serum aminotransferase lev- mance, may contain anabolic steroids. In a young male, jaundice that
els that may remain stable or diminish despite continuation of the drug. is accompanied by a cholestatic, rather than a hepatitic, laboratory pro-
Such abnormalities may appear days to many months after beginning file almost invariably will turn out to be caused by the use of one of a
therapy. A proportion of those with elevated aminotransferase levels variety of androgen congeners. Such agents have the potential to injure
have detectable hepatomegaly, and clinically important liver disease bile transport pumps and to cause intense cholestasis; the time to onset
develops in <5% of patients. Features that represent a direct effect of is variable, and resolution, which is the rule, may require many weeks
the drug on the liver and that are common to the majority of long-term to months. Initially, anorexia, nausea, and malaise may occur, followed
recipients are ultrastructural phospholipidosis, unaccompanied by clin- by pruritus in some but not all patients. Serum aminotransferase levels
ical liver disease, and interference with hepatic mixed-function oxidase are usually <100 IU/L and serum alkaline phosphatase levels are gen-
metabolism of other drugs. The cationic amphiphilic drug and its major erally moderately elevated with bilirubin levels frequently exceeding
metabolite desethylamiodarone accumulate in hepatocyte lysosomes 342 μmol/L (20 mg/dL). Examination of liver tissue reveals cholestasis
and mitochondria and in bile duct epithelium. The relatively common without substantial inflammation or necrosis. Anabolic steroids have
elevations in aminotransferase levels are also considered a predictable, also been used by prescription to treat bone marrow failure. In this
dose-dependent, direct hepatotoxic effect. On the other hand, in the rare setting, hepatic centrizonal sinusoidal dilatation and peliosis hepatis

patient with clinically apparent, symptomatic liver disease, liver injury have been reported in rare patients, as have hepatic adenomas and
resembling that seen in alcoholic liver disease is observed. The so-called hepatocellular carcinoma.
pseudoalcoholic liver injury can range from steatosis, to alcoholic hep-
atitis–like neutrophilic infiltration and Mallory’s hyaline, to cirrhosis. TRIMETHOPRIM-SULFAMETHOXAZOLE
Electron-microscopic demonstration of phospholipid-laden lysosomal HEPATOTOXICITY (IDIOSYNCRATIC
lamellar bodies can help to distinguish amiodarone hepatotoxicity from REACTION)
typical alcoholic hepatitis. This category of liver injury appears to be a This antibiotic combination is used routinely for urinary tract infections
metabolic idiosyncrasy that allows hepatotoxic metabolites to be gen- in immunocompetent persons and for prophylaxis against and ther-
erated. Rarely, an acute idiosyncratic hepatocellular injury resembling apy of Pneumocystis carinii pneumonia in immunosuppressed persons
viral hepatitis or cholestatic hepatitis occurs. Hepatic granulomas have (transplant recipients, patients with AIDS). With its increasing use, its
occasionally been observed. Because amiodarone has a long half-life, occasional hepatotoxicity is being recognized with growing frequency.
liver injury may persist for months after the drug is stopped. Its likelihood is unpredictable, but when it occurs, trimethoprim-
■■ERYTHROMYCIN HEPATOTOXICITY (CHOLESTATIC sulfamethoxazole hepatotoxicity follows a relatively uniform latency
IDIOSYNCRATIC REACTION) period of several weeks and is often accompanied by eosinophilia,
The most important adverse effect associated with erythromycin, more rash, and other features of a hypersensitivity reaction. Biochemically
common in children than adults, is the infrequent occurrence of a choles- and histologically, acute hepatocellular necrosis predominates, but
tatic reaction. Although most of these reactions have been associated cholestatic features are quite frequent. Occasionally, cholestasis with-
with erythromycin estolate, other erythromycins may also be responsi- out necrosis occurs, and, very rarely, a severe cholangiolytic pattern
ble. The reaction usually begins during the first 2 or 3 weeks of therapy of liver injury is observed. In most cases, liver injury is self-limited,
and includes nausea, vomiting, fever, right upper quadrant abdominal but rare fatalities have been recorded. The hepatotoxicity is attribut-
pain, jaundice, leukocytosis, and moderately elevated aminotransferase able to the sulfamethoxazole component of the drug and is similar in
and alkaline phosphatase levels. The clinical picture can resemble acute features to that seen with other sulfonamides; tissue eosinophilia and
cholecystitis or bacterial cholangitis. Liver biopsy reveals variable choles- granulomas may be seen. The risk of trimethoprim-sulfamethoxazole
tasis; portal inflammation comprising lymphocytes, polymorphonuclear hepatotoxicity is increased in persons with HIV infection.
leukocytes, and eosinophils; and scattered foci of hepatocyte necrosis.
Symptoms and laboratory findings usually subside within a few days ■■HMG-COA REDUCTASE INHIBITORS (STATINS)
of drug withdrawal, and evidence of chronic liver disease has not been (IDIOSYNCRATIC MIXED HEPATOCELLULAR AND
found on follow-up. The precise mechanism remains ill-defined. CHOLESTATIC REACTION)
Between 1 and 2% of patients taking lovastatin, simvastatin, pravas-
■■ORAL CONTRACEPTIVE HEPATOTOXICITY tatin, fluvastatin, or one of the newer statin drugs for the treatment of
(CHOLESTATIC REACTION) hypercholesterolemia experience asymptomatic, reversible elevations
The administration of oral contraceptive combinations of estrogenic (>threefold) of aminotransferase activity. Acute hepatitis-like histologic
and progestational steroids leads to intrahepatic cholestasis with pru- changes, centrilobular necrosis, and centrilobular cholestasis have been
ritus and jaundice in a small proportion of patients weeks to months described in a very small number of cases. In a larger proportion, minor
after taking these agents. Especially susceptible seem to be patients aminotransferase elevations appear during the first several weeks of
with recurrent idiopathic jaundice of pregnancy, severe pruritus of therapy. Careful laboratory monitoring can distinguish between patients
pregnancy, or a family history of these disorders. With the exception with minor, transitory changes, who may continue therapy and those
of liver biochemical tests, laboratory studies are normal, and extra- with more profound and sustained abnormalities, who should discon-
hepatic manifestations of hypersensitivity are absent. Liver biopsy tinue therapy. Because clinically meaningful aminotransferase elevations
reveals cholestasis with bile plugs in dilated canaliculi and striking are so rare after statin use and do not differ in meta-analyses from the
bilirubin staining of liver cells. In contrast to chlorpromazine-induced frequency of such laboratory abnormalities in placebo recipients, a

2374 panel of liver experts recommended to the National Lipid Association’s disorders, mycobacterial infection, etc.), but drug hepatotoxicity
Safety Task Force that liver test monitoring was not necessary in patients associated with HAART is an emerging and common type of liver
treated with statins and that statin therapy need not be discontinued in injury in HIV-infected persons (Chap. 197). Although no one antiviral
patients found to have asymptomatic isolated aminotransferase eleva- agent is recognized as a potent hepatotoxin, combination regimens
tions during therapy. Statin hepatotoxicity is not increased in patients including reverse transcriptase and protease inhibitors cause hepa-
with chronic hepatitis C, hepatic steatosis, or other underlying liver totoxicity in ~10% of treated patients. Implicated most frequently are
diseases, and statins can be used safely in these patients. combinations including nucleoside analogue reverse transcriptase
inhibitors zidovudine, didanosine, and, to a lesser extent, stavudine;
■■TOTAL PARENTERAL NUTRITION (STEATOSIS, protease inhibitors ritonavir and indinavir (and amprenavir when
CHOLESTASIS) used together with ritonavir), as well as tipranavir; and nonnucle-
Total parenteral nutrition (TPN) is often complicated by cholestatic oside reverse transcriptase inhibitors nevirapine and, to a lesser
hepatitis attributable to steatosis, cholestasis, or gallstones (or gall- extent, efavirenz. These drugs cause predominantly hepatocellular
bladder sludge). Steatosis or steatohepatitis may result from the injury but cholestatic injury as well, and prolonged (>6 months)
excess carbohydrate calories in these nutritional supplements and is use of reverse transcriptase inhibitors has been associated with
the predominant form of TPN-associated liver disorder in adults. The mitochondrial injury, steatosis, and lactic acidosis. Indirect hyperbi-
frequency of this complication has been reduced substantially by the lirubinemia, resulting from direct inhibition of bilirubin-conjugating
introduction of balanced TPN formulas that rely on lipid as an alter- activity by UDP-glucuronosyltransferase, usually without elevation
native caloric source. Cholestasis and cholelithiasis, caused by the of aminotransferase or alkaline phosphatase activities, occurs in ~10%
absence of stimulation of bile flow and secretion resulting from the of patients treated with the protease inhibitor indinavir. Distinguish-
lack of oral intake, is the predominant form of TPN-associated liver ing the impact of HAART hepatotoxicity in patients with HIV and
disease in infants, especially in premature neonates. Often, cholestasis hepatitis virus co-infection is made challenging by the following: (1)
in such neonates is multifactorial, contributed to by other factors such both chronic hepatitis B and hepatitis C can affect the natural history
as sepsis, hypoxemia, and hypotension; occasionally, TPN-induced of HIV infection and the response to HAART, and (2) HAART can
cholestasis in neonates culminates in chronic liver disease and liver have an impact on chronic viral hepatitis. For example, immunologic
failure. When TPN-associated liver test abnormalities occur in adults, reconstitution with HAART can result in immunologically mediated
balancing the TPN formula with more lipid is the intervention of first liver-cell injury in patients with chronic hepatitis B co-infection if
recourse. In infants with TPN-associated cholestasis, the addition of treatment with an antiviral agent for hepatitis B (e.g., the nucleo-
oral feeding may ameliorate the problem. Therapeutic interventions side analogue lamivudine) is withdrawn or if nucleoside analogue
suggested, but not shown, to be of proven benefit, include chole- resistance emerges. Infection with HIV, especially with low CD4+
cystokinin, ursodeoxycholic acid, S adenosyl methionine, and taurine.
PART 10
T cell counts, has been reported to increase the rate of hepatic fibrosis
associated with chronic hepatitis C, and HAART therapy can increase
■■ALTERNATIVE AND COMPLEMENTARY MEDICINES levels of serum aminotransferases and HCV RNA in patients with
(IDIOSYNCRATIC HEPATITIS, STEATOSIS) hepatitis C co-infection. Didanosine or stavudine should not be used
Herbal medications that are of scientifically unproven efficacy and with ribavirin in patients with HIV/HCV co-infection because of an
that lack prospective safety oversight by regulatory agencies account increased risk of severe mitochondrial toxicity and lactic acidosis.
currently for more than 20% of drug-induced liver injury in the United
States. Besides anabolic steroids, the most common category of dietary Acknowledgment
or herbal products is weight loss agents. Included among the herbal Kurt J. Isselbacher, MD, contributed to this chapter in previous editions of
remedies associated with toxic hepatitis are Jin Bu Huan, xiao-chai-hu- Harrison’s.
tang, germander, chaparral, senna, mistletoe, skullcap, gentian, comfrey
(containing pyrrolizidine alkaloids), ma huang, bee pollen, valerian root, ■■FURTHER READING
pennyroyal oil, kava, celandine, Impila (Callilepis laureola), LipoKinetix, Björnsson ES, Hoofnagle JL: Categorization of drugs implicated in
Hydroxycut, herbal nutritional supplements, and herbal teas containing causing liver injury: Critical assessment based upon published case
Camellia sinensis (green tea extract). Well characterized are the acute hep- reports. Hepatology 63:590, 2016.
atitis-like histologic lesions following Jin Bu Huan use: focal hepatocel- Chalasani N et al: Features and outcomes of 899 patients with
lular necrosis, mixed mononuclear portal tract infiltration, coagulative drug-induced liver injury: The DILIN prospective study. Gastroenter-
necrosis, apoptotic hepatocyte degeneration, tissue eosinophilia, and ology 148:1340, 2015.
microvesicular steatosis. Megadoses of vitamin A can injure the liver, Chen M et al: A model to predict severity of drug-induced liver injury
as can pyrrolizidine alkaloids, which often contaminate Chinese herbal in humans. Hepatology 64:931, 2016.
preparations and can cause a venoocclusive injury leading to sinusoidal Fontana RJ et al: Idiosyncratic drug-induced liver injury is associated
hepatic vein obstruction. Because some alternative medicines induce with substantial morbidity and mortality within 6 months from onset.
toxicity via active metabolites, alcohol and drugs that stimulate cyto- Gastroenterology 147:96, 2014.
chrome P450 enzymes may enhance the toxicity of some of these prod- Goldberg DS et al: Population-representative incidence of drug-
ucts. Conversely, some alternative medicines also stimulate cytochrome induced acute liver failure based on an analysis of an integrated
P450 and may result in or amplify the toxicity of recognized drug health care system. Gastroenterology 148:1353, 2015.
hepatotoxins. Given the widespread use of such poorly defined herbal Hayashi PH et al: Under-reporting and poor adherence to moni-
preparations, hepatotoxicity is likely to be encountered with increasing toring guidelines for severe cases of isoniazid hepatotoxicity. Clin
frequency; therefore, a drug history in patients with acute and chronic Gastroenterol Hepatol 13:1676, 2015.
liver disease should include use of “alternative medicines” and other Hoofnagle JH et al: LiverTox: A website on drug-induced liver
nonprescription preparations sold in so-called health food stores. injury. Hepatology 57:873, 2013. Available from www.livertox.nih.gov.
Accessed September 26, 2016.
■■HIGHLY ACTIVE ANTIRETROVIRAL THERAPY Kaplowitz N, Deleve LD (eds): Drug-Induced Liver Disease, 3rd ed.
(HAART) FOR HIV INFECTION (MITOCHONDRIAL London, Elsevier/Academic Press, 2013.
TOXIC, IDIOSYNCRATIC, STEATOSIS; Lee WM et al: Intravenous N-acetylcysteine improves transplant-
HEPATOCELLULAR, CHOLESTATIC, AND MIXED) free survival in early stage non-acetaminophen acute liver failure.
The recognition of drug hepatotoxicity in persons with HIV infection Gastroenterology 137:856, 2009.
is complicated in this population by the many alternative causes Medina-Caliz I et al: Definition and risk factors for chronicity following
of liver injury (chronic viral hepatitis, fatty infiltration, infiltrative acute idiosyncratic drug-induced liver injury. J Hepatol 65:532, 2016.

■■CLASSIFICATION BY CAUSE 2375
334 Chronic Hepatitis

Jules L. Dienstag
Clinical and serologic features allow the establishment of a diagnosis
of chronic viral hepatitis, caused by hepatitis B, hepatitis B plus D, or
hepatitis C; autoimmune hepatitis, including several subcategories, I and II,
based on serologic distinctions; drug-associated chronic hepatitis; and a
category of unknown cause, or cryptogenic chronic hepatitis (Table 334-1).
These are addressed in more detail below.
Chronic hepatitis represents a series of liver disorders of varying causes
and severity in which hepatic inflammation and necrosis continue for ■■CLASSIFICATION BY GRADE
at least 6 months. Milder forms are nonprogressive or only slowly pro- Grade, a histologic assessment of necroinflammatory activity, is based on
gressive, while more severe forms may be associated with scarring and examination of the liver biopsy. An assessment of important histologic
architectural reorganization, which, when advanced, lead ultimately to features includes the degree of periportal necrosis and the disruption of the
cirrhosis. Several categories of chronic hepatitis have been recognized. limiting plate of periportal hepatocytes by inflammatory cells (so-called
These include chronic viral hepatitis, drug-induced chronic hepatitis piecemeal necrosis or interface hepatitis); the degree of confluent necrosis
(Chap. 333), and autoimmune chronic hepatitis. In many cases, clinical that links or forms bridges between vascular structures—between
and laboratory features are insufficient to allow assignment into one portal tract and portal tract or even more important bridges between
of these three categories; these “idiopathic” cases are also believed to portal tract and central vein—referred to as bridging necrosis; the degree
represent autoimmune chronic hepatitis. Finally, clinical and laboratory of hepatocyte degeneration and focal necrosis within the lobule; and
features of chronic hepatitis are observed occasionally in patients with the degree of portal inflammation. Several scoring systems that take these
such hereditary/metabolic disorders as Wilson’s disease (copper over- histologic features into account have been devised, and the most popular
load), α1 antitrypsin deficiency (Chaps. 337 and 408), and nonalcoholic are the histologic activity index (HAI), used commonly in the United
fatty liver disease (Chap. 336) and even occasionally in patients with States, and the METAVIR score, used in Europe (Table 334-2). Based on
alcoholic liver injury (Chap. 335). Although all types of chronic hepatitis the presence and degree of these features of histologic activity, chronic
share certain clinical, laboratory, and histopathologic features, chronic hepatitis can be graded as mild, moderate, or severe.
viral and chronic autoimmune hepatitis are sufficiently distinct to merit
separate discussions. For discussion of acute hepatitis, see Chap. 332. ■■CLASSIFICATION BY STAGE
The stage of chronic hepatitis, which reflects the level of progression of
CLASSIFICATION OF CHRONIC HEPATITIS the disease, is based on the degree of hepatic fibrosis. When fibrosis is
so extensive that fibrous septa surround parenchymal nodules and alter
CHAPTER 334 Chronic Hepatitis

Common to all forms of chronic hepatitis are histopathologic distinc-
tions based on localization and extent of liver injury. These vary from the normal architecture of the liver lobule, the histologic lesion is defined
the milder forms, previously labeled chronic persistent hepatitis and as cirrhosis. Staging is based on the degree of fibrosis as categorized on a
chronic lobular hepatitis, to the more severe form, formerly called chronic numerical scale 0−6 (HAI) or 0−4 (METAVIR) (Table 334-2). Several non-
active hepatitis. When first defined, these designations were believed to invasive approaches have been introduced to provide approximations
of hepatic histologic stage, including serum biomarkers of fibrosis and
have prognostic implications, which were not corroborated by subse-
imaging determinations of liver elasticity.
quent observations. Categorization of chronic hepatitis based primarily
on histopathologic features has been replaced by a more informative
classification based on a combination of clinical, serologic, and his- CHRONIC VIRAL HEPATITIS
tologic variables. Classification of chronic hepatitis is based on (1) its Both the enterically transmitted forms of viral hepatitis, hepatitis A
cause; (2) its histologic activity, or grade; and (3) its degree of progres- and E, are self-limited and do not cause chronic hepatitis (rare reports
sion based on level of fibrosis, or stage. Thus, neither clinical features notwithstanding in which acute hepatitis A serves as a trigger for the
alone nor histologic features—requiring liver biopsy or noninvasive onset of autoimmune hepatitis in genetically susceptible patients or in
markers of fibrosis—alone are sufficient to characterize and distinguish which hepatitis E (Chap. 332) can cause chronic liver disease in immuno-
among the several categories of chronic hepatitis. suppressed hosts, for example, after liver transplantation). In contrast, the
TABLE 334-1 Clinical and Laboratory Features of Chronic Hepatitis

TYPE OF HEPATITIS DIAGNOSTIC TEST(s) AUTOANTIBODIES THERAPY
Chronic hepatitis B HBsAg, IgG anti-HBc, HBeAg, HBV DNA Uncommon IFN-α, PEG IFN-α
Oral agents:
First-line: entecavir, tenofovir
Second-line: lamivudine, adefovir, telbivudine
Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1a PEG IFN-α plus ribavirinb
Direct-acting oral agents:
sofosbuvir, ledipasvir, velpatasvir
ritonavir-boosted paritaprevir, ombitasvir, dasabavir
elbasvir, grazoprevir
daclatasvir, simeprevir
Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc Anti-LKM3 IFN-α, PEG IFN-αc
Autoimmune hepatitis ANAd (homogeneous), anti-LKM1 (±) ANA, anti-LKM1 anti-SLAe Prednisone, azathioprine
Hyperglobulinemia
Drug-associated — Uncommon Withdraw drug
Cryptogenic All negative None Prednisone (?), azathioprine (?)
a
Antibodies to liver-kidney microsomes type 1 (autoimmune hepatitis type II and some cases of hepatitis C). bSupplanted in almost all cases by combinations of the
direct-acting antiviral agents listed (see www.hcvguidelines.org). cEarly clinical trials suggested benefit of IFN-α therapy; PEG IFN-α is as effective, if not more so, and
has supplanted standard IFN-α. dAntinuclear antibody (autoimmune hepatitis type I). eAntibodies to soluble liver antigen (autoimmune hepatitis type III).
Abbreviations: HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D
virus; IFN-α, interferon α; IgG, immunoglobulin G; LKM, liver-kidney microsome; PEG IFN-α, pegylated interferon α; SLA, soluble liver antigen.

2376 TABLE 334-2 Histologic Grading and Staging of Chronic Hepatitis patients followed for 1−13 years, progres-
sion to more severe chronic hepatitis and
HISTOLOGIC ACTIVITY INDEX (HAI) a
METAVIR
b
cirrhosis has been observed in more than
HISTOLOGIC FEATURE SEVERITY SCORE SEVERITY SCORE
a quarter of cases.
Necroinflammatory Activity (grade) More important to consider than his-
Periportal necrosis, including piecemeal None 0 None 0 tology alone in patients with chronic
necrosis and/or bridging necrosis (BN) Mild 1 Mild 1 hepatitis B is the degree of hepatitis B
Mild/moderate 2 Moderate 2 virus (HBV) replication. As reviewed
Moderate 3 Severe 3 in Chap. 332, chronic HBV infection
Severe 4 can occur in the presence or absence of
Bridging necrosis Yes
serum hepatitis B e antigen (HBeAg), and
generally, for both HBeAg-reactive and
No
HBeAg-negative chronic hepatitis B, the
Intralobular necrosis Confluent —None 0 None or mild 0
level of HBV DNA correlates with the
—Focal 1 Moderate 1 level of liver injury and risk of progres-
—Zone 3 some 2 Severe 2 sion. In HBeAg-reactive chronic hepatitis B,
—Zone 3 most 3 two phases have been recognized based
—Zone 3 + BN few 4 on the relative level of HBV replication.
—Zone 3 + BN multiple 5 The relatively replicative phase is char-
—Panacinar/multiacinar 6 acterized by the presence in the serum
Focal —None 0 of HBeAg and HBV DNA levels well
—≤1 focus/10× field 1 in excess of 103−104 IU/mL, sometimes
—2–4 foci/10× field 2
exceeding 109 IU/mL; by the presence
in the liver of detectable intrahepatocyte
—5–10 foci/10× field 3
nucleocapsid antigens (primarily hepatitis
—>10 foci/10× field 4
B core antigen [HBcAg]); by high infectiv-
Portal Inflammation None 0 ity; and by accompanying liver injury. In
Mild 1 contrast, the relatively nonreplicative phase
Moderate 2 is characterized by the absence of the con-
PART 10
Moderate/marked 3 ventional serum marker of HBV replica-

Marked 4 tion (HBeAg), the appearance of anti-HBe,
Total 0–18 A0–A3c levels of HBV DNA below a threshold of
Fibrosis (stage) ~103 IU/mL, the absence of intrahepatoc-
ytic HBcAg, limited infectivity, and min-
None 0 F0
imal liver injury. Patients in the relatively
Portal fibrosis—some 1 F1
replicative phase tend to have more severe
Portal fibrosis—most 2 F1
chronic hepatitis, whereas those in the rel-
Bridging fibrosis—few 3 F2 atively nonreplicative phase tend to have
Bridging fibrosis—many 4 F3 minimal or mild chronic hepatitis or to be
Incomplete cirrhosis 5 F4 inactive hepatitis B carriers. The likelihood
Cirrhosis 6 F4 in a patient with HBeAg-reactive chronic
Total 6 4 hepatitis B of converting spontaneously
a
Ishak K, Baptista A, Bianchi L, et al: Histologic grading and staging of chronic hepatitis. J Hepatol 22:696, 1995. from relatively replicative to nonreplica-
b
Bedossa P, Poynard T, French METAVIR Cooperative Study Group: An algorithm for grading activity in chronic hepatitis tive infection is ~10% per year. Distinctions
C. Hepatology 24:289, 1996. cNecroinflammatory grade: A0 = none; A1 = mild; A2 = moderate; A3 = severe. in HBV replication and in histologic cat-
egory, however, do not always coincide.
entire clinicopathologic spectrum of chronic hepatitis occurs in patients In patients with HBeAg-reactive chronic HBV infection, especially when
with chronic viral hepatitis B and C as well as in patients with chronic acquired at birth or in early childhood, as recognized commonly in Asian
hepatitis D superimposed on chronic hepatitis B. countries, a dichotomy is common between very high levels of HBV rep-
lication during the early decades of life (when the level of apparent host
■■CHRONIC HEPATITIS B immunologic tolerance of HBV is relatively high) and negligible levels
The likelihood of chronicity after acute hepatitis B varies as a func- of liver injury. Yet despite the relatively immediate, apparently benign
tion of age. Infection at birth is associated with clinically silent acute nature of liver disease for many decades in this population, in the middle
infection but a 90% chance of chronic infection, whereas infection in decades, activation of liver injury emerges as what appears to be the rela-
young adulthood in immunocompetent persons is typically associated tive tolerance of the host to HBV declines, and these patients with child-
with clinically apparent acute hepatitis but a risk of chronicity of only hood-acquired HBV infection are ultimately at increased risk later in life
~1%. Most cases of chronic hepatitis B among adults, however, occur of cirrhosis, hepatocellular carcinoma (HCC) (Chap. 78), and liver-related
in patients who never had a recognized episode of clinically apparent death. A discussion of the pathogenesis of liver injury in patients with
acute viral hepatitis. The degree of liver injury (grade) in patients with chronic hepatitis B appears in Chap. 332.
chronic hepatitis B is variable, ranging from none in inactive carriers HBeAg-negative chronic hepatitis B (i.e., chronic HBV infection
to mild to moderate to severe. Among adults with chronic hepatitis with active virus replication, readily detectable HBV DNA
B, histologic features are of prognostic importance. In one long-term but without HBeAg [anti-HBe-reactive]), is more common
study of patients with chronic hepatitis B, investigators found a 5-year than HBeAg-reactive chronic hepatitis B in Mediterranean and Euro-
survival rate of 97% for patients with mild chronic hepatitis, 86% for pean countries and in Asia (and, correspondingly, in HBV genotypes
patients with moderate to severe chronic hepatitis, and only 55% for other than A). Compared to patients with HBeAg-reactive chronic
patients with chronic hepatitis and postnecrotic cirrhosis. The 15-year hepatitis B, patients with HBeAg-negative chronic hepatitis B have
survival in these cohorts was 77%, 66%, and 40%, respectively. On the HBV DNA levels several orders of magnitude lower (no more than
other hand, more recent observations do not allow us to be so sanguine 105−106 IU/mL) than those observed in the HBeAg-reactive subset.
about the prognosis in patients with mild chronic hepatitis; among such Most such cases represent precore or core-promoter mutations acquired

late in the natural history of the disease (mostly early-life onset; age range 2377
TREATMENT
40−55 years, older than that for HBeAg-reactive chronic hepatitis B); these
mutations prevent translation of HBeAg from the precore component Chronic Hepatitis B
of the HBV genome (precore mutants) or are characterized by down-
regulated transcription of precore mRNA (core-promoter mutants; Although progression to cirrhosis is more likely in severe than in
Chap. 332). Although their levels of HBV DNA tend to be lower than mild or moderate chronic hepatitis B, all forms of chronic hepatitis B
among patients with HBeAg-reactive chronic hepatitis B, patients with can be progressive, and progression occurs primarily in patients with
HBeAg-negative chronic hepatitis B can have progressive liver injury active HBV replication. Moreover, in populations of patients with
(complicated by cirrhosis and HCC) and experience episodic reactiva- chronic hepatitis B who are at risk for HCC (Chap. 78), the risk is
tion of liver disease reflected in fluctuating levels of aminotransferase highest for those with continued, high-level HBV replication and
activity (“flares”). The biochemical and histologic activity of lower for persons in whom initially high-level HBV DNA falls spon-
HBeAg-negative disease tends to correlate closely with levels of HBV taneously over time. Therefore, management of chronic hepatitis B
replication, unlike the case mentioned above of Asian patients with is directed at suppressing the level of virus replication. Although
HBeAg-reactive chronic hepatitis B during the early decades of their clinical trials tend to focus on clinical endpoints achieved over 1−2
HBV infection. Worth reiterating, the level of HBV replication is the years (e.g., suppression of HBV DNA to undetectable levels, loss of
most important risk factor for the ultimate development of cirrhosis HBeAg/HBsAg, improvement in histology, normalization of ALT),
and HCC in both HBeAg-reactive (beyond the early decades of “rela- these short-term gains translate into reductions in the risk of clinical
tively nonreplicative” infection) and HBeAg-negative patients. progression, hepatic decompensation, HCC, liver transplantation,
Although levels of HBV DNA are lower and more readily suppressed and death; regression of cirrhosis and of esophageal varices have
by therapy to undetectable levels in HBeAg-negative (compared to been documented to follow long-term pharmacologic suppression of
HBeAg-reactive) chronic hepatitis B, achieving sustained responses HBV replication. In addition, restoration of impaired HBV-specific
that permit discontinuation of antiviral therapy is less likely in T-cell function has been shown following successful suppression
HBeAg-negative patients (see below). Inactive carriers are patients of HBV replication with antiviral therapy. To date, seven drugs
with circulating hepatitis B surface antigen (HBsAg), normal serum have been approved for treatment of chronic hepatitis B: injectable
aminotransferase levels, undetectable HBeAg, and levels of HBV DNA interferon (IFN) α and pegylated interferon (long-acting IFN bound
that are either undetectable or present at a threshold of ≤103 IU/mL. to polyethylene glycol, PEG [PEG IFN]) and the oral agents lami-
This serologic profile occurs not only in inactive carriers but also in vudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir
patients with HBeAg-negative chronic hepatitis B during periods of disoproxil fumarate (TDF).

relative inactivity; distinguishing between the two requires sequential Antiviral therapy for hepatitis B has evolved rapidly since the
biochemical and virologic monitoring over many months. mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN
The spectrum of clinical features of chronic hepatitis B is broad, ranging and lamivudine were evaluated in clinical trials, HBV DNA was
from asymptomatic infection to debilitating disease or even end-stage, measured by insensitive hybridization assays with detection thresh-
fatal hepatic failure. As noted above, the onset of the disease tends to be olds of 105−106 virions/mL; when adefovir, entecavir, telbivudine,
insidious in most patients, with the exception of the very few in whom tenofovir, and PEG IFN were studied in clinical trials, HBV DNA
chronic disease follows failure of resolution of clinically apparent acute was measured by sensitive amplification assays (polymerase chain
hepatitis B. The clinical and laboratory features associated with pro- reaction [PCR]) with detection thresholds of 101−103 viral copies/mL
gression from acute to chronic hepatitis B are discussed in Chap. 332. or IU/mL. Recognition of these distinctions is helpful when com-
Fatigue is a common symptom, and persistent or intermittent jaun- paring results of clinical trials that established the efficacy of these
dice is a common feature in severe or advanced cases. Intermittent therapies (reviewed below in chronological order of publication of
deepening of jaundice and recurrence of malaise and anorexia, as well these efficacy trials).
as worsening fatigue, are reminiscent of acute hepatitis; such exacer-
bations may occur spontaneously, often coinciding with evidence of INTERFERON
virologic reactivation; may lead to progressive liver injury; and, when IFN-α was the first approved therapy (1992) for chronic hepatitis B.
superimposed on well-established cirrhosis, may cause hepatic dec- Although it is no longer used to treat hepatitis B, standard IFN is
ompensation. Complications of cirrhosis occur in end-stage chronic important historically, having provided important lessons about
hepatitis and include ascites, edema, bleeding gastroesophageal antiviral therapy in general. For immunocompetent adults with
varices, hepatic encephalopathy, coagulopathy, and hypersplenism. HBeAg-reactive chronic hepatitis B (who tend to have high-level
Occasionally, these complications bring the patient to initial clinical HBV DNA [>105−106 virions/mL] and histologic evidence of chronic
attention. Extrahepatic complications of chronic hepatitis B, similar to hepatitis on liver biopsy), a 16-week course of IFN given subcutane-
those seen during the prodromal phase of acute hepatitis B, are associ- ously at a daily dose of 5 million units, or three times a week at a dose
ated with tissue deposition of circulating hepatitis B antigen–antibody of 10 million units, resulted in a loss of HBeAg and hybridization-
immune complexes. These include arthralgias and arthritis, which are detectable HBV DNA (i.e., a reduction to levels below 105−106
common, and the more rare purpuric cutaneous lesions (leukocytoclas- virions/mL) in ~30% of patients, with a concomitant improvement
tic vasculitis), immune-complex glomerulonephritis, and generalized in liver histology. Seroconversion from HBeAg to anti-HBe occurred
vasculitis (polyarteritis nodosa) (Chaps. 332 and 356). in ~20%, and, in early trials, ~8% lost HBsAg. Successful IFN
Laboratory features of chronic hepatitis B do not distinguish ade- therapy and seroconversion were often accompanied by an acute
quately between histologically mild and severe hepatitis. Aminotrans- hepatitis-like elevation in aminotransferase activity, postulated to
ferase elevations tend to be modest for chronic hepatitis B but may result from enhanced cytolytic T cell clearance of HBV-infected
fluctuate in the range of 100−1000 units. As is true for acute viral hepatocytes. Relapse after successful therapy was rare (1 or 2%). The
hepatitis B, alanine aminotransferase (ALT) tends to be more elevated likelihood of responding to IFN was higher in patients with lower
than aspartate aminotransferase (AST); however, once cirrhosis is estab- levels of HBV DNA and substantial elevations of ALT. Although
lished, AST tends to exceed ALT. Levels of alkaline phosphatase activity children can respond as well as adults, IFN therapy was not effective
tend to be normal or only marginally elevated. In severe cases, mod- in very young children infected at birth. Similarly, IFN therapy was
erate elevations in serum bilirubin (51.3−171 μmol/L [3−10 mg/dL]) not effective in immunosuppressed persons, Asian patients with
occur. Hypoalbuminemia and prolongation of the prothrombin time neonatal acquisition of infection and minimal-to-mild ALT eleva-
occur in severe or end-stage cases. Hyperglobulinemia and detectable tions, or patients with decompensated chronic hepatitis B (in whom
circulating autoantibodies are distinctly absent in chronic hepatitis B such therapy was actually detrimental, sometimes precipitating dec-
(in contrast to autoimmune hepatitis). Viral markers of chronic HBV ompensation, often associated with severe adverse effects). Among
infection are discussed in Chap. 332. patients with HBeAg loss during therapy, long-term follow-up

2378 demonstrated that 80% experienced eventual loss of HBsAg (i.e., is necessary to identify HBV reactivation promptly and to resume
all serologic markers of infection, and normalization of ALT over a therapy. If HBeAg is unaffected by lamivudine therapy, the current
9-year posttreatment period). In addition, improved long-term and approach is to continue therapy until an HBeAg response occurs, but
complication-free survival as well as a reduction in the frequency long-term therapy may be required to suppress HBV replication and,
of HCC were documented among IFN responders, supporting the in turn, limit liver injury; HBeAg seroconversions can increase to a
conclusion that successful antiviral therapy improves the natural level of 50% after 5 years of therapy. Histologic improvement contin-
history of chronic hepatitis B. ues to accrue with therapy beyond the first year; after a cumulative
Initial trials of brief-duration IFN therapy in patients with course of 3 years of lamivudine therapy, necroinflammatory activity
HBeAg-negative chronic hepatitis B were disappointing, suppressing is reduced in the majority of patients, and even cirrhosis has been
HBV replication transiently during therapy but almost never result- shown to regress to precirrhotic stages in as many as three-quarters
ing in sustained antiviral responses. In subsequent IFN trials among of patients.
patients with HBeAg-negative chronic hepatitis B, however, more Losses of HBsAg have been few during the first year of lamivu-
protracted courses, lasting up to 1.5 years, were reported to result dine therapy, and this observation had been cited as an advantage
in sustained remissions documented to last for several years, with of IFN-based over lamivudine therapy; however, in head-to-head
suppressed HBV DNA and aminotransferase activity, in ~20%. comparisons between standard IFN and lamivudine monotherapy,
Complications of IFN therapy include systemic “flu-like” symp- HBsAg losses were rare in both groups. Trials in which lamivudine
toms; marrow suppression; emotional lability (irritability, depres- and IFN were administered in combination failed to show a benefit
sion, anxiety); autoimmune reactions (especially autoimmune of combination therapy over lamivudine monotherapy for either
thyroiditis); and miscellaneous side effects such as alopecia, rashes, treatment-naïve patients or prior IFN nonresponders.
diarrhea, and numbness and tingling of the extremities. With the In patients with HBeAg-negative chronic hepatitis B (i.e., in those
possible exception of autoimmune thyroiditis, all these side effects with precore and core-promoter HBV mutations), 1 year of lamivu-
are reversible upon dose lowering or cessation of therapy. dine therapy results in HBV DNA suppression and normalization
Although no longer competitive with the newer generation of of ALT in three-quarters of patients and in histologic improvement
antivirals, IFN did represent the first successful antiviral approach in approximately two-thirds. Therapy has been shown to suppress
and set a standard against which to measure subsequent drugs in HBV DNA by ~4.5 log10 copies/mL (baseline HBV DNA levels are
the achievement of durable virologic, serologic, biochemical, and lower than in patients with HBeAg-reactive hepatitis B) and to unde-
histologic responses; consolidation of virologic and biochemical tectable levels in ~70%, as measured by sensitive PCR amplification
benefit in the ensuing years after therapy; and improvement in the assays. Lacking HBeAg at the outset, patients with HBeAg-negative
natural history of chronic hepatitis B. Standard IFN has been sup- chronic hepatitis B cannot achieve an HBeAg response—a stopping
PART 10
planted by long-acting PEG IFN (see below), and IFN nonrespond- point in HBeAg-reactive patients; almost invariably, when therapy
ers are now treated with one of the newer oral nucleoside analogues. is discontinued, reactivation is the rule. Therefore, these patients
LAMIVUDINE require long-term therapy; with successive years, the proportion
with suppressed HBV DNA and normal ALT increases.
The first of the nucleoside analogues to be approved (in 1998) for
Clinical and laboratory side effects of lamivudine are negligible
hepatitis B, the dideoxynucleoside lamivudine inhibits reverse tran-
and indistinguishable from those observed in placebo recipients.

scriptase activity of both HIV and HBV and is an effective agent for
Still, lamivudine doses should be reduced in patients with reduced
patients with chronic hepatitis B. Although generally superseded by
creatinine clearance. During lamivudine therapy, transient ALT ele-
newer, more potent, less resistance-prone agents, lamivudine is still
vations, resembling those seen during IFN therapy and during
used in regions of the world where newer agents are not yet avail-
able or affordable. In clinical trials among patients with HBeAg- spontaneous HBeAg-to-anti-HBe seroconversions, occur in one-
reactive chronic hepatitis B, lamivudine therapy at daily doses of fourth of patients. These ALT elevations may result from restored
100 mg for 48−52 weeks suppressed HBV DNA by a median of cytolytic T cell activation permitted by suppression of HBV repli-
~5.5 log10 copies/mL and to undetectable levels, as measured by cation. Similar ALT elevations, however, occurred at an identical
PCR amplification assays, in ~40% of patients. Therapy was asso- frequency in placebo recipients; however, ALT elevations associated
ciated with HBeAg loss in 32−33%, HBeAg seroconversion (i.e., with HBeAg seroconversion in clinical trials were confined to
conversion from HBeAg-reactive to anti-HBe-reactive) in 16−21%, lamivudine-treated patients. When therapy is stopped after a year
normalization of ALT in 40−75%, improvement in histology in of therapy, two- to threefold ALT elevations occur in 20−30% of
50−60%, retardation in hepatic fibrosis in 20−30%, and preven- lamivudine-treated patients, representing renewed liver-cell injury
tion of progression to cirrhosis. HBeAg responses occur even in as HBV replication returns. Although these posttreatment flares
patients resistant to IFN (e.g., those with high-level HBV DNA) or are almost always transient and mild, rare severe exacerbations,
who failed in the past to respond to it. As is true for IFN therapy of especially in cirrhotic patients, have been observed, mandating close
chronic hepatitis B, patients with near-normal ALT activity tend not and careful clinical and virologic monitoring after discontinuation of
to experience HBeAg responses (despite suppression of HBV DNA), treatment. Many authorities caution against discontinuing therapy
whereas those with ALT levels exceeding 5 × the upper limit of nor- in patients with cirrhosis, in whom posttreatment flares could pre-
mal can expect 1-year HBeAg seroconversion rates of 50−60%. cipitate decompensation.
Generally, HBeAg seroconversions are confined to patients who Long-term monotherapy with lamivudine is associated with
achieve suppression of HBV DNA to <104 copies/mL (equivalent methionine-to-valine (M204V) or methionine-to-isoleucine (M204I)
to ~103 IU/mL). Lamivudine-associated HBeAg responses are mutations, primarily at amino acid 204 in the tyrosine-methionine-
accompanied by a delayed posttreatment HBsAg seroconversion aspartate-aspartate (YMDD) motif of the C domain of HBV DNA
rate comparable to that seen after IFN-induced HBeAg responses. polymerase, analogous to mutations that occur in HIV-infected
Among Western patients who undergo HBeAg responses during a patients treated with this drug. During a year of therapy, YMDD
year-long course of therapy and in whom the response is sustained mutations occur in 15−30% of patients; the frequency increases
for 4−6 months after cessation of therapy, the response is durable with each year of therapy, reaching 70% at year 5. Ultimately,
thereafter in the vast majority (>80%); therefore, the achievement of patients with YMDD mutants experience degradation of clinical,
an HBeAg response represents a viable stopping point in therapy. biochemical, and histologic responses; therefore, if treatment is
Reduced durability has been reported in Asian patients; therefore, begun with lamivudine monotherapy, the emergence of lami-
to support the durability of HBeAg responses, patients should vudine resistance, reflected clinically by a breakthrough from
receive a period of consolidation therapy of ≥6 months in Western suppressed levels of HBV DNA and ALT, is managed by adding
patients and ≥1 year in Asian patients after HBeAg seroconversion another antiviral to which YMDD variants are sensitive (e.g., adefovir,
(see treatment guidelines below). Close posttreatment monitoring tenofovir; see below).

Currently, although lamivudine is very safe and still used widely followed by sustained suppression of HBV DNA and ALT, but most 2379
in other parts of the world, in the United States and Europe, lamivu- HBeAg-negative patients are treated indefinitely unless HBsAg loss,
dine has been eclipsed by more potent antivirals that have superior albeit very rare, is achieved.
resistance profiles (see below); it is no longer recommended as first- Adefovir contains a flexible acyclic linker instead of the
line therapy. Still, as the first successful oral antiviral agent for use in L-nucleoside ring of lamivudine, avoiding steric hindrance by
hepatitis B, lamivudine provided proof of principle that polymerase mutated amino acids. In addition, the molecular structure of phos-
inhibitors can achieve virologic, serologic, biochemical, and histologic phorylated adefovir is very similar to that of its natural substrate;
benefits. In addition, lamivudine has been shown to be effective in therefore, mutations to adefovir would also affect binding of the
the treatment of patients with decompensated hepatitis B (for whom natural substrate, dATP. Hypothetically, these are among the rea-
IFN is contraindicated), in some of whom decompensation can be sons that resistance to adefovir dipivoxil is much less likely than
reversed. Moreover, among patients with cirrhosis or advanced fibro- resistance to lamivudine; no resistance was encountered in 1 year
sis, lamivudine has been shown to be effective in reducing the risk of clinical trial therapy. In subsequent years, however, adefovir
of progression to hepatic decompensation and, marginally, the risk resistance begins to emerge (asparagine to threonine at amino acid
of HCC. In the half decade following the introduction in the United 236 [N236T] and alanine to valine or threonine at amino acid 181
States of lamivudine therapy for hepatitis B, referral of patients with [A181V/T], primarily), occurring in 2.5% after 2 years, but in 29%
HBV-associated end-stage liver disease for liver transplantation was after 5 years of therapy (reported in HBeAg-negative patients).
reduced by ~30%, supporting further the beneficial impact of oral Among patients co-infected with HBV and HIV and who have nor-
antiviral therapy on the natural history of chronic hepatitis B. mal CD4+ T cell counts, adefovir dipivoxil is effective in suppressing
Because lamivudine monotherapy can result universally in the HBV dramatically (by 5 logs10 in one study). Moreover, adefovir
rapid emergence of YMDD variants in persons with HIV infection, dipivoxil is effective in lamivudine-resistant, YMDD-mutant HBV
patients with chronic hepatitis B should be tested for anti-HIV prior and can be used when such lamivudine-induced variants emerge.
to therapy; if HIV infection is identified, lamivudine monotherapy When lamivudine resistance occurs, adding adefovir (i.e., maintain-
at the HBV daily dose of 100 mg is contraindicated. These patients ing lamivudine to preempt the emergence of adefovir resistance) is
should be treated for both HIV and HBV with an HIV drug regimen superior to switching to adefovir. Almost invariably, patients with
that includes or is supplemented by at least two drugs active against adefovir-induced HBV mutations respond to lamivudine (or newer
HBV; antiretroviral therapy (ART) often contains two drugs with agents, such as entecavir, see below). When, in the past, adefovir had
antiviral activity against HBV (e.g., tenofovir and emtricitabine), been evaluated as therapy for HIV infection, doses of 60−120 mg
but if lamivudine is part of the regimen, the daily dose should be were required to suppress HIV, and, at these doses, the drug was

300 mg (Chap. 197). The safety of lamivudine during pregnancy has nephrotoxic. Even at 30 mg/d, creatinine elevations of 44 μmol/L
not been established; however, the drug is not teratogenic in rodents (0.5 mg/dL) occurred in 10% of patients; however, at the HBV-
and has been used safely in pregnant women with HIV infection and effective dose of 10 mg, such creatinine elevations are rarely
with HBV infection. Administration of lamivudine during the last encountered. If any nephrotoxicity does occur, it rarely appears
months of pregnancy to mothers with high-level hepatitis B viremia before 6−8 months of therapy. Although renal tubular injury is a
(≥108 IU/mL) can reduce the likelihood of perinatal transmission of rare potential side effect, and although creatinine monitoring is
hepatitis B. recommended during treatment, the therapeutic index of adefovir
dipivoxil is high, and the nephrotoxicity observed in clinical trials
ADEFOVIR DIPIVOXIL
at higher doses was reversible. For patients with underlying renal
At an oral daily dose of 10 mg, the acyclic nucleotide analogue ade- disease, frequency of administration of adefovir dipivoxil should be
fovir dipivoxil, the prodrug of adefovir (approved for hepatitis B in reduced to every 48 h for creatinine clearances of 30−49 mL/min; to
2002), reduces HBV DNA by ~3.5−4 log10 copies/mL and is equally every 72 h for creatinine clearances of 10−29 mL/min; and to once
effective in treatment-naïve patients and prior IFN nonresponders. a week, following dialysis, for patients undergoing hemodialysis.
In HBeAg-reactive chronic hepatitis B, a 48-week course of adefovir Adefovir dipivoxil is very well tolerated, and ALT elevations during
dipivoxil was shown to achieve histologic improvement (and reduce and after withdrawal of therapy are similar to those observed and
the progression of fibrosis) and normalization of ALT in just over one- described above in clinical trials of lamivudine. An advantage of
half of patients, HBeAg seroconversion in 12%, HBeAg loss in 23%, adefovir is its relatively favorable resistance profile; however, it is
and suppression to an undetectable level of HBV DNA in 13−21%, as not as potent as the other approved oral agents, it does not suppress
measured by PCR. Similar to IFN and lamivudine, adefovir dipivoxil HBV DNA as rapidly or as uniformly as the others, it is the least
is more likely to achieve an HBeAg response in patients with high likely of all agents to result in HBeAg seroconversion, and 20−50%
baseline ALT; among adefovir-treated patients with ALT level >5 × of patients fail to suppress HBV DNA by 2 log10 (“primary nonre-
the upper limit of normal, HBeAg seroconversions occurred in 25%. sponders”). For these reasons, adefovir, which has been supplanted
The durability of adefovir-induced HBeAg responses is high (91% in both treatment-naïve and lamivudine-resistant patients by the
in one study); therefore, HBeAg response can be relied upon as a more potent, less resistance-prone nucleotide analogue tenofovir
stopping point for adefovir therapy, after a period of consolidation (see below), is no longer recommended as first-line therapy.
therapy, as outlined above. Although data on the impact of addi-
tional therapy beyond 1 year are limited, biochemical, serologic, and PEGYLATED IFN
virologic outcomes improve progressively as therapy is continued. After long-acting PEG IFN was shown to be effective in the treat-
In patients with HBeAg-negative chronic hepatitis B, a 48-week ment of hepatitis C (see below), this more convenient drug was eval-
course of 10 mg/d of adefovir dipivoxil resulted in histologic uated in the treatment of chronic hepatitis B. Once-a-week PEG IFN
improvement in two-thirds, normalization of ALT in three-fourths, is more effective than the more frequently administered, standard
and suppression of HBV DNA to PCR-undetectable levels in one- IFN, and several large-scale trials of PEG IFN versus oral nucleoside
half to two-thirds. As was true for lamivudine, because HBeAg analogues were conducted among patients with HBeAg-reactive
responses—a potential stopping point—cannot be achieved in this and HBeAg-negative chronic hepatitis B.
group, reactivation is the rule when adefovir therapy is discon- In HBeAg-reactive chronic hepatitis B, two large-scale studies
tinued, and indefinite, long-term therapy is required. Treatment were done. In one study, PEG IFN-α 2b (100 μg weekly for 32 weeks,
beyond the first year consolidates the gain of the first year; then 50 μg weekly for another 20 weeks for a total of 52 weeks) was
after 5 years of therapy, improvement in hepatic inflammation and evaluated against a comparison arm of combination PEG IFN with
regression of fibrosis were observed in three-fourths of patients, oral lamivudine in 307 subjects. The other study involved PEG IFN-α
ALT was normal in 70%, and HBV DNA was undetectable in 2a (180 μg weekly for 48 weeks) in 814 primarily Asian patients,
almost 70%. In one study, stopping adefovir after 5 years was three-fourths of whom had ALT ≥2 × the upper limit of normal, with

2380 comparison arms of lamivudine monotherapy and combination initially with PEG IFN, 17% maintained HBV DNA suppression to
PEG IFN plus lamivudine. At the end of therapy (48−52 weeks) <400 copies/mL, but ALT remained normal in only 22%; HBsAg
in the PEG IFN monotherapy arms, HBeAg loss occurred in ~30%, loss increased gradually to 12%. Among the half followed who had
HBeAg seroconversion in 22−27%, undetectable HBV DNA (<400 been treated initially with lamivudine monotherapy, HBV DNA
copies/mL by PCR) in 10−25%, normal ALT in 34−39%, and a mean remained <400 copies/mL in 7% and ALT normal in 16%; by year
reduction in HBV DNA of 2 log10 copies/mL (PEG IFN-α 2b) to 4.5 5, 3.5% had lost HBsAg. As was the case for standard IFN therapy
log10 copies/mL (PEG IFN-α 2a). Six months after completing PEG in HBeAg-negative patients, only a small proportion maintained
IFN monotherapy in these trials, HBeAg losses were present in responsiveness after completion of PEG IFN therapy, raising ques-
~35%, HBeAg seroconversion in ~30%, undetectable HBV DNA in tions about the relative value of a finite period of PEG IFN, versus a
7−14%, normal ALT in 32−41%, and a mean reduction in HBV DNA longer course with a potent, low-resistance oral nucleoside analogue
of 2−2.4 log10 copies/mL. Although the combination of PEG IFN and in these patients. Moreover, the value of PEG IFN for HBeAg-
lamivudine was superior at the end of therapy in one or more sero- negative chronic hepatitis B has not been confirmed. In the only
logic, virologic, or biochemical outcomes, neither the combination other controlled clinical trial of PEG IFN for HBeAg-negative chronic
arm (in both studies) nor the lamivudine monotherapy arm (in the hepatitis B, the hepatitis C regimen of PEG IFN plus ribavirin was
PEG IFN-α 2a trial) demonstrated any benefit compared to the PEG compared to PEG IFN monotherapy. In this trial, HBV DNA sup-
IFN monotherapy arms 6 months after therapy. Moreover, HBsAg pression (<400 copies/mL) occurred in only 7.5% of the two groups
seroconversion occurred in 3−7% of PEG IFN recipients (with or combined, and no study subject lost HBsAg.
without lamivudine); some of these seroconversions were identified In patients treated with PEG IFN, HBeAg and HBsAg responses
by the end of therapy, but many were identified during the post- have been associated with IL28B genotype CC, the favorable
treatment follow-up period. The likelihood of HBeAg loss in PEG genotype identified in trials of PEG IFN for chronic hepatitis C.
IFN-treated HBeAg-reactive patients is associated with HBV geno- Also, reductions in quantitative HBsAg levels have been shown
type A > B > C > D (shown for PEG IFN-α2b but not for α-2a). PEG to correlate with and to be predictive of responsiveness to PEG
IFN-α 2a was approved in the US for hepatitis B in 2005; PEG IFN-α IFN in chronic hepatitis B. If HBsAg levels fail to fall within the
2b, not approved for hepatitis B in the US, is used in other countries. first 12–24 weeks or to reach <20,000 IU/mL by week 24, PEG IFN
Based on these results, some authorities concluded that PEG IFN therapy is unlikely to be effective and should be discontinued.
monotherapy should be the first-line therapy of choice in HBeAg- (Similar observations of HBsAg levels in oral-agent-treated patients
reactive chronic hepatitis B; however, this conclusion has been are of interest, but of limited clinical relevance, given the very high
challenged. Although a finite, 1-year course of PEG IFN results in likelihood of virologic responses during such therapy.)
a higher rate of sustained response (6 months after treatment) than
ENTECAVIR
PART 10
is achieved with oral nucleoside/nucleotide analogue therapy, the

comparison is confounded by the fact that oral agents are not dis- Entecavir, an oral cyclopentyl guanosine analogue polymerase inhib-
continued at the end of 1 year. Instead, taken orally and free of side itor (approved 2005), appears to be the most potent of the HBV
effects, therapy with oral agents is extended indefinitely or until after antivirals and is just as well tolerated as lamivudine. In a 709-subject
the occurrence of an HBeAg response. The rate of HBeAg responses clinical trial among HBeAg-reactive patients, oral entecavir, 0.5 mg
after 2 years of oral-agent nucleoside analogue therapy is at least as daily, was compared to lamivudine, 100 mg daily. At 48 weeks,
high as, if not higher than, that achieved with PEG IFN after 1 year; entecavir was superior to lamivudine in suppression of HBV DNA
favoring oral agents is the absence of injections, difficult-to-tolerate (mean 6.9 vs 5.5 log10 copies/mL), percentage with undetectable
side effects, and laboratory monitoring as well as lower direct and HBV DNA (<300 copies/mL by PCR; 67% vs 36%), histologic
indirect medical care costs and inconvenience. The association of improvement (≥2-point improvement in necroinflammatory HAI
HBsAg responses with PEG IFN therapy occurs in such a small score; 72% vs 62%), and normal ALT (68% vs 60%). The two treat-
proportion of patients that subjecting everyone to PEG IFN for the ments were indistinguishable in percentage with HBeAg loss (22%
marginal gain of HBsAg responses during or immediately after ther- vs 20%) and seroconversion (21% vs 18%). Among patients treated
apy in such a very small minority is questionable. Moreover, HBsAg with entecavir for 96 weeks, HBV DNA was undetectable cumula-
responses occur in a comparable proportion of patients treated with tively in 80% (vs 39% for lamivudine), and HBeAg seroconversions
early-generation nucleoside/nucleotide analogues in the years after had occurred in 31% (vs 26% for lamivudine). After 3–6 years of
therapy, and, with the newer, more potent nucleoside analogues, the entecavir, HBeAg seroconversions have been observed in 39–44%
frequency of HBsAg loss during the first year of therapy equals that and HBsAg loss in 5–6%. Similarly, in a 638-subject clinical trial
of PEG IFN and is exceeded during year 2 and beyond (see below). among HBeAg-negative patients, at week 48, oral entecavir, 0.5 mg
Of course, resistance is not an issue during PEG IFN therapy, but daily, was superior to lamivudine, 100 mg daily, in suppression of
the risk of resistance is much lower with new agents (≤1% up to HBV DNA (mean 5.0 vs 4.5 log10 copies/mL) and in percentage with
3−8 years in previously treatment-naïve, entecavir-treated and 0% of undetectable HBV DNA (90% vs 72%), histologic improvement (70%
tenofovir-treated patients; see below). Finally, the level of HBV DNA vs 61%), and normal ALT (78% vs 71%). No resistance mutations
inhibition that can be achieved with the newer agents, and even with were encountered in previously treatment-naïve, entecavir-treated
lamivudine, exceeds that which can be achieved with PEG IFN, in patients during 96 weeks of therapy, and in a cohort of subjects
some cases by several orders of magnitude. treated for up to 6 years, resistance emerged in only 1.2%. Entecavir-
In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α 2a induced HBeAg seroconversions are as durable as those achieved
(180 μg weekly for 48 weeks versus comparison arms of lamivudine with other antivirals. Its high barrier to resistance coupled with its
monotherapy and of combination therapy) in 564 patients showed high potency renders entecavir a first-line drug for patients with
that PEG IFN monotherapy resulted at the end of therapy in sup- chronic hepatitis B.
pression of HBV DNA by a mean of 4.1 log10 copies/mL, undetect- Entecavir is also effective against lamivudine-resistant HBV infec-
able HBV DNA (<400 copies/mL by PCR) in 63%, normal ALT in tion. In a trial of 286 lamivudine-resistant patients, entecavir, at a
38%, and loss of HBsAg in 4%. Although lamivudine monotherapy higher daily dose of 1 mg, was superior to lamivudine, as measured
and combination lamivudine−PEG IFN therapy were both superior at week 48, in achieving suppression of HBV DNA (mean 5.1 vs
to PEG IFN at the end of therapy, no advantage of lamivudine 0.48 log10 copies/mL), undetectable HBV DNA (72% vs 19%), nor-
monotherapy or combination therapy was apparent over PEG IFN mal ALT (61% versus 15%), HBeAg loss (10% vs 3%), and HBeAg
monotherapy 6 months after therapy—suppression of HBV DNA by seroconversion (8% vs 3%). In this population of lamivudine-
a mean of 2.3 log10 copies/mL, undetectable HBV DNA in 19%, and experienced patients, however, entecavir resistance emerged
normal ALT in 59%. In subjects involved in this trial followed for in 7% at 48 weeks. Although entecavir resistance requires both a
up to 5 years, among the two-thirds followed who had been treated YMDD mutation and a second mutation at one of several other sites

(e.g., T184A, S202G/I, or M250V), resistance to entecavir in lami- A comparison of the six antiviral therapies in current use 2381
vudine-resistant chronic hepatitis B has been recorded to increase appears in Table 334-3; their relative potencies in suppressing
progressively to 43% at 4 years and 57% at 6 years; therefore, ente- HBV DNA are shown in Fig. 334-1.
cavir is not as attractive a choice (and is not recommended, despite COMBINATION THERAPY
its approval for this indication) as adefovir or tenofovir for patients
with lamivudine-resistant hepatitis B. Although the combination of lamivudine and PEG IFN suppresses
In clinical trials, entecavir had an excellent safety profile. In HBV DNA more profoundly during therapy than does monother-
addition, on-treatment and posttreatment ALT flares are relatively apy with either drug alone (and is much less likely to be associated
uncommon and relatively mild in entecavir-treated patients. Doses with lamivudine resistance), this combination used for a year is no
should be reduced for patients with reduced creatinine clearance. better than a year of PEG IFN in achieving sustained responses. To
Entecavir does have low-level antiviral activity against HIV and date, combinations of oral nucleoside/nucleotide agents have not
cannot be used as monotherapy to treat HBV infection in HIV/HBV achieved an enhancement in virologic, serologic, or biochemical
efficacy over that achieved by the more potent of the combined
co-infected persons.
drugs given individually. In a 2-year trial of combination entecavir
TELBIVUDINE and tenofovir versus entecavir monotherapy, for a small subgroup of
Telbivudine, a cytosine analogue (approved 2006), is similar in effi- patients with very high HBV DNA levels (≥108 IU/mL), a reduction
cacy to entecavir but slightly less potent in suppressing HBV DNA in HBV DNA to <50 IU/mL was higher in the combination group
(a slightly less profound median 6.4 log 10 reduction in HBeAg- (79% vs 62%); however, no differences in HBeAg responses or any
reactive disease and a similar 5.2 log10 reduction in HBeAg-negative other endpoint were observed between the combination-therapy
disease). In its registration trial, telbivudine at an oral daily dose and monotherapy groups, even in the high-HBV DNA subgroup.
of 600 mg suppressed HBV DNA to <300 copies/mL in 60% of On the other hand, combining agents that are not cross-resistant
HBeAg-positive and 88% of HBeAg-negative patients, reduced ALT (e.g., lamivudine or entecavir with adefovir or tenofovir) has the
to normal in 77% of HBeAg-positive and 74% of HBeAg-negative potential to reduce the risk or perhaps even to preempt entirely the
patients, and improved histology in 65% of HBeAg-positive and emergence of drug resistance. In the future, the treatment paradigm
67% of HBeAg-negative patients. Although resistance to telbivudine may shift from the current approach of sequential monotherapy to
(M204I, not M204V, mutations) was less frequent than resistance to preemptive combination therapy, perhaps not for all patients but for
lamivudine at the end of 1 year, resistance mutations after 2 years subsets (e.g., patients with very high levels of HBV DNA, immu-
of treatment occurred in up to 22%. Generally well tolerated, telbi- nosuppressed patients); however, designing and executing clinical
vudine has been associated with a low frequency of asymptomatic trials that demonstrate superior efficacy and resistance profile of

creatine kinase elevations and with a very low frequency of periph- combination therapy over monotherapy with entecavir or tenofovir
eral neuropathy; frequency of administration should be reduced for will remain challenging. Whereas, initially, in clinical studies of ade-
patients with impaired creatinine clearance. Its excellent potency fovir as rescue therapy for lamividune resistance, adding adefovir to
notwithstanding, the inferior resistance and safety profile of telbivu- lamivudine (combination therapy) was considered a better strategy
dine has limited its appeal; telbivudine is neither recommended as than replacing lamivudine with adefovir monotherapy, according to
first-line therapy nor widely used. the 2016 treatment recommendations of the American Association
for the Study of Liver Diseases (AASLD), data to support adding or
TENOFOVIR switching agents are insufficient. Therefore, while sound virologic
TDF, an acyclic nucleotide analogue and potent antiretroviral agent principles would favor adding as opposed to switching, according
used to treat HIV infection (approved for hepatitis B in 2008), is to current recommendations involving the more potent first-line
similar to adefovir but more potent in suppressing HBV DNA and agents, entecavir for tenofovir resistance and tenofovir for entecavir
inducing HBeAg responses; it is highly active against both wild- resistance, either strategy is acceptable. For patients who already
type and lamivudine-resistant HBV and active in patients whose have acquired multidrug resistance (to both nucleoside analogues
response to adefovir is slow and/or limited. At an oral once-daily [lamivudine, entecavir, telbivudine] and nucleotide analogues [ade-
dose of 300 mg for 48 weeks, tenofovir suppressed HBV DNA fovir, tenofovir]), treatment with a combination of entecavir and
by 6.2 log10 (to undetectable levels [<400 copies/mL] in 76%) in tenofovir has been shown to be highly effective in suppressive HBV
HBeAg-positive patients and by 4.6 log10 (to undetectable levels DNA and overcoming drug resistance.
in 93%) in HBeAg-negative patients; reduced ALT to normal in
NOVEL ANTIVIRALS AND STRATEGIES
68% of HBeAg-positive and 76% of HBeAg-negative patients;
and improved histology in 74% of HBeAg-positive and 72% of In addition to the seven approved antiviral drugs for hepatitis B,
HBeAg-negative patients. In HBeAg-positive patients, HBeAg sero- emtricitabine, a fluorinated cytosine analogue very similar to lami-
conversions occurred in 21% by the end of year 1, 27% by year 2, vudine in structure, efficacy, and resistance profile, offers no advan-
34% by year 3, and 40% by year 5 of tenofovir treatment; HBsAg tage over lamivudine. A combination of emtricitabine and tenofovir
loss occurred in 3% by the end of year 1 and 6% at year 2, and 8% is approved for the treatment of HIV infection and is an appealing
by year 5. After 5 years of tenofovir therapy, 87% of patients expe- combination therapy for hepatitis B, especially for lamivudine-
rienced histologic improvement, including reduction in fibrosis resistant disease; however, neither emtricitabine nor the combination
score (51%) and regression of cirrhosis (71%). The 5-year safety is approved for hepatitis B. Several initially promising antiviral
(negligible renal toxicity, in 1%, and mild reduction in bone density, agents have been abandoned because of toxicity (e.g., clevudine,
in ~0.5%) and resistance profiles (none recorded through 8 years) which was linked to myopathy during its clinical development).
of tenofovir are very favorable as well; therefore, tenofovir has As noted above, the current formulation of tenofovir, TDF, has been
supplanted adefovir both as first-line therapy for chronic hepatitis B associated with renal toxicity and loss of bone density, especially in
and as add-on therapy for lamivudine-resistant chronic hepatitis B. patients with HIV infection, less so in patients with HBV infection.
Studies of tenofovir and entecavir reviewed in 2015 showed no A new formulation, tenofovir alafenamide (TAF), is a prodrug of
difference in long-term risks of renal and bone toxicity; however, tenofovir that is metabolized to the active agent in its target organ
among patients treated with tenofovir, instances of acute renal (the liver for HBV infection); such targeting permits higher dose
failure and of low blood phosphate levels have been reported. delivery to the liver with markedly reduced systemic exposure.
Thus, in patients receiving tenofovir, monitoring bone density is Studies in patients with chronic hepatitis B treated with 25 mg of
not recommended, but periodic (at least annual) monitoring for TAF or 300 mg of TDF demonstrate comparable virologic efficacy
renal injury is (serum creatinine and phosphate, urine glucose and as well as less reduction in bone mineral density and estimated
protein). Frequency of tenofovir administration should be reduced glomerular filtration rate for TAF. Based on its better renal and bone
for patients with impaired creatinine clearance. safety profile than TDF, TAF has been approved for HBV infection

2382 TABLE 334-3 Comparison of Pegylated Interferon (PEG IFN), Lamivudine, Adefovir, Entecavir, Telbivudine, and Tenofovir Therapy for
Chronic Hepatitis Ba
FEATURE PEG IFNB LAMIVUDINE ADEFOVIR ENTECAVIR TELBIVUDINE TENOFOVIR
Route of administration Subcutaneous Oral Oral Oral Oral Oral
injection
Duration of therapyc 48–52 weeks ≥52 weeks ≥48 weeks ≥48 weeks ≥52 weeks ≥48 weeks
Tolerability Poorly tolerated Well tolerated Well tolerated; Well tolerated Well tolerated Well tolerated;
creatinine monitoring creatinine monitoring
recommended recommended
HBeAg seroconversion
1 yr Rx 18–20% 16–21% 12% 21% 22% 21%
>1 yr Rx NA up to 50% @ 5 yrs 43% @ 3 yrsd 31% @ 2 yrs 30% @ 2 yrs 40% @ 5 yrs
44% @ 6 yrs
Log10 HBV DNA reduction
(mean copies/mL)
HBeAg-reactive 4.5 5.5 median 3.5–5 6.9 6.4 6.2
HBeAg-negative 4.1 4.4–4.7 median 3.5–3.9 5.0 5.2 4.6
HBV DNA PCR negative
(<300–400 copies/mL;
<1000 copies/mL for
adefovir) at end of yr 1
HBeAg-reactive 10–25% 36–44% 13–21% 67% (91% @ 4 yrs) 60% 76%
HBeAg-negative 63% 60–73% 48–77% 90% 88% 93%
ALT normalization at end
of yr 1
HBeAg-reactive 39% 41–75% 48–61% 68% 77% 68%
HBeAg-negative 34–38% 62–79% 48–77% 78% 74% 76%
HBsAg loss yr 1 3–4% ≤1% 0% 2% <1% 3%
PART 10
>yr 1 12% 5 yr after No data 5% at yr 5 6% at yr 6 No data 8% at yr 5

1 yr of Rx
Histologic improvement
(≥2 point reduction in HAI)
at yr 1
HBeAg-reactive 38% 6 months 49–62% 53–68% 72% 65% 74%

after
HBeAg-negative 48% 6 months 61–66% 64% 70% 67% 72%
after
Viral resistance None 15–30% @ 1 yr None @ 1 yr ≤1% @ 1 yre Up to 5% @ yr 1 0% @ yr 1
70% @ 5 yrs 29% @ 5 yrs 1.2% @ 6 yrse Up to 22% @ yr 2 0% through yr 8
Pregnancy category C Cf C C B B
Cost (US$) for 1 yr ~$18,000 ~$2,500 ~$6,500 ~$8,700g ~$6,000 ~$6,000
a
Generally, these comparisons are based on data on each drug tested individually versus placebo in registration clinical trials; because, with rare exception, these
comparisons are not based on head-to-head testing of these drugs, relative advantages and disadvantages should be interpreted cautiously. bAlthough standard
interferon α administered daily or three times a week is approved as therapy for chronic hepatitis B, it has been supplanted by PEG IFN, which is administered
once a week and is more effective. Standard interferon has no advantages over PEG IFN. cDuration of therapy in clinical efficacy trials; use in clinical practice may
vary. dBecause of a computer-generated randomization error that resulted in misallocation of drug versus placebo during the second year of clinical trial treatment,
the frequency of HBeAg seroconversion beyond the first year is an estimate (Kaplan-Meier analysis) based on the small subset in whom adefovir was administered
correctly. e7% during a year of therapy (43% at year 4) in lamivudine-resistant patients. fDespite its Class C designation, lamivudine has an extensive pregnancy safety
record in women with HIV/AIDS. gApproximately $17,400 for lamivudine-refractory patients.
Abbreviations: ALT, alanine aminotransferase; HAI, histologic activity index; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus;
NA, not applicable; PEG IFN, pegylated interferon; PCR, polymerase chain reaction; Rx, therapy; yr, year.
and provides an alternative to TDF in patients with TDF-associated competitive, unless it can be shown to go beyond current antivirals
elevations in serum creatinine and/or reductions in serum phospho- in achieving recovery (HBsAg seroconversion) from HBV infection.
rus. Direct-acting antivirals (DAAs) have been very successful in the Finally, initial emphasis in the development of antiviral therapy
management of chronic hepatitis B; however, most patients require for hepatitis B was placed on monotherapy; whether combination
long-duration, usually indefinite, therapy. Ideally, an approach to regimens will yield additive or synergistic efficacy remains to be
achieving “cure” (eradication of HBV infection) with finite-duration determined.
therapy would be welcome. Currently, innovative approaches being
investigated include viral entry inhibitors, nucleocapsid assembly TREATMENT RECOMMENDATIONS
inhibitors, HBV secretion (HBsAg release) inhibitors, immunomod- Several learned societies and groups of expert physicians have
ulators (e.g., toll receptor agonists, T-cell vaccines, programmed issued treatment recommendations for patients with chronic
cell death [PD-1] blockade, reconstitution of innate and adap- hepatitis B; the most authoritative and updated (and free of finan-
tive immune responses, HBV mRNA recognition and activation of cial support by pharmaceutical companies) are those of the AASLD
innate immune signaling by retinoic acid-inducible gene-I [RIG-I]), and of the European Association for the Study of the Liver (EASL).
covalently closed circular (ccc) DNA silencing/inhibition/cleavage, Although the recommendations differ slightly, a consensus has
RNA interference, and HBx inhibitors. While data supporting sev- emerged on most of the important points (Table 334-4). No treat-
eral of these unconventional approaches have begun to appear, ment is recommended or available for inactive “nonreplicative”
none has been shown to “cure” hepatitis B, and none is likely to be hepatitis B carriers (undetectable HBeAg with normal ALT and HBV

0 for those >40 years of age, ALT persistently at the high end of the 2383
twofold range, and/or with a family history of HCC, especially if the
–1 liver biopsy shows moderate to severe necroinflammatory activity
or fibrosis. In this group, when, eventually, ALT becomes elevated
Log10 HBV DNA –2
later in life, antiviral therapy should be instituted. For patients with
–3 HBeAg-negative chronic hepatitis B, ALT >2 × the upper limit of
normal (above the upper limit of normal according to EASL), and
–4 –3.5
HBV DNA >2 × 103 IU/mL, antiviral therapy is recommended. If
–5 –4.5 HBV DNA is >2 × 103 IU/mL and ALT is 1 to >2 × the upper limit
of normal, liver biopsy should be considered to help in arriving at
–6 –5.5 a decision to treat if substantial liver injury is present (treatment in
–6.2 this subset would be recommended according to EASL guidelines,
–6.4
–7 because ALT is elevated). Per current AASLD recommendations,
–6.9
antiviral treatment with oral agents can be stopped after HBeAg
ADV PEG IFN LAM TDF TBV ETV
seroconversion in noncirrhotics, and the suggested period of con-
FIGURE 334-1 Relative potency of antiviral drugs for hepatitis B, as reflected by solidation therapy is 12 months with close monitoring for recurrent
median log10 HBV DNA reduction in HBeAg-positive chronic hepatitis B. These viremia (monthly × 6, then every 3 months for the rest of a year) after
data are from individual reports of large, randomized controlled registration trials
that were the basis for approval of the drugs. In most instances, these data do not cessation of therapy. For patients with HBeAg-negative chronic hep-
represent direct comparisons among the drugs, because study populations were atitis, the current recommendation with oral agents is for indefinite
different, baseline patient variables were not always uniform, and the sensitivity therapy; although sufficient data are lacking, stopping therapy in
and dynamic range of the HBV DNA assays used in the trials varied. ADV, adefovir this group can be considered after HBsAg loss.
dipivoxil; ETV, entecavir; LAM, lamivudine; PEG IFN, pegylated interferon α2a; TBV, For patients with compensated cirrhosis, because antiviral ther-
telbivudine; TDF, tenofovir disoproxil fumarate. apy has been shown to retard clinical progression, treatment is
recommended regardless of HBeAg status and ALT as long as HBV
DNA ≤103 IU/mL documented serially over time). In patients with DNA is detectable at >2 × 103 IU/mL (detectable at any level accord-
detectable HBeAg and HBV DNA levels >2 × 104 IU/mL, treatment ing to the EASL); monitoring without therapy is recommended for
is recommended by the AASLD for those with ALT levels above those with HBV DNA <2 × 103 IU/mL, unless ALT is elevated. For
2 × the upper limit of normal. (The EASL recommends treatment patients with decompensated cirrhosis, treatment is recommended

in HBeAg-positive patients for HBV DNA levels >2 × 103 IU/mL regardless of serologic and biochemical status, as long as HBV DNA
and ALT above the upper limit of normal.) For HBeAg-positive is detectable. Patients with decompensated cirrhosis should be eval-
patients with ALT ≤2 × the upper limit of normal, in whom sustained uated as candidates for liver transplantation.
responses are not likely and who would require multiyear therapy, Among the seven available drugs for hepatitis B, PEG IFN has
antiviral therapy is not recommended currently. This pattern is supplanted standard IFN, entecavir has supplanted lamivudine,
common during the early decades of life among Asian patients and tenofovir has supplanted adefovir. PEG IFN, entecavir, or
infected at birth; even in this group, therapy would be considered tenofovir is recommended as first-line therapy (Table 334-3). PEG
TABLE 334-4 Recommendations for Treatment of Chronic Hepatitis Ba

HBeAg STATUS CLINICAL HBV DNA (IU/mL) ALT RECOMMENDATION
HBeAg-reactive b
>2 × 104 ≤2 × ULNc,d No treatment; monitor. In patients >40, with family history of
hepatocellular carcinoma, and/or ALT persistently at the high end
of the twofold range, liver biopsy may help in decision to treat
Chronic hepatitis >2 × 104d >2 × ULNd Treate
Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
Cirrhosis decompensated <2 × 103 >ULN Consider treatmentf
Detectable < or > ULN Treate with oral agentsg, not PEG IFN; refer for liver transplantation
Undetectable < or > ULN Observe; refer for liver transplantation
HBeAg-negative b
≤2 × 103 ≤ULN Inactive carrier; treatment not necessary
Chronic hepatitis >103 1 to >2 × ULNd Consider liver biopsy; treath if biopsy shows moderate to severe
inflammation or fibrosis
Chronic hepatitis >104 >2 × ULNd Treath,i
Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
<2 × 103 >ULN Consider treatmentf
Cirrhosis decompensated Detectable < or > ULN Treath with oral agentsg, not PEG IFN; refer for liver transplantation
Undetectable < or > ULN Observe; refer for liver transplantation
a
Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD). Except as indicated in footnotes, these guidelines are similar to
those issued by the European Association for the Study of the Liver (EASL). bLiver disease tends to be mild or inactive clinically; most such patients do not undergo
liver biopsy. cThis pattern is common during early decades of life in Asian patients infected at birth. dAccording to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/
mL and ALT >ULN. eOne of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line therapy (see text). These
oral agents, but not PEG IFN, should be used for interferon-refractory/intolerant and immunocompromised patients. PEG IFN is administered weekly by subcutaneous
injection for a year; the oral agents are administered daily for at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion.
f
According to EASL guidelines, patients with compensated cirrhosis and detectable HBV DNA at any level, even with normal ALT, are candidates for therapy. Most
authorities would treat indefinitely, even in HBeAg-positive disease after HBeAg seroconversion. gBecause the emergence of resistance can lead to loss of antiviral
benefit and further deterioration in decompensated cirrhosis, a low-resistance regimen is recommended—entecavir or tenofovir monotherapy or combination therapy
with the more resistance-prone lamivudine (or telbivudine) plus adefovir. Therapy should be instituted urgently. hBecause HBeAg seroconversion is not an option, the
goal of therapy is to suppress HBV DNA and maintain a normal ALT. PEG IFN is administered by subcutaneous injection weekly for a year; caution is warranted in relying
on a 6-month posttreatment interval to define a sustained response, because the majority of such responses are lost thereafter. Oral agents, entecavir or tenofovir, are
administered daily, usually indefinitely or until, as very rarely occurs, virologic and biochemical responses are accompanied by HBsAg seroconversion. iFor older patients
and those with advanced fibrosis, consider lowering the HBV DNA threshold to >2 × 103 IU/mL.
Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EASL, European Association for the Study of the Liver;
HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PEG IFN, pegylated interferon; ULN, upper limit of normal.

2384 IFN requires finite-duration therapy, achieves the highest rate of pooled rate of durable biochemical remission after therapy in this
HBeAg responses after a year of therapy, and does not support viral population was 76%. Even for HBeAg-negative chronic hepatitis B,
mutations, but it requires subcutaneous injections and is associated for which most authorities recommend indefinite therapy, pooled
with inconvenience, more intensive clinical and laboratory moni- rates of virologic remissions maintained after cessation of oral-agent
toring, and intolerability. Oral nucleoside analogues require long- therapy were 44%, 31%, and 30% at posttreatment months 12, 24,
term therapy in most patients, and when used alone, lamivudine and 36, and the pooled rate of durable biochemical remission in this
and telbivudine foster the emergence of viral mutations, adefovir population was 57%.
somewhat less so, and entecavir (except in lamivudine-experienced Although adefovir and tenofovir are safe, renal monitoring (e.g.,
patients) and tenofovir rarely at all. Oral agents do not require serum creatinine and phosphate, urine glucose and protein) is rec-
injections or cumbersome laboratory monitoring, are very well tol- ommended. Substantial experience with lamivudine during preg-
erated, lead to improved histology in 50−90% of patients, suppress nancy (see above) has identified no teratogenicity; although widely
HBV DNA more profoundly than PEG IFN, and are effective even used during pregnancy, lamivudine remains classified as pregnancy
in patients who fail to respond to IFN-based therapy. Although category C. Although IFNs do not appear to cause congenital anom-
oral agents are less likely to result in HBeAg responses during alies, these have antiproliferative properties and should be avoided
the first year of therapy, as compared to PEG IFN, treatment with during pregnancy. Adefovir during pregnancy has not been associ-
oral agents tends to be extended beyond the first year and, by the ated with birth defects; however, the risk of spontaneous abortion
end of the second year, yields HBeAg responses (and even HBsAg may be increased, and adefovir is categorized as pregnancy cate-
responses) comparable in frequency to those achieved after 1 year gory C. Data on the safety of entecavir during pregnancy have not
of PEG IFN (and without the associated side effects) (Table 334-5). been published (pregnancy category C). Sufficient data in animals
In a 2016 systematic review of 1716 patients involved in 25 clinical and limited data in humans suggest that telbivudine and tenofovir
trials, responses after oral-agent therapy were found to be durable. (both pregnancy category B) can be used safely during pregnancy;
Among patients with HBeAg-reactive chronic hepatitis B, the pooled however, telbivudine is not an acceptable first-line drug. In general,
rates of durable HBeAg seroconversions maintained after cessation then, except for lamivudine and tenofovir, and until additional
of nucleoside/nucleotide analogue therapy (including all the oral data become available, the other antivirals for hepatitis B should be
agents) were 92% and 88% at posttreatment months 12 and 24, avoided or used with extreme caution during pregnancy.
respectively, unaffected by the duration of post-HBeAg-response For children aged 2 to <18 with HBeAg-reactive hepatitis B (most
consolidation therapy (>6 months in all studies evaluated); the children will be HBeAg-reactive; no studies have been done in
children with HBeAg-negative chronic hepatitis B), treatment is rec-
TABLE 334-5 Pegylated Interferon Versus Oral Nucleoside Analogues ommended if HBV DNA is detectable and ALT levels are elevated,
PART 10
for the Treatment of Chronic Hepatitis B but not if ALT levels are normal. Each of the available drugs, except
NUCLEOSIDE
telbivudine, is approved for different childhood age groups (stan-
PEG IFN ANALOGUES dard IFN α-2b age ≥1 year; PEG IFN α-2a age ≥5 years [approved
Administration Weekly injection Daily, orally for hepatitis C, not B, but can be used in hepatitis B]; lamivudine
and entecavir age ≥2 years; adefovir and tenofovir age ≥12 years).
Tolerability Poorly tolerated, Well tolerated, limited

intensive monitoring monitoring Package inserts should be consulted for childhood doses.
Duration of therapy Finite 48 weeks ≥1 year, indefinite in
As noted above, some physicians prefer to begin with PEG IFN,
most patients while other physicians and patients prefer oral agents as first-line
Maximum mean HBV DNA 4.5 log10 6.9 log10 therapy. For patients with decompensated cirrhosis, the emergence
suppression of resistance can result in further deterioration and loss of antiviral
Effective in high-level HBV DNA No Yes effectiveness. Therefore, in this patient subset, the threshold for rely-
(≥109 IU/mL) ing on therapy with a very favorable resistance profile (e.g., entecavir
HBeAg seroconversion or tenofovir) or on combination therapy is low. PEG IFN should not
During 1 year of therapy ~30% ~20% be used in patients with compensated or decompensated cirrhosis.
During >1 year of therapy Not applicable 30% (year 2) to up to
For patients with end-stage chronic hepatitis B who undergo liver
50% (year 5) transplantation, reinfection of the new liver is almost universal in
HBeAg-negative posttreatment 17% @ 5 years 7% @ 4 years the absence of antiviral therapy. The majority of patients become
HBV DNA suppression (lamivudine) high-level viremic carriers with minimal liver injury. Before the
HBsAg loss availability of antiviral therapy, an unpredictable proportion experi-
During 1 year of therapy 3–4% 0–3%
enced severe hepatitis B−related liver injury, sometimes a fulminant-
like hepatitis and sometimes a rapid recapitulation of the original
During >1 year of therapy Not applicable 3–8% @ 5 years of
therapy severe chronic hepatitis B (Chap. 332). Currently, however, pre-
vention of recurrent hepatitis B after liver transplantation has been
After 1 year of 12% @ 5 years 3.5% @ 5 years
therapy–HBeAg-negative achieved definitively by combining hepatitis B immune globulin with
Antiviral resistance None Lamivudine: ~30%
one of the low-resistance oral nucleoside (entecavir) or nucleotide
year 1, ~70% year 5 analogues (tenofovir) (Chap. 338); preliminary data suggest that the
Adefovir: 0% year 1, newer, more potent, and less resistance-prone oral agents may be
~30% year 5 used instead of hepatitis B immune globulin for posttransplantation
Telbivudine: up to 4% therapy. In patients documented at the time of liver transplantation
year 1, 22% year 2 to have undetectable HBV DNA in serum and cccDNA in the liver
Entecavir: ≤1.2% (i.e., with low risk for recurrence of HBV infection), a preliminary
through year 6 clinical trial suggested that, after patients received 5 years of com-
Tenofovir: 0% through bined therapy, both hepatitis B immune globulin and oral-agent
year 8 therapy can be withdrawn sequentially (over two 6-month periods)
Use in cirrhosis, No Yes with a success rate, as monitored over a median of 6 years postwith-
transplantation, drawal, of 90% and an anti-HBs seroconversion rate of 60% (some
immunosuppressed with transient reappearance of HBV DNA and/or HBsAg).
Cost, 1 year of therapy ++++ + to ++ Patients with HBV-HIV co-infection can have progressive HBV-
Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, associated liver disease and, occasionally, a severe exacerbation of
hepatitis B surface antigen; PEG IFN, pegylated interferon. hepatitis B resulting from immunologic reconstitution following

ART. Lamivudine should never be used as monotherapy in patients may become indolent after several years of infection. A distinguishing 2385
with HBV-HIV infection because HIV resistance emerges rapidly to serologic feature of chronic hepatitis D is the presence in the circulation
both viruses. Adefovir has been used successfully to treat chronic of antibodies to liver-kidney microsomes (anti-LKM); however, the
hepatitis B in HBV-HIV co-infected patients but is no longer con- anti-LKM seen in hepatitis D, anti-LKM3, are directed against uridine
sidered a first-line agent for HBV. Entecavir has low-level activity diphosphate glucuronosyltransferase and are distinct from anti-LKM1
against HIV and can result in selection of HIV resistance; therefore, seen in patients with autoimmune hepatitis and in a subset of patients
it should be avoided in HBV-HIV co-infection. Tenofovir and the with chronic hepatitis C (see below). The clinical and laboratory
combination of tenofovir and emtricitabine in one pill are approved features of chronic HDV infection are summarized in Chap. 332.
therapies for HIV and represent excellent choices for treating HBV
infection in HBV-HIV co-infected patients. Generally, even for
HBV-HIV co-infected patients who do not yet meet treatment criteria
TREATMENT
for HIV infection, treating for both HBV and HIV is recommended. Chronic Hepatitis D
Patients with chronic hepatitis B who undergo cytotoxic chemo-
therapy for treatment of malignancies as well as patients treated Management is not well defined, and the host cellular RNA poly-
with immunosuppressive, anticytokine, or antitumor necrosis factor merase upon which HDV replication depends cannot be targeted
therapies (the risk varies, from highest [e.g., B-cell-depleting agents, by conventional antiviral agents. Glucocorticoids are ineffective and
anthracycline derivatives, moderate/high-dose corticosteroids for are not used. Preliminary experimental trials of IFN-α suggested
≥4 weeks] to moderate [e.g., tumor necrosis factor alpha inhib- that conventional doses and durations of therapy lower levels of
itors, cytokine or integrin inhibitors, tyrosine kinase inhibitors, HDV RNA and aminotransferase activity only transiently during
low-dose corticosteroids for ≥4 weeks], to lowest [e.g., immunosup- treatment but have no impact on the natural history of the disease.
pressive agents like methotrexate and azathioprine, intraarticular In contrast, high-dose IFN-α (9 million units three times a week) for
corticosteroids, any dose of corticosteroids for ≤1 week]) experience 12 months was reported to be associated with a sustained loss of
enhanced HBV replication and viral expression on hepatocyte mem- HDV replication and clinical improvement in up to 50% of patients.
branes during chemotherapy coupled with suppression of cellular Moreover, in anecdotal reports, the beneficial impact of treatment
immunity. When chemotherapy is withdrawn, such patients are has been observed to persist for 15 years and to be associated with
at risk for reactivation of hepatitis B, often severe and occasionally a reduction in grade of hepatic necrosis and inflammation, rever-
fatal. Such rebound reactivation represents restoration of cytolytic sion of advanced fibrosis (improved stage), and clearance of HDV
T cell function against a target organ enriched in HBV expression. RNA in some patients. A suggested approach to therapy has been

Preemptive treatment with the first of the oral HBV antivirals, lami- high-dose, long-term IFN for at least a year and, in responders,
vudine, prior to the initiation of chemotherapy was shown to reduce extension of therapy until HDV RNA and HBsAg clearance; how-
the risk of such reactivation substantially; treating after reactivation ever, extension of therapy to a second year provided no advantage,
has occurred is less effective. The newer, more potent oral antiviral and sustained responses after completion of therapy have been rare.
agents, entecavir and tenofovir, which are even more effective in PEG IFN has also been shown to be more effective in the treatment
preventing hepatitis B reactivation and with a lower risk of antiviral of chronic hepatitis D (e.g., after 48 weeks of therapy, associated
drug resistance, are preferred. The optimal duration of antiviral ther- with undetectable HDV RNA, durable for at least 24 posttreatment
apy after completion of chemotherapy is not known, but a suggested weeks, in a quarter to a half of patients) and is a more convenient
approach is 6 months (12 months for B-cell-depleting agents) for replacement for standard IFN; however, loss of virologic responses
inactive hepatitis B carriers and longer-duration therapy in patients (reappearance of HDV RNA) was observed during long-term
with baseline HBV DNA levels >2 × 103 IU/mL, until standard clin- (median 4.5-year) monitoring in over half of initial, 24-week-post-
ical endpoints are met (Table 334-4). Such chemotherapy-associated treatment responders. Even extending PEG IFN therapy for 5 years
reactivation of hepatitis B is common (4–68%, median 25%, in a and driving treatment doses up to 270 μg weekly (of PEG IFN- α2a),
meta-analysis) in persons with ongoing HBV infection (HBsAg- as reported in a small trial among 13 patients, while achieving sero-
reactive); however, such reactivation can occur albeit less commonly logic, virologic, histologic, biochemical, and clinical improvement,
in persons who have cleared HBsAg, but express anti-HBc (moderate yielded sustained virologic responses (SVRs) in only 3 patients (58–
risk, <10%) and rarely (<5%) even in persons with serologic evi- 246 weeks of posttreatment observation). None of the nucleoside
dence of recovery from HBV infection (anti-HBs-reactive, anti-HBc- analogue antiviral agents for hepatitis B is effective in hepatitis D,
reactive). Therefore, most authorities (e.g., Centers for Disease Con- and adding oral nucleoside agents to PEG IFN is no more effective
trol and Prevention; AASLD; American Gastroenterological Associa- than PEG IFN monotherapy. While recommended, PEG IFN therapy
tion; EASL) recommend HBsAg and anti-HBc (± anti-HBs) screening is far from satisfactory. Preliminary trials have been performed with
of all patients undergoing such chemotherapy and preemptive an oral prenylation inhibitor, lonafarnib, and with an inhibitor of
antiviral prophylaxis for HBsAg-reactive persons and close on- HBV/HDV viral entry into hepatocytes, myrcludex B. Prenylation,
therapy monitoring of anti-HBc-reactive/anti-HBs-reactive persons the posttranslational covalent addition of the prenyl lipid farnesyl
with treatment if and when reactivation occurs. to large HDV antigen, is required for this HDV protein to interact
and form secreted viral particles with HBsAg. In 14 patients treated
twice daily for 28 days with 100 or 200 mg of lonafarnib, HDV RNA
■■CHRONIC HEPATITIS D (DELTA HEPATITIS) fell by 0.73 log10 IU/mL and 1.54 log10 IU/mL, respectively, before
Chronic hepatitis D virus (HDV) may follow acute co-infection with HBV rebounding after completion of therapy. Hepatitis B virus entry into
but at a rate no higher than the rate of chronicity of acute hepatitis B. hepatocytes requires the binding of the myristolated N-terminal pre-
That is, although HDV co-infection can increase the severity of acute S1 peptide of large HBsAg to sodium taurocholate co-transporting
hepatitis B, HDV does not increase the likelihood of progression to peptide, the functional receptor for HBV into hepatocytes. The appli-
chronic hepatitis B. When, however, HDV superinfection occurs in a cation of myrcludex B, a synthetic homologous myristolated lipo-
person who is already chronically infected with HBV, long-term HDV peptide that competes for binding with HBsAg, was reported in a
infection is the rule, and a worsening of the liver disease is the expected study of 24 patients (with a baseline mean of 4.1–4.2 log10 copies/mL
consequence. Except for severity, chronic hepatitis B plus D has simi- of HDV RNA) randomized to 24 weeks of treatment with myrcludex
lar clinical and laboratory features to those seen in chronic hepatitis B (2 mg daily subcutaneously) as monotherapy or combined with
B alone. Relatively severe and progressive chronic hepatitis, with or PEG IFN compared to PEG IFN alone. A reduction in HDV RNA
without cirrhosis, is the rule, and mild chronic hepatitis is the excep- occurred in all three groups, by 1.67 log10 copies/mL (in two of eight
tion. Occasionally, however, mild hepatitis or even, rarely, inactive car- patients RNA became undetectable), 2.59 log10 copies/mL (in five of
riage occurs in patients with chronic hepatitis B plus D, and the disease eight patients RNA became undetectable), and 2.17 log10 copies/mL

2386 (in two of eight patients RNA became undetectable), respectively. chronic hepatitis C in a majority of patients is relatively benign.
No change occurred, however, in the level of HBsAg, which would Mortality >10−20 years among patients with transfusion-associated
have been expected. In these two exploratory brief-duration trials, chronic hepatitis C has been shown not to differ from mortality in a
sustained responses were not achieved, and toxicities were encoun- matched population of transfused patients in whom hepatitis C did not
tered (e.g., intermittent vomiting and weight loss [lonafarnib] and develop. Although death in the hepatitis group is more likely to result
transient amylase and lipase elevations [myrcludex B]); however, from liver failure, and although hepatic decompensation may occur in
from these proof-of-principle trials, potentially, more definitive and ~15% of such patients over the course of a decade, the majority (almost
larger-scale studies will follow. 60%) of patients remain asymptomatic and well compensated, with
In patients with end-stage liver disease secondary to chronic no clinical sequelae of chronic liver disease. Overall, chronic hepatitis
hepatitis D, liver transplantation has been effective. If hepatitis D C tends to be very slowly and insidiously progressive, if at all, in the
recurs in the new liver without the expression of hepatitis B vast majority of patients, whereas in approximately one-fourth of cases,
(an unusual serologic profile in immunocompetent persons but chronic hepatitis C will progress eventually to end-stage cirrhosis. In
common in transplant patients), liver injury is limited. In fact, the fact, because HCV infection is so prevalent, and because a proportion
outcome of transplantation for chronic hepatitis D is superior to of patients progress inexorably to end-stage liver disease, hepatitis C
that for chronic hepatitis B; in such patients, combination hepatitis is the most frequent indication for liver transplantation (Chap. 338). In
B immune globulin and nucleoside analogue therapy for hepatitis B the United States, hepatitis C accounts for up to 40% of all chronic liver
is indicated (Chap. 338). disease; as of 2007, mortality caused by hepatitis C surpassed that associ-
ated with HIV/AIDS, and as of 2012, reported deaths caused by hepatitis
C surpassed those associated with all other notifiable infectious diseases
■■CHRONIC HEPATITIS C (HIV, tuberculosis, hepatitis B, and 57 other infectious diseases). More-
Regardless of the epidemiologic mode of acquisition of hepatitis C over, because the prevalence of HCV infection is so much higher in the
virus (HCV) infection, chronic hepatitis follows acute hepatitis C in “baby boomer” cohort born between 1945 and 1965, three-quarters of the
50−70% of cases; chronic infection is common even in those with a return mortality associated with hepatitis C occurs in this age cohort. Referral
to normal in aminotransferase levels after acute hepatitis C, adding up bias may account for the more severe outcomes described in cohorts of
to an 85% likelihood of chronic HCV infection after acute hepatitis C. patients reported from tertiary care centers (20-year progression of ≥20%)
Few clues had emerged to explain host differences associated with versus the more benign outcomes in cohorts of patients monitored from
chronic infection until recently, when variation in a single nucleotide initial blood-product-associated acute hepatitis or identified in commu-
polymorphism (SNP) on chromosome 19, IL28B (which codes for nity settings (20-year progression of only 4−7%). Still unexplained, how-
IFN-λ3), was identified that distinguished between responders and ever, are the wide ranges in reported progression to cirrhosis, from 2%
nonresponders to IFN-based antiviral therapy (see below). The same
PART 10
over 17 years in a population of Irish women with hepatitis C infection

variants correlated with spontaneous resolution after acute infection: acquired from contaminated anti-D immune globulin to 30% over
53% in genotype C/C, 30% in genotype C/T, but only 23% in genotype ≤11 years in recipients of contaminated intravenous immune globulin.
T/T. The association with HCV clearance after acute infection is even Progression of liver disease in patients with chronic hepatitis C has
stronger when IL28B haplotype is combined with haplotype G/G of a been reported to be more likely in patients with older age, longer dura-
SNP near human leukocyte antigen (HLA) Class II DBQ1*03:01. tion of infection, advanced histologic stage and grade, more complex
In patients with chronic hepatitis C followed for 20 years, progression HCV quasispecies diversity, increased hepatic iron, concomitant other
to cirrhosis occurs in about 20−25%. Such is the case even for patients liver disorders (alcoholic liver disease, chronic hepatitis B, hemochro-
with relatively clinically mild chronic hepatitis, including those without matosis, α1 antitrypsin deficiency, and steatohepatitis), HIV infection,
symptoms, with only modest elevations of aminotransferase activity, and obesity. Among these variables, however, duration of infection
and with mild chronic hepatitis on liver biopsy. Even in cohorts of appears to be one of the most important, and some of the others prob-
well compensated patients with chronic hepatitis C referred for clinical ably reflect disease duration to some extent (e.g., quasispecies diver-
research trials (no complications of chronic liver disease and with normal sity, hepatic iron accumulation). No other epidemiologic or clinical
hepatic synthetic function), the prevalence of cirrhosis may be as high as features of chronic hepatitis C (e.g., severity of acute hepatitis, level of
50%. Most cases of hepatitis C are identified initially in asymptomatic aminotransferase activity, level of HCV RNA, presence or absence of
patients who have no history of acute hepatitis C (e.g., those discovered jaundice during acute hepatitis) are predictive of eventual outcome.
while attempting to donate blood, while undergoing lab testing as part Despite the relatively benign nature of chronic hepatitis C over time
of an application for life insurance, or as a result of routine laboratory in many patients, cirrhosis following chronic hepatitis C has been
tests). The source of HCV infection in many of these cases is not defined, associated with the late development, after several decades, of HCC
although a long-forgotten percutaneous exposure (e.g., injection drug (Chap. 78); the annual rate of HCC in cirrhotic patients with hepatitis
use) in the remote past can be elicited in a substantial proportion and C is 1−4%, occurring primarily in patients who have had HCV infection
probably accounts for most infections; most of these infections were for 30 years or more.
acquired in the 1960s and 1970s, coming to clinical attention decades later. Perhaps the best prognostic indicator in chronic hepatitis C is liver
Approximately one-third of patients with chronic hepatitis C have histology; the rate of hepatic fibrosis may be slow, moderate, or rapid.
normal or near-normal aminotransferase activity; although one-third Patients with mild necrosis and inflammation as well as those with
to one-half of these patients have chronic hepatitis on liver biopsy, the limited fibrosis have an excellent prognosis and limited progression to
grade of liver injury and stage of fibrosis tend to be mild in the vast cirrhosis. In contrast, among patients with moderate to severe necro-
majority. In some cases, more severe liver injury has been reported— inflammatory activity or fibrosis, including septal or bridging fibrosis,
even, rarely, cirrhosis, most likely the result of previous histologic activ- progression to cirrhosis is highly likely over the course of 10−20 years.
ity. Among patients with persistent normal aminotransferase activity The pace of fibrosis progression may be accelerated by such factors
sustained over ≥5−10 years, histologic progression has been shown to as concomitant HIV infection, other causes of liver disease, excessive
be rare; however, approximately one-fourth of patients with normal alcohol use, and hepatic steatosis. Among patients with compensated
aminotransferase activity experience subsequent aminotransferase cirrhosis associated with hepatitis C, the 10-year survival rate is close
elevations, and histologic injury can be progressive once abnormal to 80%; mortality occurs at a rate of 2−6% per year; decompensation at
biochemical activity resumes. Therefore, continued clinical monitoring a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4%
and antiviral therapy are indicated, even for patients with normal per year. Estimates of the natural history of chronic hepatitis C have
aminotransferase activity. been made, based on data available on the prevalence of HCV infec-
Despite this substantial rate of progression of chronic hepatitis tion in the U.S. population and on the rate of disease progression.
C, and despite the fact that liver failure can result from end-stage Weighted primarily by the concentration of chronic hepatitis C in the
chronic hepatitis C, the long-term prognosis over 1–2 decades for baby boomer generation, the peak prevalence was estimated to have

occurred in 2015. The calculated frequency of cirrhosis in U.S. patients 2387
Peginterferon and Ribavirin
with hepatitis C was 5% in 1990, 25% in 2010, and is projected to be 7
37% in 2020. Estimated peak mortality has been predicted to occur in
2032. A discussion of the pathogenesis of liver injury in patients with 6
HCV RNA log10 IU/ml

chronic hepatitis C appears in Chap. 332. Null
5
Clinical features of chronic hepatitis C are similar to those described Nonresponse
above for chronic hepatitis B. Generally, fatigue is the most common 4 Partial
symptom; jaundice is rare. Immune complex−mediated extrahepatic Relapse
3
complications of chronic hepatitis C are less common than in chronic
hepatitis B (despite the fact that assays for immune complexes are 2
often positive in patients with chronic hepatitis C), with the exception RVR EVR ETR SVR
1
of essential mixed cryoglobulinemia (Chap. 332), which is linked to Undetectable
cutaneous vasculitis and membranoproliferative glomerulonephritis 0
as well as lymphoproliferative disorders such as B-cell lymphoma and –8 –4 –2 0 4 8 12 16 20 24 32 40 48 52 60 72
unexplained monoclonal gammopathy. In addition, chronic hepatitis Weeks after start of therapy
C has been associated with extrahepatic complications unrelated to FIGURE 334-2 Classification of virologic responses based on outcomes during
immune-complex injury. These include Sjögren’s syndrome, lichen and after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin
planus, porphyria cutanea tarda, type 2 diabetes mellitus, and the antiviral therapy in patients with hepatitis C, genotype 1 or 4 (for genotype
metabolic syndrome (including insulin resistance and steatohepatitis). 2 or 3, the course would be 24 weeks). Nonresponders can be classified as
null responders (hepatitis C virus [HCV] RNA reduction of <2 log10 IU/mL) or
Laboratory features of chronic hepatitis C are similar to those in partial responders (HCV RNA reduction ≥2 log10 IU/mL but not suppressed to
patients with chronic hepatitis B, but aminotransferase levels tend to undetectable) by week 24 of therapy. In responders, HCV RNA can become
fluctuate more (the characteristic episodic pattern of aminotransferase undetectable, as shown with sensitive amplification assays, within 4 weeks (RVR,
activity) and to be lower, especially in patients with long-standing dis- rapid virologic response); can be reduced by ≥2 log10 IU/mL within 12 weeks
ease. An interesting and occasionally confusing finding in patients with (early virologic response, EVR; if HCV RNA is undetectable at 12 weeks, the
chronic hepatitis C is the presence of autoantibodies. Rarely, patients designation is “complete” EVR); or at the end of therapy, 48 weeks (ETR, end-
treatment response). In responders, if HCV RNA remains undetectable for 24 weeks
with autoimmune hepatitis (see below) and hyperglobulinemia have after ETR, week 72, the patient has a sustained virologic response (SVR), but if
false-positive immunoassays for anti-HCV. On the other hand, some HCV RNA becomes detectable again, the patient is considered to have relapsed.
patients with serologically confirmable chronic hepatitis C have circu- The posttreatment week-24 SVR (SVR24) has been supplanted by an SVR at week

lating anti-LKM. These antibodies are anti-LKM1, as seen in patients 12 (SVR12), which has been shown to be equivalent to an SVR24. In patients
with autoimmune hepatitis type 2 (see below), and are directed against treated with DAA therapy, RVR and EVR milestones are largely irrelevant, being
a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence of met by almost all patients. (Reproduced with permission, courtesy of Marc G.
Ghany, National Institute of Diabetes and Digestive and Kidney Diseases, National
anti-LKM1 in some patients with chronic hepatitis C may result from Institutes of Health and the American Association for the Study of Liver Diseases.
the partial sequence homology between the epitope recognized by Hepatology 49:1335, 2009.)
anti-LKM1 and two segments of the HCV polyprotein. In addition, the
presence of this autoantibody in some patients with chronic hepatitis C
suggests that autoimmunity may be playing a role in the pathogenesis not increasing the dose or changing IFN preparations—increased
of chronic hepatitis C. the SVR rate to ~20%, and addition to the regimen of daily ribavirin,
Histopathologic features of chronic hepatitis C, especially those that an oral guanosine nucleoside, increased the SVR rate to 40%. When
distinguish hepatitis C from hepatitis B, are described in Chap. 332. used alone, ribavirin is ineffective and does not reduce HCV RNA
levels appreciably, but ribavirin enhances the efficacy of IFN by
reducing the likelihood of virologic relapse after the achievement of
TREATMENT an end-treatment response (Fig. 334-2) (response measured during,
Chronic Hepatitis C and maintained to the end of, treatment). Proposed mechanisms
to explain the role of ribavirin include subtle direct reduction of
Therapy for chronic hepatitis C has evolved substantially in the HCV replication, inhibition of host inosine monophosphate dehy-
25 years since IFN-α was introduced for this indication in 1991. The drogenase activity (and associated depletion of guanosine pools),
therapeutic armamentarium grew to include PEG IFN with ribavirin immune modulation, induction of virologic mutational catastrophe,
and, then, in 2011, the introduction of the first protease inhibitors, and enhancement of IFN-stimulated gene expression. Ribavirin,
telaprevir and boceprevir, used in combination with PEG IFN and despite its poorly understood mechanism of action, retains a mod-
ribavirin in patients with HCV genotype 1. The field of antiviral est role in supporting DAA agents as well (see below). IFN therapy
therapy for hepatitis C was transformed beginning in 2013, with the results in activation of the JAK-STAT signal transduction pathway,
approval of the first nucleoside analogue, sofosbuvir. As of 2016, no which culminates in the intracellular elaboration of genes and their
fewer than six, all-oral, highly effective (>95%), low-resistance, well protein products that have antiviral properties. Hepatitis C proteins
tolerated, short-duration (usually 12 weeks) combination regimens inhibit JAK-STAT signaling at several steps along the pathway, and
of DAA drugs are available. The remarkable historical evolution of exogenous IFN restores expression of IFN-stimulated genes and
antiviral therapy for hepatitis C is instructive. their antiviral effects.
Treatment with the combination of PEG IFN and ribavirin
THE INTERFEON ERA (1991–2011) increased responsiveness (frequency of SVR) to as high as 55% over-
IFN-based therapy has been supplanted by DAA agents introduced all—to >40% in genotypes 1 and 4, and to >80% in genotypes 2 and
in the second decade of the twenty-first century; however, many 3. Even in the absence of biochemical and virologic responses, his-
important lessons about antiviral therapy for chronic hepatitis C tologic improvement occurred in approximately three-fourths of all
were learned from the experience with IFN-based treatment, and treated patients. In chronic hepatitis C, ALT levels fall precipitously
many of the limitations of—and disparities in responsiveness to— during therapy, and up to 90% of virologic responses are achieved
IFN-based therapy have been overcome by current-generation DAA within the first 12 weeks of therapy; responses thereafter are rare.
treatments. When first approved, IFN-α was administered via sub- Most relapses occur within the first 12 weeks after treatment; there-
cutaneous injection three times a week for 6 months but achieved fore, an SVR at week 12 posttreatment (SVR12) is roughly equivalent
an SVR (Fig. 334-2) (defined then as a reduction of HCV RNA to to a 24-week SVR, and SVR12 has become the new standard. SVRs
undetectable levels by PCR when measured ≥24 weeks after com- are very durable; normal ALT, improved histology, and absence of
pletion of therapy) <10%. Doubling the duration of therapy—but HCV RNA in serum and liver have been documented a decade after

2388 successful therapy, and “relapses” 2 years after sustained responses Ribavirin can also cause nasal and chest congestion, pruritus, and
are almost unheard of. Thus, an SVR to antiviral therapy of chronic precipitation of gout. Combination IFN-ribavirin therapy is more
hepatitis C is tantamount to a cure, which is followed by marked difficult to tolerate than IFN monotherapy and more likely to lead
improvements in liver-disease outcomes (see below). to dose reductions and discontinuation of therapy.
Patient variables that correlate with sustained virologic respon- Studies of viral kinetics have shown that despite a virion half-life
siveness to IFN-based therapy include favorable genotype (geno- in serum of only 2−3 h, the level of HCV is maintained by a high rep-
types 2 and 3 as opposed to genotypes 1 and 4; genotype 1b as lication rate of 1012 hepatitis C virions per day. IFN-α blocks virion
opposed to genotype 1a); low baseline HCV RNA level (<800,000 production or release with an efficacy that increases with increasing
IU/mL), low HCV quasispecies diversity, and histologically mild drug doses; moreover, the calculated death rate for infected cells
hepatitis and minimal fibrosis, especially absence of cirrhosis; during IFN therapy is inversely related to the level of HCV RNA.
immunocompetence, low liver iron levels, age <40; female gender; Patients with the most rapid death rate of infected hepatocytes are
and absence of obesity, insulin resistance, type 2 diabetes mellitus, more likely to achieve undetectable HCV RNA at 3 months; in prac-
and hepatic steatosis. High levels of HCV RNA, more histologically tice, failure to achieve an early virologic response (EVR), a ≥2-log10
advanced liver disease, and high HCV quasispecies diversity all go reduction in HCV RNA by week 12, predicts failure to experience a
hand in hand with advanced duration of infection and reduced IFN subsequent SVR. Similarly, patients in whom HCV RNA becomes
responsiveness. Also associated with poor responses to IFN-based undetectable within 4 weeks (i.e., who achieve a rapid virologic
therapy are African-American ethnicity (contributed to, but not response [RVR]) have a very high likelihood of achieving an SVR
explained entirely by, a higher proportion with genotype 1, slower (Fig. 334-2). Surprisingly, however, high-dose induction with IFN-
early treatment viral kinetics, impaired HCV-specific immunity, and based therapy did not yield higher SVR rates.
host genetic differences in IL28B alleles, described below), Latino For the treatment of chronic hepatitis C, standard IFNs were
ethnicity, and poor treatment adherence (<80% of IFN and ribavi- supplanted beginning in 2001 by PEG IFNs. These have elimination
rin doses and <80% of prescribed duration of therapy). Ironically, times up to sevenfold longer than standard IFNs (i.e., a substantially
patients whose disease was least likely to progress were the ones longer half-life) and achieve prolonged concentrations, permitting
most likely to respond to IFN and vice versa. For patients treated administration once (rather than three times) a week. Instead of the
with combination IFN-ribavirin, therapy for those with genotype 1 frequent drug peaks (linked to side effects) and troughs (when drug is
usually required a full 48 weeks with SVRs in the range of 40–45%, absent) associated with frequent administration of short-acting IFNs,
whereas in those with genotypes 2 and 3, a 24-week course of administration of PEG IFNs results in drug concentrations that are
therapy sufficed with SVRs in the range of 80% (although refined more stable and sustained over time. Once-a-week PEG IFN mono-
tailoring of treatment duration could be indicated based on rapidity therapy is twice as effective as monotherapy with its standard IFN
PART 10
of response or associated cofactors, see below). counterpart, approaches the efficacy of combination standard IFN
Genetic changes in the virus may explain differences in treatment plus ribavirin, and is as well tolerated as standard IFNs, without more
responsiveness in some patients (e.g., among patients with genotype 1b, difficult-to-manage thrombocytopenia and leukopenia than standard
responsiveness to IFN is enhanced in those with amino-acid- IFNs. For most of the decade prior to 2011, when protease inhibitors
substitution mutations in the nonstructural protein 5A gene). As were introduced for HCV genotype 1 (see below), the standard of care
described above in the discussion of spontaneous recovery from was a combination of PEG IFN plus ribavirin for all HCV genotypes.
acute hepatitis C, IFN gene variants discovered in genome-wide Two PEG IFNs are available: PEG IFN-α2b, a 12-kD, linear PEG
association studies were shown to have a substantial impact on molecule bound to IFN-α2b, and PEG IFN-α2a, a larger, 40-kD,
responsiveness of patients with genotype 1 to antiviral therapy. In branched PEG molecule bound to IFN-α2a; because of its larger
studies of patients treated with PEG IFN and ribavirin, variants of size and smaller volume of extravascular distribution, PEG IFN-α2a
the IL28B SNP that code for IFN-λ3 (a type III IFN, the receptors can be given at a uniform dose independent of weight, whereas the
for which are more discretely distributed than IFN-α receptors dose of the smaller PEG IFN-α2b, which has a much wider volume
and more concentrated in hepatocytes) correlate significantly with distribution, must be weight-based. The standard dose of PEG IFN
responsiveness. Patients homozygous for the C allele at this locus α2a was 180 μg and of PEG IFN-α2b 1.5 μg/kg. The ribavirin dose
have the highest frequency of achieving an SVR (~80%), those adopted for both PEG IFNs was, for genotype 1, 1000 mg (for patients
homozygous for the T allele at this locus are least likely to achieve <75 kg) to 1200 mg (for patients ≥75 kg) and, for genotypes 2 and 3,
an SVR (~25%), and those heterozygous at this locus (C/T) have an 800 mg; a broader ribavirin dose/weight range was approved subse-
intermediate level of responsiveness (SVRs in ~35%). quently for PEG IFN-α2b in patients with genotype 1: <65 kg, 800 mg;
Side effects of IFN therapy are described in the section on 65−85 kg, 1000 mg; >85−105 kg, 1200 mg; and >105 kg, 1400 mg. For
treatment of chronic hepatitis B. The most pronounced side effect both drugs, recommended treatment durations were 48 weeks for
of ribavirin therapy is hemolysis—an expected reduction in hemo- genotype 1 and 24 weeks for genotypes 2 and 3 (somewhat more
globin of up to 2−3 g or in hematocrit of 5−10% but also a small, refractory, justifying a full 48 weeks especially for advanced hepatic
unpredictable proportion with profound, brisk hemolysis, result- fibrosis or cirrhosis and/or high-level HCV RNA). Between the two
ing in symptomatic anemia; therefore, close monitoring of blood PEG IFNs, PEG IFN-α2a appeared to be slightly better tolerated and
counts is crucial, and ribavirin should be avoided in patients slightly more effective than PEG IFN-α2b in registration trials (SVRs
with anemia or hemoglobinopathies; in patients with coronary for genotype 1: 41–51% vs 40–42%, respectively) as well as in sub-
artery disease or cerebrovascular disease, in whom anemia can sequent head-to-head trials and a systematic review of randomized
precipitate an ischemic event; in patients with renal insufficiency trials (SVR in genotypes 1–4: 48–55% vs 32–40%, respectively).
(the drug is excreted renally); and in pregnancy (the drug is terato- Until the 2011 introduction of protease inhibitors, unless ribavi-
genic, mandating scrupulous use of efficient contraception during, rin was contraindicated (see above), combination PEG IFN plus
and for several months after, therapy in women of child-bearing ribavirin was the recommended course of therapy. Even after the
age [because of their antiproliferative properties, IFNs also are introduction of protease inhibitors for genotypes 1 and 4, however,
contraindicated during pregnancy]). When symptomatic anemia PEG IFN–ribavirin remained the standard of care for patients with
occurs, ribavirin dose reductions or addition of erythropoietin to genotypes 2 and 3 until late 2013. For patients treated with combi-
boost red blood cell levels may be required; erythropoietin was nation PEG IFN–ribavirin, measurement of quantitative HCV RNA
shown to improve patients’ quality of life but not the likelihood levels at 12 weeks was helpful in guiding therapy; if a 2-log10 drop in
of achieving an SVR. If ribavirin was stopped during therapy, SVR HCV RNA had not been achieved by this time, chances for an SVR
rates fell, but responsiveness could be maintained as long as ribavi- were negligible, and additional therapy was futile. If the 12-week
rin was not stopped and the total ribavirin dose exceeded 60% of HCV RNA had fallen by 2 log10 (EVR), the chances for an SVR at the
the planned dose. end of therapy were approximately two-thirds; if the 12-week HCV

RNA was undetectable (“complete” EVR), the chances for an SVR Because resistance developed rapidly during monotherapy with 2389
exceeded 80% (Fig. 334-2). telaprevir and boceprevir, these drugs had to be used in combination
The frequency of an SVR to PEG IFN–ribavirin therapy could be with PEG IFN and ribavirin. Ribavirin in particular appeared to reduce
increased by tailoring therapy according to baseline variables and relapse rates significantly in protease inhibitor-based regimens, such
on-treatment virologic responsiveness. In patients with baseline vari- that those who could not take or were intolerant to ribavirin were
ables weighing against a response (e.g., HCV RNA >800,000 IU/mL, unlikely to benefit from the addition of these agents. Telaprevir and
weight >85 kg), by raising the dose of PEG IFN (e.g., to as high as boceprevir regimens consisted of periods of triple therapy (protease
270 μg of PEG IFN-α2a) and/or the dose of ribavirin to as high as inhibitor plus PEG IFN plus ribavirin) and periods of dual therapy
1600 mg daily (if tolerated or supplemented by erythropoietin); or (PEG IFN plus ribavirin). Telaprevir regimens began with 12 weeks of
by extending therapy from 48 to 72 weeks for patients with genotype 1 triple therapy followed by dual therapy of a duration based on HCV
and a slow virologic response (i.e., failure of HCV RNA to fall rap- RNA status at weeks 4 and 12 (“response-guided therapy”) and prior
idly to undetectable levels within 4 weeks [absence of a RVR]), SVR treatment status. Boceprevir-based regimens consisted of a 4-week
rates could be improved somewhat. In contradistinction, in patients lead-in period of dual (PEG IFN–ribavirin) therapy followed by triple
with genotype 1 (and 4) who had a 4-week RVR (which occurred therapy and, in some instances, a further extension of dual therapy,
in ≤20%), especially in the subset with low baseline HCV RNA, with duration of response-guided therapy based on HCV RNA status
abbreviating the duration of therapy to 24 weeks, resulted in SVR at weeks 4, 8, and 24 and prior treatment status.
rates of ~90%. Responsiveness to IFN-ribavirin-based therapy was For patients with HCV genotype 1, protease inhibitors improved
diminished in immunocompromised patients and in patients with the frequency of RVRs and SVRs significantly as compared to
HIV-HCV co-infection and contraindicated in patients with decom- PEG IFN plus ribavirin alone. In treatment-naïve patients, telapre-
pensated liver disease or end-stage renal disease. The cumbersome vir-based SVRs were achieved in up to 79% of patients who received
nature of IFN-ribavirin-based therapy (injections, complicated labo- 12 weeks of triple therapy followed by 12–36 weeks of dual therapy,
ratory monitoring, side effects and poor tolerability, modest efficacy, and among those with EVRs (undetectable HCV RNA at weeks 4
variables and patient subsets associated with poor responsiveness, and 12) and response-guided therapy stopped at week 24 (12 weeks
tailored therapy, futility rules, etc.) was supplanted eventually (in of triple therapy, then 12 weeks of dual therapy), SVRs occurred
2016) by DAAs for all genotypes (see below). Most of the variables in 83–92%. In studies with boceprevir in treatment-naïve patients,
associated with poor responsiveness to IFN-based therapy became SVRs occurred in 59–66% of patients, and among those with unde-
irrelevant, and difficult-to-treat patient subpopulations began to tectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%.
experience responses to DAAs that were indistinguishable from Adding to the complexity of treatment with these protease inhibitors

responses in standard patients (see below). were absolute stopping rules for futility, that is, absence of HCV
Persons with chronic HCV infection have been shown to suffer RNA reductions at critical treatment milestones, which were shown
increased liver-related mortality. On the other hand, successful antivi- to be invariably predictive of nonresponse (telaprevir: HCV RNA
ral therapy of chronic hepatitis C resulting in an SVR has been shown >1000 IU/mL at weeks 4 or 12, or detectable at week 24; boceprevir:
to improve survival (and to reduce the need for liver transplantation); HCV RNA ≥100 IU/mL at week 12, or detectable at week 24).
to lower the risk of liver failure, liver-related death, and all-cause mor- In patients previously treated unsuccessfully with PEG IFN plus
tality; to slow the progression of chronic hepatitis C; and to reverse ribavirin, telaprevir-based treatment achieved SVRs in 83–88% of
fibrosis and even cirrhosis. Whereas the 10-year and 20-year survival prior relapsers, 54–59% of partial responders (HCV RNA reduced
in the absence of an SVR is reduced in cirrhotic patients with chronic by ≥2 log10 IU/mL but not to undetectable levels), and 29–33%
hepatitis C, survival at these intervals after an SVR has been found to of null responders (HCV RNA reduced by <2 log10 IU/mL). With
be indistinguishable from that of the general population. Although boceprevir, a similar degradation in SVR rate occurred as a func-
successful treatment reduces mortality and liver failure (3-4-fold tion of prior responsiveness—in 75% of prior relapsers, in 40–52%
10-year reduction) in cirrhotic patients (and in those with advanced of previous partial responders; in ~30–40% of null responders.
fibrosis) and reduces the need for liver transplantation and the like- In a substantial proportion of protease inhibitor nonresponders,
lihood of HCC (14-fold 10-year reduction), the risk of liver-related resistance-associated substitutions (RASs, previously referred to
death and HCC persists, albeit at a much reduced level, necessitating as resistance-associated variants, RAVs) could be identified, but
continued clinical monitoring and cancer surveillance after SVR in these variants were not archived, and wild-type HCV reemerged in
cirrhotics. On the other hand, in the absence of an SVR, IFN-based almost all cases within 1.5 to 2 years. SVRs to these protease inhib-
therapy does not reduce the risk of HCC. Similarly, for nonresponders itors were highest in prior relapsers and treatment-naïve patients
to PEG IFN–ribavirin therapy, three trials of long-term maintenance (white > black ethnicity), lower in prior partial responders, lower still
therapy with PEG IFN showed no benefit in reducing the risk of his- in prior null responders, and lowest in cirrhotic prior null responders,
tologic progression or clinical decompensation, including the devel- for whom no benefit accrued over PEG IFN/ribavirin treatment.
opment of HCC. Fortunately, PEG IFN-ribavirin nonresponders can Responses to protease inhibitor triple-drug regimens were higher in
now be retreated with DAAs and experience SVR rates comparable to patients with IL28B C than non-C genotypes, HCV genotype 1b than
those in treatment-naïve persons (see below). genotype 1a, less advanced than more advanced fibrosis stage, whites
than blacks, lower body mass index (BMI) than elevated BMI, and,
FIRST-GENERATION PROTEASE INHIBITORS (2011–2013) for boceprevir, achievement of a >1 log10 HCV RNA reduction during
The HCV RNA genome encodes a single polyprotein, which is 4 weeks of PEG IFN–ribavirin lead-in therapy. Age and HCV RNA
cleaved during and after translation by host and viral-encoded pro- level were less influential and insulin resistance was noninfluential
teases. One protease involved in the cleavage of the viral polyprotein on response to these antiviral agents.
is an NS3/4A viral protein that has serine protease activity. Telapre- Both of these protease inhibitors had substantial toxicities. Telapre-
vir and boceprevir are serine protease inhibitors that target NS3/4A. vir was associated with a severe, generalized (trunk and extremi-
In 2011, telaprevir and boceprevir used in combination with PEG ties), often confluent, maculopapular, pruritic rash in ~6% of treated
IFN and ribavirin were approved by the U.S. Food and Drug patients (that required careful dermatologic monitoring in all patients
Administration (FDA) as the first oral DAA agents for the treatment and systemic corticosteroid therapy in the most severely affected).
of hepatitis C genotype 1 (not other genotypes) in adults with stable Other common side effects included pruritus, rectal burning, nausea,
liver disease, both in patients who had not been treated before or diarrhea, fatigue, dysgeusia (altered or unpleasant taste), and anemia,
who had failed previous treatment. Although now replaced by more which required close monitoring, could be relatively refractory, occa-
effective, all-oral regimens, these first-in-class agents represented a sionally requiring transfusion and even hospitalization (especially in
breakthrough in the treatment of chronic hepatitis C and established cirrhotic prior nonresponders). Anemia occurred in half of bocepre-
milestones against which subsequent therapies could be measured. vir-treated patients, neutropenia in up to 30% and thrombocytopenia

2390 in 3–4%. Other side effects of boceprevir include fatigue, nausea, (95% SVR12) patients without cirrhosis and in treatment-naïve (88%
headache, dysgeusia, dry mouth, vomiting, and diarrhea. SVR12) or treatment-refractory (79% SVR12) patients with cirrhosis (it
Both drugs came with an inconveniently high pill burden and remains one of the recommended regimens for genotype 1).
had to be administered every 8 hours with food (TVR with a 20-g Sofosbuvir: Sofosbuvir, the first nonprotease inhibitor DAA to be
fat meal). Use of protease inhibitors was further complicated by approved, has an excellent profile—high potency, high barrier to
numerous drug-drug interactions. As telaprevir and boceprevir are resistance, pangenotypic activity, very well tolerated with limited
both eliminated by and inhibit CYP3A4, these agents could not be adverse effects (most commonly mild fatigue, insomnia, headache,
administered with other medications that induce CYP3A4 or are and nausea), once-daily oral administration, and relative freedom
dependent on CYP3A4 for elimination. Care had to be taken to from major drug-drug interactions. Sofosbuvir has efficacy in all
examine for any potential interactions between these protease inhib- genotypes (1 to 6); in treatment-naïve subjects and prior nonre-
itors and other medications the patient was taking, and a convenient sponders to PEG IFN-based and protease-inhibitor-based therapy;
website became available to check for such drug-drug interactions with PEG IFN-RBV or in IFN-free regimens; in combination with
(www.hep-druginteractions.org). RBV or with NS5A inhibitors; and for treatment periods as brief
Despite the improvement in SVRs with protease-inhibitor-based as 8 to 12 weeks to as long as 24 weeks. Currently, sofosbuvir is
regimens for genotype 1 compared to PEG IFN-ribavirin (e.g., in used in combination with either the protease inhibitor simeprevir
treatment-naïve patients 66–79% vs 38–44%), triple-drug protease- (as described above) or, more commonly, with one of three NS5A
inhibitor therapy was hampered by amplified intolerability, the inhibitors. Thus, sofosbuvir is a component of four of the six rec-
complexity of response-guided regimens and futility stopping rules, ommended DAA regimens for genotype 1, two of the four regimens
the inconvenience of thrice-daily dosing with meals and a high pill for genotype 4, and both of the regimens for genotypes 2, 3, 5, and
burden, the need for PEG IFN injections and ribavirin with all their 6 (Table 334-6).
intolerability, and multiple drug-drug interactions. Moreover, side Sofosbuvir/ledipasvir: The DAA combination that has had a dom-
effects appeared to be more severe and burdensome once these inant role in the treatment of hepatitis C is sofosbuvir (400 mg)
drugs entered practice, especially in cirrhotic nonresponders, in plus the NS5A inhibitor ledipasvir (90 mg) in a once-a-day, fixed-
whom studies reported from Europe showed serious adverse events dose, single pill, approved in October 2014 for genotype 1 and in
in up to 45% and deaths in up to 3%. All these issues, as well as November 2015 for genotypes 4, 5, and 6. Phase-III trials were con-
rapidly accelerating progress on next-generation and all-oral DAA ducted in treatment-naïve noncirrhotic patients, in treatment-naïve
therapy (see below), conspired to temper enthusiasm for these new cirrhotic and noncirrhotic patients, and in treatment-experienced
antivirals; after a brief stint as recommended therapy (2011–2013), cirrhotic and noncirrhotic patients treated for 8, 12, or 24 weeks,
these drugs became obsolete and are no longer recommended. both with and without ribavirin. In treatment-naïve noncirrhotics,
PART 10
an SVR12 was achieved in 97–99% of subjects, and no benefit was

CONTEMPORARY DIRECT-ACTING ANTIVIRAL COMBINATION observed by extending therapy from 12 to 24 weeks or by adding
THERAPY (2013–) ribavirin. Moreover, for treatment-naïve, noncirrhotic patients with
Since late 2013, the number of new antiviral agents for hepatitis C baseline HCV RNA <6 × 106 IU/mL, a treatment duration of 8
has expanded substantially, and, currently, PEG IFN-based treat- weeks was as effective as one of 12 weeks (94–95% SVR12), which
ments have been supplanted by six therapeutic regimens: all oral, may be a consideration for a proportion of patients. In cirrhotic
IFN-free, highly efficacious (>95% SVR), well tolerated, with high patients, SVR12 was achieved in 97–100% of treatment-naïve sub-
barriers to resistance, simple dosing and low pill burdens, treatment jects (no advantage of extending therapy from 12 to 24 weeks or
durations as brief as 8 to 12 weeks, and, in many cases, pangenotypic of adding ribavirin); however, for cirrhotic prior nonresponders to
efficacy (Table 334-6). These drugs are distributed among three IFN-based therapy, 12 weeks of therapy was inferior (86% SVR12)
classes of DAAs: NS3/4 protease inhibitors (which cleave the single to 24 weeks of therapy (100% SVR12). This combination, which is
HCV polyprotein into constituent structural and nonstructural pro- equally effective in patients with HIV-HCV co-infection and in
teins), NS5B nucleoside and nonnucleoside polymerase inhibitors African-American patients, has been shown to be highly effective
(which interfere with the RNA-dependent RNA polymerase [a in patients with decompensated cirrhosis and in patients with
replicase] involved in synthesis of viral RNA), and NS5A inhibitors hepatitis C after liver transplantation and after kidney transplan-
(which interfere with a membrane-associated phosphoprotein essen- tation. On the other hand, the safety and efficacy of sofosbuvir/
tial to the HVC RNA replication complex). ledipasvir in patients with advanced renal failure have not been
The first of the new DAA agents (approved in November 2013) was established, and all sofosbuvir-containing regimens can be associ-
simeprevir, a second-generation protease inhibitor for genotype 1, ated with severe bradycardia in patients taking the antiarrhythmic
followed shortly thereafter (December 2013) by sofosbuvir, a pange- agent amiodarone, especially along with beta blockers; sofosbuvir-
notypic nucleoside polymerase inhibitor. For genotype 1, both of containing combinations are contraindicated with amiodarone.
these agents had to be combined with PEG IFN and ribavirin; for Drug-drug interactions are few, but P-gp inducers, like St. John’s
genotypes 2 and 3, sofosbuvir was administered with ribavirin, wort and rifampin, and proton-pump gastric acid inhibitors, like
without PEG IFN; however, these treatment regimens have been omeprazole, may reduce sofosbuvir/ledipasvir concentrations.
supplanted by combinations of all-oral, IFN-free, DAAs, and ribavi- Generally, responsiveness to sofosbuvir/ledipasvir is not reduced
rin is rarely needed, retained only for very limited indications. in patients with baseline RASs to these agents, with the exception
Simeprevir: When simeprevir was used with PEG IFN, its effi- of treatment-experienced patients who have baseline NS5A RASs
cacy (genotype 1b > 1a) was similar to that of first-generation pro- (for whom EASL recommends adding ribavirin or, if ribavirin in
tease inhibitors, but required only once-a-day dosing without the contraindicated, extending treatment to 24 weeks).
complexity of response-guided therapy. Similar to first-generation Paritaprevir/ritonavir, ombitasvir, and dasabuvir: The combination of
protease inhibitors, simeprevir was hampered by many drug-drug ritonavir (100 mg)-boosted paritaprevir (150 mg), a protease inhib-
interactions and side effects (including photosensitivity, rash, and itor; ombitasvir (25 mg), an NS5A inhibitor; dasabuvir (250 mg),
mild hyperbilirubinemia); moreover, patients, with HCV NS3 poly- a nonnucleoside polymerase inhibitor; ± weight-based ribavirin
morphism Q80K had markedly reduced drug efficacy, necessitating (total of five drugs) was approved in December 2014 for genotypes
pretreatment genetic testing and disqualifying a substantial propor- 1 and 4. Paritaprevir/ritonavir and ombitasvir, formulated in a
tion (approximately a third) of potential treatment candidates. Little single tablet, are taken once daily, and both dasabuvir (a separate
about simeprevir supported its adoption in combination with PEG pill) and weight-based ribavirin (when included in the regimen) are
IFN and ribavirin. On the other hand, the combination of simeprevir taken twice daily. In clinical trials, this combination achieved SVR12
(150 mg) along with sofosbuvir (400 mg) for 12 weeks was found to rates of 87–100% in treatment-naïve and treatment-experienced
be effective in treatment-naïve (97% SVR12) or treatment-experienced patients with genotype 1; without ribavirin, this combination in

TABLE 334-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca 2391
Standard Indications for Therapy FAILED PRIOR PEG IFN/RIBAVIRIN THERAPY, NO CIRRHOSIS
All patients with chronic HCV infection (detectable HCV RNA, with or without
elevated ALT) except for those with short life expectancies owing to comorbid Genotype 1a
conditions. ledipasvir + sofosbuvir 12 weeks
Any stage of fibrosis; highest priority for advanced fibrosis [METAVIR stage 3]/ paritaprevir/ritonavir + ombitasvir + dasabuvir + RBV 12 weeks
cirrhosis [METAVIR stage 4] (pretreatment biopsy is no longer embraced and sofosbuvir + simeprevir 12 weeks
has been supplanted by noninvasive measures of fibrosis, e.g., imaging to
daclatasvir + sofosbuvir 12 weeks
determine liver elasticity)
grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs) or + RBV x
Responsiveness in groups previously refractory to interferon-based therapy (HIV-
16 weeks (ELB NS5A RASs)
HCV co-infection, renal insufficiency, African American and Latino ethnicity, IL28B
non-C haplotype, obesity, insulin resistance, hepatic decompensation, etc.) is sofosbuvir + velpatasvir 12 weeks
not diminished to contemporary direct-acting oral combination regimens. Genotype 1b
Retreatment Recommended ledipasvir + sofosbuvir 12 weeks
Relapsers, partial responders, or nonresponders after a previous course of paritaprevir/ritonavir + ombitasvir + dasabuvir 12 weeks
interferon-based therapy or prior direct-acting antiviral therapy (see genotype- sofosbuvir + simeprevir 12 weeks
specific recommendations below).
daclatasvir + sofosbuvir 12 weeks
Antiviral Therapy Not Recommended
grazoprevir + elbasvir 12 weeks
Pregnancy: No clinical studies of direct-acting antivirals during pregnancy
are available. Ribavirin is contraindicated during pregnancy; therefore, any sofosbuvir + velpatasvir 12 weeks
regimen including ribavirin should not be used. Sofosbuvir; sofosbuvir + Genotype 2
ledipasvir; and paritaprevir/ritonavir + ombitasvir + dasabuvir are classified sofosbuvir + velpatasvir 12 weeks
as pregnancy category B, but the other direct-acting antivirals do not have a daclatasvir + sofosbuvir 12 weeks
pregnancy classification. Therefore, these therapies are not indicated routinely
in pregnancy and should be used, with caution, only if the benefit of treatment Genotype 3
outweighs the potential for fetal risk. sofosbuvir + velpatasvir 12 weeks
Therapeutic Regimens (based on AASLD-IDSA recommendations, daclatasvir + sofosbuvir 12 weeks
www.hcvguidelines.org)b Genotype 4
The European Association for the Study of the Liver (EASL) issued sofosbuvir + velpatasvir 12 weeks
recommendations in 2016; divergences from AASLD-IDSA recommendations

ledipasvir + sofosbuvir 12 weeks
are summarized as a footnote below.c
paritaprevir/r + ombitasvir + RBV 12 weeks (no dasabuvir)
TREATMENT-NAÏVE OR RELAPSED AFTER PRIOR PEG IFN/ grazoprevir + elbasvir 12 weeks (prior relapse) or + RBV 16 weeks
RIBAVIRIN THERAPY (prior nonresponse)
Genotype 1a Genotypes 5, 6
ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic patients sofosbuvir + velpatasvir 12 weeks
with HCV RNA <6 × 106 IU/mL) ledipasvir + sofosbuvir 12 weeks
paritaprevir/ritonavir + ombitasvir + dasabuvir + RBV 12 weeks (no FAILED PRIOR PEG IFN/RIBAVIRIN THERAPY, COMPENSATED
cirrhosis) or 24 weeks (cirrhosis) CIRRHOSIS
sofosbuvir + simeprevir 12 weeks (no cirrhosis) or ± RBV 24 weeks (cirrhosis)
daclatasvir + sofosbuvir 12 weeks (no cirrhosis) or ± RBV 24 weeks (cirrhosis) Genotype 1a
grazoprevir + elbasvir 12 weeks (no cirrhosis or cirrhosis sans ELB NS5A ledipasvir + sofosbuvir + RBV 12 weeks
RASs) or + RBV × 16 weeks (ELB NS5A RASs) ledipasvir + sofosbuvir 24 weeks
sofosbuvir + velpatasvir 12 weeks sofosbuvir + velpatasvir 12 weeks
Genotype 1b grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs) or + RBV ×
ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic patients 16 weeks (ELB NS5A RASs)
with HCV RNA <6 × 106 IU/mL) paritaprevir/ritonavir + ombitasvir + dasabuvir + RBV 24 weeks
paritaprevir/ritonavir + ombitasvir + dasabuvir 12 weeks sofosbuvir + simeprevir ± RBV 24 weeks (no Q80K variant)
sofosbuvir + simeprevir 12 weeks (no cirrhosis) or ± RBV 24 weeks (cirrhosis) daclatasvir + sofosbuvir ± RBV 24 weeks
daclatasvir + sofosbuvir 12 weeks (no cirrhosis) or ± RBV 24 weeks (cirrhosis) Genotype 1b
grazoprevir + elbasvir 12 weeks ledipasvir + sofosbuvir + RBV 12 weeks
sofosbuvir + velpatasvir 12 weeks ledipasvir + sofosbuvir 24 weeks
Genotype 2 sofosbuvir + velpatasvir 12 weeks
sofosbuvir + velpatasvir 12 weeks grazoprevir + elbasvir 12 weeks
daclatasvir + sofosbuvir (no cirrhosis) 12 weeks or 16–24 weeks (cirrhosis) paritaprevir/ritonavir + ombitasvir + dasabuvir 12 weeks
Genotype 3 sofosbuvir + simeprevir ± RBV 24 weeks
sofosbuvir + velpatasvir 12 weeks daclatasvir + sofosbuvir ± RBV 24 weeks
daclatasvir + sofosbuvir 12 weeks (no cirrhosis) or ± RBV 24 weeks (cirrhosis) Genotype 2
Genotype 4 sofosbuvir + velpatasvir 12 weeks
sofosbuvir + velpatasvir 12 weeks sofosbuvir + daclatasvir 16 or 24 weeks
ledipasvir + sofosbuvir 12 weeks Genotype 3
paritaprevir/r + ombitasvir + RBV 12 weeks (no dasabuvir) sofosbuvir + velpatasvir 12 weeks
grazoprevir + elbasvir 12 weeks daclatasvir + sofosbuvir + RBV 24 weeks
Genotypes 5, 6 Genotype 4
sofosbuvir + velpatasvir 12 weeks sofosbuvir + velpatasvir 12 weeks
ledipasvir + sofosbuvir 12 weeks ledipasvir + sofosbuvir + RBV 12 weeks
(Continued)

2392 TABLE 334-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca (Continued)
paritaprevir/ritonavir + ombitasvir + RBV 12 weeks (no dasabuvir) FEATURES ASSOCIATED WITH REDUCED RESPONSIVENESS
grazoprevir + elbasvir 12 weeks (prior relapse) or + RBV 16 weeks TO DIRECT-ACTING ANTIVIRAL COMBINATION THERAPY
(prior nonresponse)
Genotype and subtype (genotype 1a less responsive than genotype 1b for
ledipasvir + sofosbuvir 24 weeks several drugs)
Genotypes 5, 6 Treatment experience
sofosbuvir + velpatasvir 12 weeks Advanced fibrosis (bridging fibrosis, cirrhosis)
ledipasvir + sofosbuvir 12 weeks Reduced adherence
a
Rapidly evolving new recommendations continue to be issued; for up-to-date treatment recommendations, please see www.hcvguidelines.org. bClass-I recommendations
in bold font, all others are Class-II recommendations cThe following EASL recommendations differ from those of AASLD-IDSA (Please note that, although mentioned in
EASL recommendations, testing for baseline RASs is not recommended routinely, but, if reliable resistance testing available, results can be used to guide therapy.):
Genotype 1
For genotype 1, simeprevir + sofosbuvir is not recommended.
For genotype 1a, treatment-experienced patients (IFN-based regimen failures) treated with sofosbuvir + ledipasvir should have weight-based ribavirin added. If reliable
testing for RASs is available, ribavirin is needed only if baseline RASs are present, and, in such patients, if ribavirin is contraindicated, sofosbuvir + ledipasvir should be
extended to 24 weeks.
For genotype 1b, in treatment-naïve, noncirrhotic patients receiving paritaprevir/ritonavir + ombitasvir + dasabuvir a treatment duration of 8 weeks can be considered.
For genotype 1a, in patients treatment with grazoprevir + elbasvir, EASL recommends testing for ELB RASs even in noncirrhotics. If resistance testing is not done, the
level of baseline HCV RNA should determine whether ribavirin is added and the duration of therapy. If HCV RNA >800,000 IU/mL, add ribavirin and treat for 16 weeks;
if HCV RNA ≤800,000 IU/mL, ribavirin is not added, and treatment for 12 weeks suffices. If baseline testing for RASs is available, patients with HCV RNA >800,000 IU/mL
and detectable RASs should be treated with ribavirin for 16 weeks. Treatment without ribavirin and for 12 weeks suffices if HCV RNA ≤800,000 IU/mL even with
detectable RASs or even if HCV RNA >800,000 IU/mL with undetectable RASs.
For genotype 1a, in treatment-experienced patients (IFN-based regimen failures) treated with daclatasvir + sofosbuvir, follow the same recommendations described
above for ledipasvir + sofosbuvir regarding the addition of ribavirin.
Genotype 2
EASL recommendations are the same as those of AASLD-IDSA.
Genotype 3
For treatment-experienced patients (IFN-based regimen failures) treated with sofosbuvir + velpatasvir or sofosbuvir + daclatasvir, if testing for baseline RASs is not
available, add weight-based ribavirin. If resistance testing is available, ribavirin is needed only if baseline RASs are present, and, in such patients, if ribavirin is
contraindicated, treatment should be extended to 24 weeks.
PART 10
Genotype 4
Treatment-experienced patients (IFN-based regimen failures) treated with sofosbuvir + ledipasvir should have weight-based ribavirin added, and, in such patients, if
ribavirin is contraindicated, treatment should be extended to 24 weeks.
In treatment-experienced patients (IFN-based regimen failures) treated with grazoprevir + elbasvir, if HCV RNA >800,000 IU/mL, weight-based ribavirin should be added,
and treatment should be extended to 16 weeks.
EASL recommends two additional treatment options for genotype 4 (noncirrhotic or cirrhotic) that are not included in AASLD-IDSA guidelines: sofosbuvir + daclatasvir
and sofosbuvir + simeprevir. For both these options, treatment-naïve patients should be treated for 12 weeks without ribavirin; treatment-experienced (IFN-based
regimen failures) patients should be treated with ribavirin for 12 weeks or, if ribavirin is contraindicated, without ribavirin for 24 weeks.
Genotypes 5 and 6
Treatment-experienced patients (IFN-based regimen failures) treated with sofosbuvir + ledipasvir should have weight-based ribavirin added, and, in such patients, if
ribavirin is contraindicated, treatment should be extended to 24 weeks.
EASL recommends an additional treatment option for genotype 5 and 6 (noncirrhotic or cirrhotic) that is not included in AASLD-IDSA guidelines: sofosbuvir + daclatasvir.
Treatment-naïve patients should be treated for 12 weeks without ribavirin; treatment-experienced (IFN-based regimen failures) patients should be treated with ribavirin
for 12 weeks or, if ribavirin is contraindicated, without ribavirin for 24 weeks.
Drug doses: sofosbuvir 400 mg; ledipasvir 90 mg; paritaprevir 150 mg; ritonavir 100 mg; ombitasvir 25 mg; dasabuvir 250 mg; ribavirin, weight-based: 1000 mg
(<75 Kg)–1200 mg (≥75 kg); simeprevir 150 mg; daclatasvir 60 mg; elbasvir 50 mg; grazoprevir 100 mg; velpatasvir 100 mg.
Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; ELB NS5A RASs, elbasvir NS5A resistance-associated
substitutions; HCV, hepatitis C virus; IFN, interferon; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; IU, international units (1 IU/mL is
equivalent to ~2.5 copies/mL); RASs, resistance-associated substitutions; RBV, ribavirin.
genotype 1a is ~7% less responsive than genotype 1b. Therefore, allowing once-a-day instead of twice-a-day treatment; for genotype 1a,
in treatment-naïve patients with genotype 1a, this combination is twice-daily ribavirin dosing remains.
administered with ribavirin for 12 weeks in the absence of cirrhosis This combination is well tolerated with generally mild side
(95–97% SVR12) or for 24 weeks in the presence of compensated effects, for example, fatigue, asthenia, insomnia, headache, and pru-
cirrhosis (94% SVR12), while in patients with genotype 1b, the com- ritus. Hyperbilirubinemia (primarily unconjugated) and elevations
bination does not require ribavirin, and the duration of therapy is in alanine aminotransferase activity may occur but resolve during
12 weeks for both noncirrhotics and cirrhotics (99–100% SVR12). In or shortly after treatment. Because of occasional hyperbilirubinemia
prior nonresponders without cirrhosis, the combination is adminis- and potential hepatotoxicity (FDA warning letter issued October
tered for 12 weeks, with ribavirin in genotype 1a (96% SVR12), without 2015 regarding hepatic failure/decompensation reported in treated
ribavirin in genotype 1b (100% SVR12). In prior nonresponders cirrhotic patients), this combination is not recommended in patients
with cirrhosis, the combination is administered for 24 weeks with with decompensated cirrhosis, and treated cirrhotic patients should
ribavirin in genotype 1a (SVR12 100% in prior relapsers and partial be monitored closely for decompensation; however, the safety and
responders, 95% in prior null responders [in whom treatment efficacy of this combination have been demonstrated for patients
without ribavirin was associated with an 80% SVR12]), but only with advanced renal insufficiency. Similar to other regimens con-
for 12 weeks and without ribavirin in genotype 1b (100% SVR12). For taining protease inhibitors, drug-drug interactions are common with
genotype 4, the regimen is given for 12 weeks with ribavirin, but other drugs that induce CYP3A4 or are dependent on CYP3A4 for
without dasabuvir in treatment-naïve and treatment-experienced elimination. Checking for potential drug-drug interactions is impor-
patients (100% SVR12), including those with compensated cirrhosis. tant prior to initiating therapy with this drug combination (www
In July 2016, the FDA approved a long-acting formulation of dasabuvir, .hep-druginteractions.org). Responsiveness to this multidrug

regimen is not reduced in patients with baseline RASs to these reduce efficacy of elbasvir/grazoprevir (unlike baseline RASs to the 2393
agents. most of the other combination DAA regimens described above and
Compared to sofosbuvir/ledipasvir, this regimen has the disad- below) from 99% to 58% in treatment-naïve patients. Therefore, all
vantage of requiring twice-a-day ribavirin therapy for genotype 1a patients with genotype 1a require baseline RAS testing; if these RASs
and of being contraindicated in decompensated cirrhosis; however, are present, treatment extension to 16 weeks and the addition of
it has the advantage of offering a 12-week, ribavirin-free regimen weight-based ribavirin bring the SVR12 up to expected levels of close
for prior null responders with cirrhosis and providing an option for to 100%. In treatment-experienced patients, both extending treatment
patients with renal failure. to 16 weeks and adding ribavirin were studied; however, generally,
Sofosbuvir and Daclatasvir: Daclatasvir, an NS5A inhibitor, along in the absence of baseline NS5A RASs, SVR12 rates were not increased
with the polymerase inhibitor sofosbuvir, was approved by the FDA over those without ribavirin for 12 weeks (94–97%). For genotype 1a,
in July 2015 for genotype 3 and in February 2016 for genotype 1 among prior nonresponders to PEG IFN/ribavirin, 12 weeks of elbas-
(AASLD-Infectious Diseases Society of America [IDSA] guidelines vir/grazoprevir suffices without ribavirin except for patients with
[see below] include its recommendation as well for genotype 2; in baseline NS5A RASs, who require 16 weeks of therapy and ribavirin.
August 2014, this combination was approved in Europe for geno- Among nonresponders to prior protease-inhibitor therapy, even in
types 1, 2, 3, and 4, and EASL recommends it for all these genotypes the absence of baseline NS5A RASs, ribavirin should be added to a
as well as for genotypes 5 and 6). At the time of its approval for 12-week regimen; in the presence of baseline NS5A RASs, treatment
genotype 3, daclatasvir filled a need inadequately met by other should be extended to 16 weeks and ribavirin added. For genotype
available combination DAAs. Although data on genotype 3 are the 1b, NS5A RASs are not an issue, and the only subgroup requiring
most robust, clinical trials of this combination in genotypes 1 and 2 modification of a 12-week course of therapy are prior nonreponders
support its efficacy and recommendations for first-line (genotype 1) to protease-inhibitor regimens, for whom ribavirin is added. For
and alternative (genotype 2) treatment, in some cases with ribavirin genotype 4, the recommended regimen for all prior nonresponders
(Table 334-6). Daclatasvir, a 60-mg tablet, and sofosbuvir, a separate (whether to PEG IFN/ribavirin or protease inhibitor regimens) is 16
400 mg tablet are taken once-a-day for 12 to 24 weeks. weeks of elbasvir/grazoprevir plus ribavirin (Table 334-6).
In clinical trials among treatment-naïve or treatment-experienced This combination is just as effective in patients with HIV-HCV
patients, SVR12 rates for 12 weeks of daclatasvir plus sofosbuvir co-infection and in patients with advanced renal failure (including
were 98% with genotype 1 (comparable results in genotypes 1a and those requiring hemodialysis); however, it is contraindicated in dec-
1b), 92% for genotype 2, and 89% for genotype 3. For noncirrhotic ompensated cirrhosis. Like other protease inhibitor regimens, elbasvir/
patients, the addition of ribavirin or the extension of therapy to grazoprevir can be associated with aminotransferase elevations and

24 weeks did not improve efficacy. In patients with compensated potential hepatotoxicity; because these drugs are excreted by the
cirrhosis, limited prospective data and data from observational liver, in decompensated liver disease, plasma drug concentrations
cohorts suggested that extending therapy to 24 weeks, with or with- may become elevated substantially. Therefore, all treated patients
out ribavirin, improved efficacy. In cirrhotics, SVR12 was achieved in should have alanine aminotransferase screening periodically during
93% with Child Class-Pugh A and B but in only 56% with Class-C therapy, and the drug should be stopped for elevations exceeding
decompensated cirrhosis. For patients with genotype 3 and cirrho- 10-fold or for elevations of conjugated bilirubin, alkaline phos-
sis, the combination was effective in treatment-naïve patients (94% phatase, or prothrombin time.
SVR12), but less so in prior nonresponders (69% SVR12). Outcomes in Elbasvir/grazoprevir is well tolerated, with only low levels of
patients with HIV-HCV co-infection were comparable. mild adverse effects (fatigue, headache, nausea in 5–11%) seen just
Like other sofosbuvir-NS5A inhibitor combinations, daclatasvir as frequently in placebo recipients. Both elbasvir and grazoprevir are
plus sofosbuvir is well tolerated (mild fatigue, headache, nausea, substrates for CYP3A and are subject to multiple potential drug-drug
diarrhea in 5–14%), but can cause severe bradycardia when adminis- interactions. Therefore, this combination should not be used with
tered with amiodarone (contraindicated), especially along with beta potent CYP3A inducers; conversely, CYP3A and OATP1B1 inhibitors
blockers. Because daclatasvir is a substrate for CYP3A, CYP3A induc- can lead to untoward elevations of plasma elbasvir/grazoprevir con-
ers can reduce daclatasvir levels, and CYP3A inhibitors reduce dacla- centrations. Checking for potential drug-drug interactions is advis-
tasvir levels. Similarly, daclatasvir, an inhibitor of P-gp, OATP1B1 able prior to initiating therapy (www.hep-druginteractions.org).
and 1B3, and BCP, can increase the levels of drugs that are substrates Compared to other available regimens for genotypes 1 and
of these transporters. As noted above for other DAAs, checking for 4, elbasvir/grazoprevir has the disadvantage/inconvenience of
potential drug-drug interactions is advisable prior to initiating ther- requiring baseline NS5A RAS testing but the advantages of a com-
apy (www.hep-druginteractions.org). Responsiveness to daclatasvir- parable regimen for cirrhotics and noncirrhotics, for treatment-naïve
containing drug-combination therapy is reduced in cirrhotic patients and treatment-experienced patients, and for patients with normal
with genotype 1a and in both cirrhotic and noncirrhotic patients with renal function and with renal failure.
genotype 3 who have baseline daclatasvir-associated NS5A RASs. Sofosbuvir/velpatasvir: The combination in a single, fixed-dose
Although daclatasvir-sofosbuvir is approved for genotypes 1 and pill of velpatasvir (100 mg), a highly potent, pangenotypic NS5A
3 and recommended as an alternative for genotype 2, better docu- inhibitor, along with the polymerase inhibitor sofosbuvir (400 mg)
mented efficacy and simplicity of other regimens have limited the was approved in June 2016 for genotypes 1–6, in treatment-naïve
popularity of this drug combination. and treatment-experienced noncirrhotics and cirrhotics. Ribavirin is
Elbasvir/Grazoprevir: Elbasvir (50 mg), an NS5A inhibitor, com- not required, including in patients with genotypes 2 and 3, except in
bined in a single, fixed-dose pill with grazoprevir (100 mg), an NS3/4 patients with decompensated cirrhosis.
protease inhibitor, was approved in January 2016 as a once-a-day In a series of clinical trials, this combination for 12 weeks in the
(with or without food) treatment for genotypes 1 and 4. In clinical absence of ribavirin was shown to yield 99% SVR12 (range 97–100%)
trials, a 12-week course was effective in treatment-naïve and treat- in genotypes 1, 2, 4, 5, and 6 and 95% in genotype 3. Baseline NS5A
ment-experienced patients without cirrhosis or with compensated RASs had no impact on responsiveness.
cirrhosis. In treatment-naïve patients, this combination yielded an Prior to the availability of this drug combination, patients with
SVR12 in 92% of patients with genotype 1a, 99% with genotype genotype 3, especially those with cirrhosis and prior null response
1b, and 100% with genotype 4 (very small numbers, however); 10 to other therapies, proved to be the most refractory subset of
patients with genotype 6 were included, but only 80% achieved patients. In treatment-naïve patients with genotype 3, 12 weeks
SVR12. Cirrhotic and noncirrhotic patients had comparable rates of sofosbuvir/velpatasvir (95% SVR12) was superior to 24 weeks
of SVR12, 97% and 94%, respectively. For this drug combination, of sofosbuvir plus ribavirin (80% SVR12). In patients with genotype 3,
however, ~11% of patients with genotype 1a harbor NS5A poly- the combination of sofosbuvir/velpatasvir for 12 weeks was compa-
morphisms, that is, RASs, at baseline. If present, these NS5A RASs rable in noncirrhotics (97% SVR12) and cirrhotics (91% SVR12) and in

2394 treatment-naïve (97% SVR12) and treatment-experienced (90% SVR12) these alternative approaches may not be practical or competitive;
patients, superior in all these categories to 24 weeks of sofosbuvir moreover, development of both approaches has been retarded by
plus ribavirin (87%, 66%, 86%, and 63%, respectively). In cirrhotic emerging toxicities such as pancreatitis associated with cyclophilin
null responders, most available IFN-free regimens for genotype 3 inhibitors and jaundice associated with micro-RNA-122.
(including daclatasvir plus sofosbuvir, approved specifically for Although data on the impact of DAAs on the natural history of
this genotype) achieved SVR12 rates in the range of ~60–75%, while chronic hepatitis C are still limited, preliminary findings are that
the combination of PEG IFN, ribavirin, and sofosbuvir could boost successful therapy is associated with a gradual reduction in fibro-
SVR12 to the mid-80% range. For treatment-experienced patients sis progression and a regression of advanced fibrosis (cirrhosis),
with genotype 3, sofosbuvir/velpatasvir in noncirrhotics and cir- improvement in survival among patients with decompensated cir-
rhotics had similarly high efficacy (91% and 89% SVR12, respec- rhosis, and a decline in the number of patients with hepatitis C being
tively); this was the highest recorded SVR12 for genotype-3 cirrhotic referred for liver transplantation. Based on the known prevalence,
null responders treated with IFN-free DAA regimens. Finally, in natural history, and rate of progression of chronic hepatitis C and on
patients with genotypes 1–4 and 6 and with decompensated, Class-B the efficacy of DAA therapies and their impact on the complications
cirrhosis (55% treatment-experienced), sofosbuvir/velpatasvir plus of hepatitis C, modeling estimates have suggested that the availabil-
ribavirin for 12 weeks yielded an SVR12 in 94%; this result was better ity and application of these therapies have the potential to reduce
than sofosbuvir/velpatasvir without ribavirin for 12 weeks (83% the hepatitis C-associated disease burden including liver-related
SVR12) or 24 weeks (86% SVR12). death, HCC, decompensated cirrhosis, and liver transplantation by
Like other all-oral DAAs, sofosbuvir/velpatasvir was very well 50–70% between 2015 and 2050.
tolerated; in noncirrhotic and compensated cirrhotic patients, mild
headache and fatigue was seen in >10%—this occurred in a compa- TREATMENT RECOMMENDATIONS
rable proportion of placebo recipients; in decompensated cirrhosis, Because the pace of new drug development and approval has been
mild fatigue, headache, nausea, insomnia, diarrhea, and anemia so rapid, the AASLD and the IDSA have been providing a consensus
(ribavirin was part of the regimen) was seen in >10%. Like other of updated treatment recommendations for patients with hepatitis C;
sofosbuvir-containing regimens, sofosbuvir/velpatasvir should not these recommendations, which continue to be revised regularly
be administered along with amiodarone (potential serious brady- based on new data, are available online at www.hcvguidelines.org
cardia); in addition, P-gp inducers and moderate-to-potent CYP3A and should be consulted before initiating therapy (Table 334-6). The
inducers can reduce plasma levels of sofosbuvir and/or velpatasvir. EASL issues similar (but not identical) treatment recommendations
Checking for drug-drug interactions prior to therapy is advis- annually for hepatitis C (www.easl.eu), most recently in September
able (www.hep-druginteractions.org). Baseline RASs do not influence 2016. Divergences between AASLD-IDSA and EASL recommenda-
PART 10
responsiveness to this combination. tions are noted in Table 334-6.

Prior to therapy, HCV genotype should be determined, because
FUTURE DIRECT-ACTING ANTIVIRAL COMBINATION the genotype dictates which treatment regimens are indicated
THERAPY (2017–) (Table 334-6). Monitoring of serum HCV RNA levels pretreatment,
Most treatment needs have been met by contemporary DAA regimens during treatment, and posttreatment is crucial in assessing response
described above; however, several additional, highly potent, pangeno- to therapy; moreover, the baseline level may contribute to deter-
typic drug combinations are in development. For example, an inves- mining the duration of therapy (e.g., in noncirrhotic patients with
tigative protease inhibitor (voxilaprevir) added to the polymerase genotype 1 and HCV RNA <6 × 106 IU/mL, 8 [instead of the usual 12]
inhibitor/NS5A inhibitor combination of sofosbuvir/velpatasvir weeks of sofosbuvir/ledipasvir may be a consideration). The goal of
yields a very well tolerated triple-drug combination with 97% SVR12 treatment is to eradicate HCV RNA during therapy and to document
across all HCV genotypes and patient subgroups. These include non- that the virus remains undetectable for at least 12 weeks after com-
cirrhotic/cirrhotic, treatment-naïve/treatment-experienced groups, pletion of therapy (SVR12). Several reports have appeared describing
including those who had prior NS5A treatment and results were inde- hepatitis B reactivation, often severe, during and after DAA therapy
pendent of the number of prior DAA drug classes received; no effects in patients coinfected with HCV and HBV who were not being
of baseline NS5A RASs were noted. Several experimental combina- treated for their HBV infections. Therefore, screening for HBV infec-
tions may allow even briefer durations of therapy. In a small, explor- tion is recommended prior to initiating DAA therapy for hepatitis C
atory trial, a 6-week combination of sofosbuvir plus an experimental (which should have been done to determine HBV-immunity status
pangenotypic, very high potency, very low resistance NS5A inhibitor as a prelude to recommended hepatitis B vaccination in patients
(odalasvir) achieved SVR12 in 100% of 12 patients with genotype 1. with chronic hepatitis C), and therapy for HBV infection (for those
Similarly, in a 6-week triple combination of odalasvir with the protease meeting HBV treatment criteria, see above) should be initiated prior
inhibitor simeprevir and an experimental polymerase inhibitor (“AL- to or simultaneously with HCV therapy.
335”), SVR12 was observed in 100% of 20 treatment-naïve noncirrhotic
patients with genotype 1. In phase-II clinical trials, 8 weeks of an INDICATIONS FOR ANTIVIRAL THERAPY
experimental combination of two high-potency, pangenotypic DAAs, Patients with chronic hepatitis C who have detectable HCV RNA
a protease inhibitor (“ABT-493”) plus an NS5A inhibitor (“ABT-530”), in serum, whether or not aminotransferase levels are increased,
yielded 100% SVR12 in treatment-naïve noncirrhotic patients with and chronic hepatitis of any grade and stage are candidates for
genotypes 1, 2, and 3. In cirrhotics with genotype 3 and in patients with antiviral therapy with DAA agents. The only exception would be
genotypes 4, 5, and 6, 12 weeks of therapy with this DAA combination patients with short life expectancies, for whom treating hepatitis C
yielded 100% SVR12. In patients with prior DAA treatment failure, would have no influence on longevity. Certainly, for patients
12 weeks of this double-combination sufficed to achieve a ≥95% SVR12; with advanced liver disease, early treatment merits a high prior-
neither baseline NS5A nor protease inhibitor RASs influenced SVR12 ity. Although patients with persistently normal aminotransferase
rates. No safety issues have been encountered, and the potential for activity tend to progress histologically very slowly or not at all, they
drug-drug interactions is limited. These promising combinations are respond to antiviral therapy just as well as do patients with elevated
undergoing phase-II and phase-III trials. aminotransferase levels; therefore, such patients are potential can-
Less advanced is the development of inhibitors of host pro- didates for antiviral therapy. As noted above, antiviral therapy has
teins, such as oral, nonimmunosuppressive inhibitors of cyclo- been shown to improve survival and complication-free survival and
philin A (which interacts with NS5A during HCV replication) and to slow progression of and to reverse fibrosis.
subcutaneous antisense antagonists of host liver-expressed micro- HCV genotype determines the regimen to be selected (Table 334-6).
RNA-122 (which promotes HCV replication). Given the accelerated Similarly, the absence or presence of cirrhosis/advanced fibrosis
progress of all-oral, short-treatment-duration, high-efficacy, DAAs, determines the treatment options from which to select, including

the antiviral agents to be used, the duration of therapy, and the need who were not candidates for IFN-based antiviral therapy, respond 2395
for ribavirin (Table 334-6). A pretreatment liver biopsy to assess well to DAA therapy regimens consisting of combinations of poly-
histologic grade and stage provides substantial information about merase inhibitors and NS5A inhibitors (e.g., sofosbuvir/ledipasvir,
progression of hepatitis C in the past, has prognostic value for future sofosbuvir/velpatasvir); however, protease-inhibitor-containing
progression, and can identify such histologic factors as steatosis and combinations have been associated with potential hepatotoxicity
stage of fibrosis, which can influence responsiveness to therapy. As and hepatic decompensation and are contraindicated in this patient
therapy has improved for patients with a broad range of histologic subset. Patients with decompensated cirrhosis should be referred to
severity, and as noninvasive measures of the stage of fibrosis (e.g., a liver transplantation center. DAAs are highly effective not only for
assessment of liver elasticity by imaging) have gained in accuracy patients with end-stage liver disease awaiting liver transplantation
and popularity, noninvasive approaches have supplanted histology but also for patients with recurrent hepatitis C after liver transplan-
in most cases. If cirrhosis/advanced fibrosis is present prior to ther- tation. Ideally, patients should be treated prior to liver transplanta-
apy, the risk of HCC, although reduced substantially by successful tion; however, a concern is that eradication of HCV infection will
therapy, is not eliminated, and twice yearly posttreatment imaging disqualify such patients from accepting donor livers from persons
for HCC surveillance (and endoscopic surveillance for esophageal with HCV infection, thus contracting the potential donor pool and
varices at intervals of 1–3 years) is indicated even after an SVR. In limiting accessibility to donor organs and timely transplantation. In
patients with low-level fibrosis at baseline, achievement of an SVR addition, responsiveness to DAA therapy appears to be reduced in
allows the cessation of such surveillance. patients with decompensated cirrhosis and with high model for end-
Patients who have relapsed after, or failed to respond to, a course stage liver disease (MELD) scores; in this subgroup, responsiveness
of IFN-based or DAA agent-based therapy are candidates for retreat- after liver transplantation would be substantially better. Therefore,
ment with a DAA therapy regimen (Table 334-6). For patients who advocacy has been expressed (recommended by EASL) for post-
have failed to respond to a DAA combination, options include increas- poning DAA therapy in patients with high-MELD HCV-associated
ing the duration of therapy with the failed regimen, adding ribavirin, end-stage liver disease until after liver transplantation; the decision
or changing the drug class (e.g., after failed protease and polymerase whether to treat pretransplantation or posttransplantation should be
inhibitors, switching to an NS5A-containing combination). In the individualized thoughtfully for each patient, based on such factors
presence of cirrhosis or a need for urgent retreatment, patients who as MELD score, time anticipated prior to availability of a donor
have failed protease inhibitor plus polymerase inhibitor combination organ, relative clinical stability, and co-morbidities (Chap. 338). The
therapy or who have failed an NS5A combination are candidates for cutaneous and renal vasculitis of HCV-associated essential mixed
RAS testing and tailored therapy based on such resistance testing. If cryoglobulinemia (Chap. 332) may respond to antiviral therapy, but

reliable RAS testing is not available, adding ribavirin or extending sustained responses were rare after discontinuation of therapy in
the duration of therapy are options. For prior nonresponders to IFN- the IFN era, and prolonged, potentially indefinite, therapy was rec-
based therapy, NS5A inhibitor-containing regimens are highly effec- ommended. Now that more effective DAAs are available, a 12-week
tive; however, reduced responsiveness can be encountered, especially course of sofosbuvir-based combination therapy has been shown to
in cirrhotic patients. For this relatively refractory group, ideally, the most yield an SVR12 rate exceeding 80% in cryoglobulinemic vasculitis.
potent/effective NS5A regimen should be selected to give such patients Anecdotal reports suggest that IFN-based antiviral therapy may be
the best chance of responding and to avoid treatment-emergent NS5A effective in porphyria cutanea tarda or lichen planus associated with
RASs. Additional details for treatment of such patient subgroups can hepatitis C; whether the more appealing DAAs are effective in these
be found at www.hcvguidelines.org. groups remains to be documented.
Persons with acute hepatitis C are also candidates for antiviral In patients with HCV/HIV co-infection, hepatitis C is more
therapy (Chap. 332) with the same DAA agents approved for chronic progressive and severe than in HCV-monoinfected patients.
hepatitis C; delaying the initiation of therapy for an observation Although patients with HCV/HIV co-infection responded less well
period of 12–16 weeks (and even up to 6 months) has been recom- to IFN-based antiviral therapy for hepatitis C, they respond as well
mended to allow for spontaneous recovery, especially in light of the as patients with HCV infection alone to DAA combination regimens.
fact that most cases of acute hepatitis C are not clinically severe or In HCV/HIV-infected patients, ribavirin can potentiate the toxicity
rapidly progressive. The duration of therapy for acute hepatitis C of didanosine (e.g., lactic acidosis) and the lipoatrophy of stavudine,
has not been determined definitively; however, in a small study of 20 and zidovudine can exacerbate ribavirin-associated hemolytic
patients, 6 weeks of sofosbuvir/ledipasvir sufficed for a 100% SVR12. anemia; therefore, these drug combinations should be avoided.
According to 2016 EASL recommendations, patients with acute Patients with a history of injection drug use and alcoholism can
hepatitis C should be treated for 8 weeks with a genotype-appropriate be treated successfully for chronic hepatitis C, preferably in conjunc-
DAA regimen consisting of sofosbuvir plus one of the three approved tion with drug and alcohol treatment programs. Moreover, because
NS5A inhibitors without ribavirin (extended to 12 weeks for patients injection-drug users, as a source of transmission to others, account
with acute hepatitis C and HIV co-infection or for patients with acute disproportionately for perpetuating the spread of HCV infection in
hepatitis C and a baseline HCV RNA level >1 million IU/mL). In the population, the impact of treating active injection-drug users is
patients with biochemically and histologically mild chronic hepatitis C, amplified by reducing such transmission. The approved oral com-
the rate of progression is slow; however, such patients respond just binations of DAAs are effective in patients with mild-modest renal
as well to antiviral therapy as those with elevated aminotransferase failure and require no dose adjustments; however, in patients with
levels and more histologically severe hepatitis. Because of the high severe renal impairment (creatinine clearances <30 mL/minute),
cost of DAA treatments, initially a higher priority was assigned to data are limited on the use of sofosbuvir-containing combinations.
patients with advanced fibrosis/cirrhosis; however, this controver- For such patients, including those undergoing hemodialysis, rec-
sial approach was relied upon by some medical insurers and phar- ommended combinations are 12 weeks of elbasvir/grazoprevir for
macy benefit management organizations to withhold therapy from genotypes 1a, 1b, and 4 or 12 weeks of paritaprevir/ritonavir, ombi-
patients with low-level fibrosis. Unfortunately, delaying therapy tasvir, and dasabuvir for genotype 1b. In genotype 1a, the addition
until fibrosis becomes advanced misses the opportunity to prevent of 200 mg/day of ribavirin to paritaprevir/ritonavir, ombitasvir, and
all the dire consequences of chronic hepatitis C (liver failure, death/ dasabuvir, if the hemoglobin level exceeds 10 g/dL, is an alternative
transplantation, HCC), which can be reduced, but not eliminated regimen but requires vigilance for the onset of ribavirin-induced
completely once advanced fibrosis is established. Therefore, therapy hemolytic anemia. For patients with severe renal impairment and
for patients with mild disease is justified as well as cost-effective. HCV genotypes 2, 3, 5, or 6, PEG IFN with low-dose ribavirin
Patients with compensated cirrhosis can respond to therapy, and (200 mg daily, if the hemoglobin exceeds 10 g/dL) is recommended.
their likelihood of a sustained response with DAAs is comparable After renal transplantation, levels of SVR12 in patients treated with
to that in noncirrhotics. Patients with decompensated cirrhosis, the approved oral DAA combinations have approached 100%.

2396 No clinical studies of the use of DAAs during pregnancy are described in whom apparently self-limited cases of acute hepatitis A,
available. Ribavirin is contraindicated during pregnancy; therefore, B, or C led to autoimmune hepatitis, presumably because of genetic
any regimen including ribavirin should not be used. Sofosbuvir; susceptibility or predisposition. Evidence to support an autoimmune
sofosbuvir + ledipasvir; and paritaprevir/ritonavir, ombitasvir, and pathogenesis in this type of hepatitis includes the following: (1) in the
dasabuvir are classified as pregnancy category B; the other DAAs liver, the histopathologic lesions are composed predominantly of cyto-
do not have a pregnancy classification. Therefore, these therapies toxic T cells and plasma cells; (2) circulating autoantibodies (nuclear,
are not indicated routinely in pregnancy and should be used, with smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyper-
caution, only if the benefit of treatment is compelling and justified globulinemia are common; (3) other autoimmune disorders—such as
compared to the potential for fetal risk. autoimmune thyroiditis, rheumatoid arthritis, autoimmune hemolytic
Choosing among available treatment options: The large num- anemia, ulcerative colitis, membranoproliferative glomerulonephri-
ber of recommended all-oral DAA combinations can be daunt- tis, juvenile diabetes mellitus, vitiligo, celiac disease, and Sjögren’s
ing to treating clinicians. In some instances, the combination syndrome—occur with increased frequency in patients and in their
approved is determined by insurance payers; however, cost relatives who have autoimmune hepatitis; (4) histocompatibility haplo-
considerations aside, how is the clinician to choose among the types associated with autoimmune diseases, such as HLA-B1, B8, DR3,
options? The most popular of the regimens has been fixed-dose, and DR4 as well as extended haplotype DRB1*0301 and DRB1*0401
single-pill sofosbuvir/ledipasvir, which is effective for all geno- alleles, are common in patients with autoimmune hepatitis; and (5) this
types except 2 and 3, which requires no baseline RAS testing, and type of chronic hepatitis is responsive to glucocorticoid/immunosup-
which can be used in noncirrhotic patients with genotype 1 and pressive therapy, effective in a variety of autoimmune disorders.
low-level viremia for as brief a period as 8 weeks. For genotypes Cellular immune mechanisms appear to be important in the patho-
2 and 3, fixed-dose, single-pill sofosbuvir/velpatasvir appears to genesis of autoimmune hepatitis. In vitro studies have suggested that
be the combination of choice; because this combination is so effec- in patients with this disorder, CD4+ T lymphocytes are capable of
tive across all genotypes, in the future, for simplicity, clinicians becoming sensitized to hepatocyte membrane proteins and of destroy-
may resort to a “one-size-fits-all” regimen such as this one in all ing liver cells. Molecular mimicry by cross-reacting antigens that con-
patients (except for those with advanced renal failure). In addi- tain epitopes similar to liver antigens is postulated to activate these
tion, this regimen is the only one that can be used in almost all T cells, which infiltrate, and result in injury to, the liver. Abnormalities of
situations (independent of genotype, treatment experience, and immunoregulatory control over cytotoxic lymphocytes (impaired regu-
cirrhosis) without ribavirin, and the duration of which is almost latory CD4+CD25+ T cell influences) may play a role as well. Studies of
always 12 weeks; exceptions: (a) ribavirin recommended for dec- genetic predisposition to autoimmune hepatitis demonstrate that cer-
ompensated cirrhosis, (b) EASL recommends adding ribavirin in tain haplotypes are associated with the disorder, as enumerated above,
PART 10
treatment-experienced patients with genotype 3 or, if ribavirin is as are polymorphisms in cytotoxic T lymphocyte antigens (CTLA-4)
contraindicated, extending treatment to 24 weeks (Table 334-6, and tumor necrosis factor α (TNFA*2). The precise triggering factors,
footnote c). As noted above, protease-inhibitor-containing DAA genetic influences, and cytotoxic and immunoregulatory mechanisms
regimens (elbasvir/grazoprevir; paritaprevir/ritonavir, ombitas- involved in this type of liver injury remain incompletely defined.
vir, and dasabuvir; simeprevir and sofosbuvir) are contraindi- Intriguing clues into the pathogenesis of autoimmune hepatitis
cated in decompensated cirrhosis. For advanced renal failure, come from the observation that circulating autoantibodies are preva-
safety and efficacy have been documented for elbasvir/grazopre- lent in patients with this disorder. Among the autoantibodies described
vir and paritaprevir/ritonavir, ombitasvir, and dasabuvir, but not in these patients are antibodies to nuclei (so-called antinuclear antibod-
for sofosbuvir-NS5A combinations. ies [ANAs], primarily in a homogeneous pattern) and smooth muscle
(so-called anti-smooth-muscle antibodies, directed at actin, vimentin,
AUTOIMMUNE HEPATITIS and skeletin), antibodies to F-actin, anti-LKM (see below), antibodies
to “soluble liver antigen” (directed against a uracil-guanine-adenine
■■DEFINITION transfer RNA suppressor protein), antibodies to α-actinin, and antibod-
Autoimmune hepatitis is a chronic disorder characterized by contin- ies to the liver-specific asialoglycoprotein receptor (or “hepatic lectin”)
uing hepatocellular necrosis and inflammation, usually with fibrosis, and other hepatocyte membrane proteins. Although some of these pro-
which can progress to cirrhosis and liver failure. When fulfilling criteria vide helpful diagnostic markers, their involvement in the pathogenesis
of severity, this type of chronic hepatitis, when untreated, may have a of autoimmune hepatitis has not been established.
6-month mortality of as high as 40%. Based on contemporary estimates Humoral immune mechanisms have been shown to play a role in the
of the natural history of autoimmune hepatitis, the 10-year survival is extrahepatic manifestations of autoimmune and idiopathic hepatitis.
80−98% for treated and 67% for untreated patients. The prominence of Arthralgias, arthritis, cutaneous vasculitis, and glomerulonephritis
extrahepatic features of autoimmunity and seroimmunologic abnor- occurring in patients with autoimmune hepatitis appear to be medi-
malities in this disorder supports an autoimmune process in its patho- ated by the deposition of circulating immune complexes in affected
genesis; this concept is reflected in the prior labels lupoid and plasma cell tissue vessels, followed by complement activation, inflammation, and
hepatitis. Autoantibodies and other typical features of autoimmunity, tissue injury. While specific viral antigen-antibody complexes can be
however, do not occur in all cases; among the broader categories of identified in acute and chronic viral hepatitis, the nature of the immune
“idiopathic” or cryptogenic chronic hepatitis, many, perhaps the major- complexes in autoimmune hepatitis has not been defined.
ity, are probably autoimmune in origin. Cases in which hepatotropic
viruses, metabolic/genetic derangements (including nonalcoholic fatty ■■CLINICAL FEATURES
liver disease), and hepatotoxic drugs have been excluded represent Many of the clinical features of autoimmune hepatitis are similar to
a spectrum of heterogeneous liver disorders of unknown cause, a those described for chronic viral hepatitis. The onset of disease may
proportion of which are most likely autoimmune hepatitis. be insidious or abrupt; the disease may present initially like, and be
confused with, acute viral hepatitis; a history of recurrent bouts of what
■■IMMUNOPATHOGENESIS had been labeled acute hepatitis is not uncommon. In approximately a
The weight of evidence suggests that the progressive liver injury in quarter of patients, the diagnosis is made in the absence of symptoms,
patients with autoimmune hepatitis is the result of a cell-mediated based on abnormal liver laboratory tests. A subset of patients with
immunologic attack directed against liver cells in the setting of a loss of, autoimmune hepatitis has distinct features. Such patients are predomi-
or failed, immunologic tolerance for self liver antigens. In all likelihood, nantly young to middle-aged women with marked hyperglobulinemia
predisposition to autoimmunity is inherited, whereas the liver specific- and high-titer circulating ANAs. This is the group with positive lupus
ity of this injury is triggered by environmental (e.g., chemical, drug erythematosus (LE) preparations (initially labeled “lupoid” hepatitis)
[e.g., minocycline], or viral) factors. For example, patients have been in whom other autoimmune features are common. Fatigue, malaise,

anorexia, amenorrhea, acne, arthralgias, and jaundice are common. autoimmune hepatitis, the antibody is anti-LKM1, directed against 2397
Occasionally, arthritis, maculopapular eruptions (including cutaneous cytochrome P450 2D6. This is the same anti-LKM seen in some patients
vasculitis), erythema nodosum, colitis, pleurisy, pericarditis, anemia, with chronic hepatitis C. Anti-LKM2 is seen in drug-induced hepatitis,
azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia) occur. and anti-LKM3 (directed against uridine diphosphate glucuronyltrans-
In some patients, complications of cirrhosis, such as ascites and edema ferases) is seen in patients with chronic hepatitis D. Another autoanti-
(associated with portal hypertension and hypoalbuminemia), encepha- body observed in type II autoimmune hepatitis is directed against liver
lopathy, hypersplenism, coagulopathy, or variceal bleeding may bring cytosol formiminotransferase cyclodeaminase (anti-liver cytosol 1).
the patient to initial medical attention. Liver biopsy abnormalities are similar to those described for chronic
The course of autoimmune hepatitis may be variable. In patients viral hepatitis. Expanding portal tracts and extending beyond the plate
with mild disease or limited histologic lesions (e.g., piecemeal necrosis of periportal hepatocytes into the parenchyma (designated interface
without bridging), progression to cirrhosis is limited, but, even in this hepatitis or piecemeal necrosis) is a mononuclear cell infiltrate that, in
subset, clinical monitoring is important to identify progression; up to autoimmune hepatitis, may include the presence of plasma cells.
half left untreated can progress to cirrhosis over the course of 15 years. Necroinflammatory activity characterizes the lobular parenchyma, and
In North America, cirrhosis at presentation is more common in African evidence of hepatocellular regeneration is reflected by “rosette” for-
Americans than in whites. In those with severe symptomatic autoim- mation, the occurrence of thickened liver cell plates, and regenerative
mune hepatitis (aminotransferase levels >10 times normal, marked “pseudolobules.” Septal fibrosis, bridging fibrosis, and cirrhosis are
hyperglobulinemia, “aggressive” histologic lesions—bridging necrosis frequent. In patients with early autoimmune hepatitis presenting as an
or multilobular collapse, cirrhosis), the 6-month mortality without ther- acute-hepatitis-like illness, lobular and centrilobular (as opposed to the
apy may be as high as 40%. Such severe disease accounts for only 20% more common periportal) necrosis has been reported. Bile duct injury
of cases; the natural history of milder disease is variable, often accen- and granulomas are uncommon; however, a subgroup of patients
tuated by spontaneous remissions and exacerbations. Especially poor with autoimmune hepatitis has histologic, biochemical, and serologic
prognostic signs include the presence histologically of multilobular features overlapping those of primary biliary cirrhosis (Chap. 337).
collapse at the time of initial presentation and failure of serum bilirubin
to improve after 2 weeks of therapy. Death may result from hepatic ■■DIAGNOSTIC CRITERIA
failure, hepatic coma, other complications of cirrhosis (e.g., variceal An international group has suggested a set of criteria for establish-
hemorrhage), and intercurrent infection. In patients with established ing a diagnosis of autoimmune hepatitis. Exclusion of liver disease
cirrhosis, HCC may be a late complication (Chap. 78) but occurs less caused by genetic disorders, viral hepatitis, drug hepatotoxicity, and
frequently than in cirrhosis associated with viral hepatitis. alcohol are linked with such inclusive diagnostic criteria as hyperglob-

Laboratory features of autoimmune hepatitis are similar to those seen ulinemia, autoantibodies, and characteristic histologic features. This
in chronic viral hepatitis. Liver biochemical tests are invariably abnor- international group has also suggested a comprehensive diagnostic
mal but may not correlate with the clinical severity or histopathologic scoring system that, rarely required for typical cases, may be helpful
features in individual cases. Many patients with autoimmune hepatitis when typical features are not present. Factors that weigh in favor of
have normal serum bilirubin, alkaline phosphatase, and globulin lev- the diagnosis include female gender; predominant aminotransferase
els with only minimal aminotransferase elevations. Serum AST and elevation; presence and level of globulin elevation; presence of nuclear,
ALT levels are increased and fluctuate in the range of 100−1000 units. smooth muscle, LKM1, and other autoantibodies; concurrent other
In severe cases, the serum bilirubin level is moderately elevated autoimmune diseases; characteristic histologic features (interface hepa-
(51−171 μmol/L [3−10 mg/dL]). Hypoalbuminemia occurs in patients titis, plasma cells, rosettes); HLA-DR3 or DR4 markers; and response to
with very active or advanced disease. Serum alkaline phosphatase lev- treatment (see below). A more simplified, more specific scoring system
els may be moderately elevated or near normal. In a small proportion relies on four variables: autoantibodies, serum IgG level, typical or
of patients, marked elevations of alkaline phosphatase activity occur; compatible histologic features, and absence of viral hepatitis markers.
in such patients, clinical and laboratory features overlap with those of Weighing against the diagnosis are predominant alkaline phosphatase
primary biliary cirrhosis (Chap. 337). The prothrombin time is often elevation, mitochondrial antibodies, markers of viral hepatitis, history
prolonged, particularly late in the disease or during active phases. of hepatotoxic drugs or excessive alcohol, histologic evidence of bile
Polyclonal hypergammaglobulinemia (>2.5 g/dL) is common in duct injury, or such atypical histologic features as fatty infiltration, iron
autoimmune hepatitis, as is the presence of rheumatoid factor. As noted overload, and viral inclusions.
above, circulating autoantibodies are also prevalent, most characteris-
tically ANAs in a homogeneous staining pattern. Smooth-muscle anti- ■■DIFFERENTIAL DIAGNOSIS
bodies are less specific, seen just as frequently in chronic viral hepatitis. Early during the course of chronic hepatitis, autoimmune hepatitis
Because of the high levels of globulins achieved in the circulation of some may resemble typical acute viral hepatitis (Chap. 332). Without histo-
patients with autoimmune hepatitis, occasionally the globulins may bind logic assessment, severe chronic hepatitis cannot be readily distin-
nonspecifically in solid-phase binding immunoassays for viral antibod- guished based on clinical or biochemical criteria from mild chronic
ies. This has been recognized most commonly in tests for antibodies to hepatitis. In adolescence, Wilson’s disease (Chaps. 337 and 408) may
hepatitis C virus, as noted above. In fact, studies of autoantibodies in present with features of chronic hepatitis long before neurologic
autoimmune hepatitis have led to the recognition of new categories of manifestations become apparent and before the formation of Kay-
autoimmune hepatitis. Type I autoimmune hepatitis is the classic syndrome ser-Fleischer rings (copper deposition in Descemet’s membrane in the
prevalent in North America and northern Europe occurring in young periphery of the cornea). In this age group, serum ceruloplasmin and
women, associated with marked hyperglobulinemia, lupoid features, serum and urinary copper determinations plus measurement of liver
circulating ANAs, and HLA-DR3 or HLA-DR4 (especially B8-DRB1*03). copper levels establish the correct diagnosis. Postnecrotic or cryptogenic
Also associated with type I autoimmune hepatitis are autoantibodies cirrhosis and primary biliary cirrhosis (Chap. 337) share clinical features
against actin and atypical perinuclear antineutrophilic cytoplasmic anti- with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 335)
bodies (pANCA). Included in the spectrum of type-I autoimmune hepa- and nonalcoholic steatohepatitis (Chap. 336) may present with many
titis is a subset of patients who lack ANA and anti-LKM1, but who have features common to autoimmune hepatitis; historic, biochemical, sero-
circulating antibodies to soluble liver antigen. Most of these patients are logic, and histologic assessments are usually sufficient to allow these
women and have clinical features similar to, perhaps more severe than, entities to be distinguished from autoimmune hepatitis. Of course,
those of other patients with type I autoimmune hepatitis. the distinction between autoimmune and chronic viral hepatitis is
Type II autoimmune hepatitis, often seen in children, more common in not always straightforward, especially when viral antibodies occur in
Mediterranean populations, and linked to HLA- DRB1 and HLA-DQB1 patients with autoimmune disease or when autoantibodies occur in
haplotypes, is associated not with ANA but with anti-LKM. Actually, patients with viral disease. Furthermore, the presence of extrahepatic
anti-LKM represent a heterogeneous group of antibodies. In type II features such as arthritis, cutaneous vasculitis, or pleuritis—not to

2398 mention the presence of circulating autoantibodies—may cause con- promptly, but improvements in AST and ALT alone do not appear
fusion with rheumatologic disorders such as rheumatoid arthritis and to be reliable markers of recovery in individual patients; histologic
systemic LE. The existence of clinical and biochemical features of pro- improvement, characterized by a decrease in mononuclear infil-
gressive necroinflammatory liver disease distinguishes chronic hepa- tration and in hepatocellular necrosis, may be delayed for 6−24
titis from these other disorders, which are not associated with severe months. Still, if interpreted cautiously, aminotransferase levels
liver disease. Rarely, hepatic venous outflow obstruction (Budd-Chiari are valuable indicators of relative disease activity, and, although
syndrome) may present with features suggestive of autoimmune hep- recommended, many authorities do not advocate for serial liver
atitis, but painful hepatomegaly, ascites, and vascular imaging pro- biopsies to assess therapeutic success or to guide decisions to
vide distinguishing diagnostic clues. Other diagnostic considerations alter or stop therapy. Rapidity of response is more common in
would include celiac disease and ischemic liver disease, which would older patients (≥69 years) and those with HLA DBR1*04; although
be readily distinguishable by clinical and laboratory features from rapid responders may progress less slowly to cirrhosis and liver
autoimmune hepatitis. transplantation, they are no less likely than slower responders
Finally, occasionally, features of autoimmune hepatitis overlap with to relapse after therapy. Therapy should continue for at least
features of autoimmune biliary disorders such as primary biliary cirrho- 12−18 months. After tapering and cessation of therapy, the like-
sis, primary sclerosing cholangitis (Chaps. 337 and 339), or, even more lihood of relapse is at least 50%, even if posttreatment histology
rarely, mitochondrial antibody-negative autoimmune cholangitis. Such has improved to show mild chronic hepatitis, and the majority of
overlap syndromes are difficult to categorize, and often response to patients require therapy at maintenance doses indefinitely. Continu-
therapy may be the distinguishing factor that establishes the diagnosis. ing azathioprine alone (2 mg/kg body weight daily) after cessation
of prednisone therapy has been shown to reduce the frequency of
relapse. Long-term maintenance with low-dose prednisone (≤10 mg
TREATMENT daily) has also been shown to keep autoimmune hepatitis in check
Autoimmune Hepatitis without the theoretical risk of azathioprine marrow suppression
and, in young women of child-bearing age, teratogenicity; however,
The mainstay of management in autoimmune hepatitis is glucocor- maintenance azathioprine is more effective in preserving remission.
ticoid therapy. Several controlled clinical trials have documented In medically refractory cases, an attempt should be made to inten-
that such therapy leads to symptomatic, clinical, biochemical, and sify treatment with high-dose glucocorticoid monotherapy (60 mg
histologic improvement as well as increased survival. A therapeutic daily) or combination glucocorticoid (30 mg daily) plus high-dose
response can be expected in up to 80% of patients. Unfortunately, azathioprine (150 mg daily) therapy. After a month, doses of pred-
therapy has not been shown in clinical trials to prevent ultimate nisone can be reduced by 10 mg a month, and doses of azathioprine
PART 10
progression to cirrhosis; however, instances of reversal of fibrosis can be reduced by 50 mg a month toward ultimate, conventional
and cirrhosis have been reported in patients responding to treat- maintenance doses. Patients refractory to this regimen may be
ment, and rapid treatment responses within 1 year do translate into treated with cyclosporine, tacrolimus, or mycophenolate mofetil.
a reduction in progression to cirrhosis. Although some advocate Similarly, in exploratory studies, infusions of monoclonal antibod-
the use of prednisolone (the hepatic metabolite of prednisone), ies directed at tumor necrosis factor (infliximab) and against the
prednisone is just as effective and is favored by most authorities. B-lymphocyte antigen CD20 (rituximab) have been reported to be of
Therapy may be initiated at 20 mg/d, but a popular regimen in clinical benefit (improved aminotransferase levels, immunoglobulin
the United States relies on an initiation dose of 60 mg/d. This high G levels, histologic inflammatory activity) as rescue therapy for
dose is tapered successively over the course of a month down to a refractory autoimmune hepatitis. To date, however, only limited,
maintenance level of 20 mg/d. An alternative, but equally effective, often anecdotal, data in small numbers of patients support these
more appealing approach is to begin with half the prednisone dose alternative approaches. If medical therapy fails, or when chronic hep-
(30 mg/d) along with azathioprine (50 mg/d). With azathioprine atitis progresses to cirrhosis and is associated with life-threatening
maintained at 50 mg/d, the prednisone dose is tapered over complications of liver decompensation, liver transplantation is the
the course of a month down to a maintenance level of 10 mg/d. only recourse (Chap. 338); in patients with severe autoimmune
The advantage of the combination approach is a reduction, over hepatitis, failure of the bilirubin to improve after 2 weeks of therapy
the span of an 18-month course of therapy, in serious, life-threat- should prompt early consideration of the patient for liver transplan-
ening complications of steroid therapy (e.g., cushingoid features, tation. Recurrence of autoimmune hepatitis in the new liver occurs
hypertension, diabetes, osteoporosis) from 66% down to under rarely in most experiences but in as many as 35−40% of cases in
20%. Genetic analysis for thiopurine S-methyltransferase allelic others; nonetheless, 5-year patient and graft survival exceed 80%.
variants does not correlate with azathioprine-associated cytopenias Like all patients with chronic liver disease, patients with auto-
or efficacy and is not assessed routinely in patients with autoim- immune hepatitis should be vaccinated against hepatitis A and
mune hepatitis. In combination regimens, 6-mercaptopurine may be B, ideally before immunosuppressive therapy is begun, if practi-
substituted for its prodrug azathioprine, but this is rarely required. cal. Patients with autoimmune hepatitis and cirrhosis should be
Azathioprine alone, however, is not effective in achieving remission, screened for HCC with ultrasound at 6-month intervals and for
nor is alternate-day glucocorticoid therapy. Limited experience with gastroesophageal varices with upper gastrointestinal endoscopy at
budesonide in noncirrhotic patients suggests that this steroid side intervals of 1–3 years, based on severity of liver disease.
effect−sparing drug may be effective; however, the few randomized
controlled trials of budesonide have not consistently shown efficacy. ■■FURTHER READING
Although therapy has been shown to be effective for severe autoim- AASLD/IDSA HCV GUIDANCE PANEL: Hepatitis C guidance:
mune hepatitis (AST ≥10 × the upper limit of normal or ≥5 × the upper AASLD-IDSA recommendations for testing, managing, and treat-
limit of normal in conjunction with serum globulin greater than or ing adults infected with hepatitis C virus. Hepatology 62:932,
equal to twice normal; bridging necrosis or multilobular necrosis 2015. Updated regularly and available at http://www.hcvguidelines.org.
on liver biopsy; presence of symptoms), therapy is not indicated for Accessed September 22, 2016.
mild forms of chronic hepatitis, and the efficacy of therapy in mild or Carbone M, Neuberger JM: Autoimmune liver disease, autoimmunity
asymptomatic autoimmune hepatitis has not been established. and liver transplantation. J Hepatol 60:210, 2014.
Improvement of fatigue, anorexia, malaise, and jaundice tends European Association for the Study of the Liver: EASL clinical
to occur within days to several weeks; biochemical improve- practice guidelines: Management of chronic hepatitis B virus infection.
ment occurs over the course of several weeks to months, with J Hepatol 57:167, 2012.
a fall in serum bilirubin and globulin levels and an increase European Association for the Study of the Liver: EASL clinical
in serum albumin. Serum aminotransferase levels usually drop practice guidelines: autoimmune hepatitis. J Hepatol 63:971, 2015.

European Association for the Study of the Liver: EASL Recom- TABLE 335-1 Risk Factors for Alcoholic Liver Disease 2399
mendations on treatment of hepatitis C 2016. J Hepatol 2016 in press.
RISK FACTOR COMMENT
Available at http://dx.doi.org/10.1016/j. jhep.2016.09.001. Accessed
Quantity In men, 40–80 g/d of ethanol produces fatty liver;
September 22, 2016. 160 g/d for 10–20 years causes hepatitis or
Lok ASG et al: Antiviral therapy for chronic hepatitis B viral infection cirrhosis. Only 15% of alcoholics develop alcoholic
in adults: A systematic review and meta-analysis. Hepatology 63:284, liver disease.
2016. Gender Women exhibit increased susceptibility to alcoholic
Manns MP et al: AASLD Practice Guidelines: Diagnosis and manage- liver disease at amounts >20 g/d; two drinks per day
ment of autoimmune hepatitis. Hepatology 51;2193, 2010. is probably safe.
Pawlotsky J-M et al: From non-A, non-B hepatitis to hepatitis C virus Hepatitis C HCV infection concurrent with alcoholic liver disease
cure. J Hepatol 62:S87, 2015. is associated with younger age for severity, more
Terrault N et al: AASLD guidelines for treatment of chronic hepatitis B. advanced histology, and decreased survival.
Hepatology 63:261, 2016. Genetics Patatin-like phospholipase domain-containing protein
Wedemeyer H et al: Peginterferon plus adefovir versus either drug 3 (PNPLA3) has been associated with alcoholic
cirrhosis.
alone for hepatitis delta. N Engl J Med 364:322, 2011.
Fatty liver Alcohol injury does not require malnutrition, but
obesity and nonalcoholic fatty liver are risk factors.
Patients should receive vigorous attention to
nutritional support.
335 Alcoholic Liver Disease

Mark E. Mailliard, Michael F. Sorrell
differences result from poorly understood effects of estrogen, propor-
tion of body fat, and the gastric metabolism of alcohol. Obesity, a high-
fat diet, and the protective effect of coffee have been postulated to play
a part in the development of the pathogenic process.
Chronic infection with hepatitis C virus (HCV) (Chap. 334) is an
Chronic and excessive alcohol ingestion is a major cause of liver disease important comorbidity in the progression of alcoholic liver disease to
and is responsible for nearly 50% of the mortality from all cirrhosis. cirrhosis in chronic drinkers. Even light to moderate alcohol intake of
CHAPTER 335 Alcoholic Liver Disease

The pathology of alcoholic liver disease consists of three major lesions, 15–30 g/d increases the risk of cirrhosis and hepatocellular cancer in
with the progressive injury rarely existing in a pure form: (1) fatty liver, HCV-infected individuals. Patients with both alcoholic liver injury and
(2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in >90% HCV infection develop decompensated liver disease at a younger age
of daily as well as binge drinkers. A much smaller percentage of heavy and have poorer overall survival. Increased liver iron stores and, rarely,
drinkers will progress to alcoholic hepatitis, thought to be a precursor porphyria cutanea tarda can occur as a consequence of the overlapping
to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; injurious processes secondary to alcohol and HCV infection.
the mortality of patients with alcoholic hepatitis concurrent with cir- The pathogenesis of alcoholic liver injury is unclear. The present con-
rhosis is nearly 60% at 4 years. Although alcohol is considered a direct ceptual foundation is that alcohol acts as a direct hepatotoxin and that
hepatotoxin, only between 10 and 20% of alcoholics will develop alco- malnutrition does not have a major role. Ingestion of alcohol initiates
holic hepatitis. The explanation for this apparent paradox is unclear but an inflammatory cascade by its metabolism, resulting in a variety of
involves the complex interaction of facilitating factors such as drinking metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and
patterns, diet, obesity, and gender. There are no diagnostic tools that depression of fatty acid oxidation appears secondary to effects on sterol
can predict individual susceptibility to alcoholic liver disease. regulatory transcription factor and peroxisome proliferator-activated
receptor α (PPAR-α). Intestinal-derived endotoxin initiates a pathogenic
■■GLOBAL CONSIDERATIONS process through toll-like receptor 4 and tumor necrosis factor α (TNF-α)
Alcohol is the world's third largest risk factor for disease bur- that facilitates hepatocyte apoptosis and necrosis. The cell injury and
den. The harmful use of alcohol results in about 3.5 million endotoxin release initiated by ethanol and its metabolites also activate
deaths worldwide each year. Most of the mortality attributed innate and adaptive immunity pathways releasing proinflammatory
to alcohol is secondary to cirrhosis. Mortality from cirrhosis is directly cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells.
related to alcohol consumption, with the Eastern European countries The effect of chronic ethanol ingestion on intestinal permeability influ-
the most significantly burdened. Cirrhosis and its complications are ences liposaccharide hepatic influx as well as microbiome dysbiosis,
closely correlated with volume of alcohol consumed per capita popula- further contributing to the pathogenic process. The production of toxic
tion and are regardless of gender. protein-aldehyde adducts, generation of reducing equivalents, and oxi-
dative stress also play a role. Hepatocyte injury and impaired regener-
■■ETIOLOGY AND PATHOGENESIS ation following chronic alcohol ingestion are ultimately associated with
Quantity and duration of alcohol intake are the most important risk fac- stellate cell activation and collagen production; key events in fibrogen-
tors involved in the development of alcoholic liver disease (Table 335-1). esis. The resulting fibrosis from continuing alcohol use determines the
The roles of beverage type(s), i.e., wine, beer, or spirits, and pattern of architectural derangement of the liver and associated pathophysiology.
drinking (daily versus binge drinking) are less clear. Progress beyond
the fatty liver stage seems to require additional risk factors that remain ■■PATHOLOGY
incompletely defined. Although there are genetic predispositions for The liver has a limited repertoire in response to injury. Fatty liver is the
alcoholism (Chap. 445), gender is a strong determinant for alcoholic initial and most common histologic response to hepatotoxic stimuli,
liver disease. Women are more susceptible to alcoholic liver injury including excessive alcohol ingestion. The accumulation of fat within the
when compared to men. They develop advanced liver disease with perivenular hepatocytes coincides with the location of alcohol dehydroge-
substantially less alcohol intake. In general, the time it takes to develop nase, the major enzyme responsible for alcohol metabolism. Continuing
liver disease is directly related to the amount of alcohol consumed. It is alcohol ingestion results in fat accumulation throughout the entire hepatic
useful in estimating alcohol consumption to understand that one beer, lobule. Despite extensive fatty change and distortion of the hepatocytes
four ounces of wine, or one ounce of 80% spirits all contain ~12 g of with macrovesicular fat, the cessation of drinking results in normalization
alcohol. The threshold for developing alcoholic liver disease is higher of hepatic architecture and fat content. Alcoholic fatty liver has tradition-
in men (>14 drinks per week), while women are at increased risk for ally been regarded as entirely benign, but similar to the spectrum of non-
liver injury by consuming >7 drinks per week. Gender-dependent alcoholic fatty liver disease, the appearance of steatohepatitis and certain

2400 pathologic features such as giant mitochondria, perivenular fibrosis, and as 4.6 X (the prolongation of the prothrombin time above control [sec-
macrovesicular fat may be associated with progressive liver injury. onds]) + serum bilirubin (mg/dL) can identify patients with a poor
The transition between fatty liver and the development of alcoholic prognosis (discriminant function >32). A Model for End-Stage Liver
hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte Disease (MELD) score (Chap. 338) ≥21 also is associated with signifi-
injury characterized by ballooning degeneration, spotty necrosis, poly- cant mortality in alcoholic hepatitis. The presence of ascites, variceal
morphonuclear infiltrate, and fibrosis in the perivenular and perisinusoi- hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts
dal space of Disse. Mallory-Denk bodies are often present in florid cases a dismal prognosis. The pathologic stage of the injury can be helpful in
but are neither specific nor necessary to establish the diagnosis. Alcoholic predicting prognosis. Liver biopsy should be performed whenever pos-
hepatitis is thought to be a precursor to the development of cirrhosis. sible to establish the diagnosis and to guide the therapeutic decisions.
However, like fatty liver, it is potentially reversible with cessation of
drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven TREATMENT
alcoholic hepatitis, and its regression is uncertain, even with abstention.
Alcoholic Liver Disease
■■CLINICAL FEATURES
The clinical manifestations of alcoholic fatty liver are subtle and charac- Complete abstinence from alcohol is the cornerstone in the treatment
teristically detected as a consequence of the patient's visit for a seemingly of alcoholic liver disease. Improved survival and the potential for
unrelated matter. Previously unsuspected hepatomegaly is often the only reversal of histologic injury regardless of the initial clinical pre-
clinical finding. Occasionally, patients with fatty liver will present with sentation are associated with total avoidance of alcohol ingestion.
right upper quadrant discomfort, nausea, and, rarely, jaundice. Differenti- Referral of patients to experienced alcohol counselors and/or alco-
ation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless hol treatment programs should be routine in the management of
an accurate drinking history is ascertained. In every instance where liver patients with alcoholic liver disease. Attention should be directed
disease is present, a thoughtful and sensitive drinking history should be to the nutritional and psychosocial states during the evaluation and
obtained. Standard, validated questions accurately detect alcohol-related treatment periods. Because of data suggesting that the pathogenic
problems (Chap. 445). Alcoholic hepatitis is associated with a wide gamut mechanisms in alcoholic hepatitis involve cytokine release and
of clinical features. Fever, spider nevi, jaundice, and abdominal pain the perpetuation of injury by immunologic processes, glucocorti-
simulating an acute abdomen represent the extreme end of the spectrum, coids have been extensively evaluated in the treatment of alcoholic
while many patients will be entirely asymptomatic. Portal hypertension, hepatitis. Patients with severe alcoholic hepatitis, defined as a dis-
ascites, or variceal bleeding can occur in the absence of cirrhosis. Recogni- criminant function >32 or MELD >20, should be given prednisone,
tion of the clinical features of alcoholic hepatitis is central to the initiation 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a ste-
of an effective and appropriate diagnostic and therapeutic strategy. It is roid taper (Fig. 335-1). Exclusion criteria include active gastrointesti-
PART 10
important to recognize that patients with alcoholic cirrhosis often exhibit nal bleeding, renal failure, or pancreatitis. Patients with infection can
clinical features identical to other causes of cirrhosis. be concurrently treated with antibiotics and steroids. Women with
encephalopathy from severe alcoholic hepatitis may be particularly
■■LABORATORY FEATURES good candidates for glucocorticoids. A Lille score >0.45, at http://
Patients with alcoholic liver disease are often identified through routine
www.lillemodel.com, uses pretreatment variables plus the change in

screening tests. The typical laboratory abnormalities seen in fatty liver are total bilirubin at day 7 of glucocorticoids to identify those patients
nonspecific and include modest elevations of aspartate aminotransferase unresponsive to therapy.
(AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase The role of TNF-α expression and receptor activity in alco-
(GGTP), often accompanied by hypertriglyceridemia and hyperbiliru- holic liver injury has led to an examination of pentoxifylline, the
binemia. In alcoholic hepatitis and in contrast to other causes of fatty nonspecific TNF inhibitor, either by itself, or with glucocorticoids
liver, AST and ALT are usually elevated two- to sevenfold. They are rarely for severe alcoholic hepatitis. In one study, pentoxifylline demon-
>400 IU, and the AST/ALT ratio is >1 (Table 335-2). Hyperbilirubinemia strated an improved survival in the therapy of severe alcoholic
is accompanied by modest increases in the alkaline phosphatase level. hepatitis, primarily due to a decrease in hepatorenal syndrome.
Derangement in hepatocyte synthetic function indicates more serious Subsequent clinical trials failed to find an increased benefit from
disease. Hypoalbuminemia and coagulopathy are common in advanced pentoxifylline, either by itself or in combination with prednisolone
liver injury. Ultrasonography is useful in detecting fatty infiltration of (Fig. 335-2).
the liver and determining liver size. The demonstration by ultrasound of
portal vein flow reversal, ascites, and intraabdominal venous collaterals
indicates serious liver injury with less potential for complete reversal.
100
■■PROGNOSIS 84.6 3.4%
Critically ill patients with alcoholic hepatitis have short-term (30-day)
mortality rates >50%. Severe alcoholic hepatitis is heralded by coagul- p = .001
75
Cumulative survival, %
opathy (prothrombin time increased >5 s), anemia, serum albumin con-
centrations <25 g/L (2.5 mg/dL), serum bilirubin levels >137 μmol/L
65.1 4.8%
(8 mg/dL), renal failure, and ascites. A discriminant function calculated
50
TABLE 335-2 Laboratory Diagnosis of Alcoholic Fatty Liver and
Alcoholic Hepatitis
TEST COMMENT 25
AST Increased two- to sevenfold, <400 IU/L, greater than ALT
ALT Increased two- to sevenfold, <400 IU/L
AST/ALT Usually >1 0
GGTP Not specific to alcohol, easily inducible, elevated in all forms 0 7 14 21 28
of fatty liver Days
Bilirubin May be markedly increased in alcoholic hepatitis despite FIGURE 335-1 Effect of glucocorticoid therapy of severe alcoholic hepatitis on
modest elevation in alkaline phosphatase short-term survival: the result of a meta-analysis of individual data from three
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; studies. Prednisolone, solid line; placebo, dotted line. (Adapted from P Mathurin
GGTP, γ-glutamyl transpeptidase. et al: J Hepatol 36:480, 2002, with permission from Elsevier Science.)

as greater than one drink per day in women or two drinks per day in 2401
Alcoholic Hepatitis men), they are considered to have NAFLD. NAFLD is strongly associ-
ated with overweight/obesity and insulin resistance. However, it can
also occur in lean individuals and is particularly common in those with
Alcohol abstinence a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial factors
Nutritional support also appear to influence liver fat accumulation; the documented prev-
alence of NAFLD is lowest in African Americans (~25%), highest in
Americans of Hispanic ancestry (~50%), and intermediate in American
Discriminant function ≥32 whites (~33%).
or MELD ≥21 NAFLD encompasses a spectrum of liver pathology with different
(with absence of co-morbidity) clinical prognoses. The simple accumulation of triglyceride within
hepatocytes (hepatic steatosis) is on the most clinically benign extreme
of the spectrum. On the opposite, most clinically ominous extreme,
No GI bleeding, renal are cirrhosis (Chap. 337) and primary liver cancer (Chap. 78). The risk
failure, or pancreatitis of developing cirrhosis is extremely low in individuals with chronic
hepatic steatosis, but increases as steatosis becomes complicated by
histologically conspicuous hepatocyte death and inflammation (i.e.,
nonalcoholic steatohepatitis [NASH]). NASH itself is also a heteroge-
Prednisolone 32
or Prednisone 40 mg
neous condition; sometimes it improves to steatosis or normal histol-
p.o daily for 4 weeks ogy, sometimes it remains relatively stable for years, but sometimes
it results in progressive accumulation of fibrous scar that eventuates
in cirrhosis. Once NAFLD-related cirrhosis develops, the annual inci-
FIGURE 335-2 Treatment algorithm for alcoholic hepatitis. As identified by a
calculated discriminant function >32 or MELD >20 (see text), patients with severe dence of primary liver cancer can be as high as 3%.
alcoholic hepatitis, without the presence of gastrointestinal bleeding, renal failure Abdominal imaging is not able to determine which individuals with
or pancreatitis would be candidates for glucocorticoids. NAFLD have associated liver cell death and inflammation (i.e., NASH),
and specific blood tests to diagnose NASH are not yet available. How-
ever, population-based studies that have used elevated serum ALT as a
Liver transplantation is an accepted indication for treatment in marker of liver injury indicate that about 6–8% of American adults have
CHAPTER 336 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

select patients with complications of cirrhosis secondary to alcohol serum ALT elevations that cannot be explained by excessive alcohol
abuse. Outcomes are equal or superior to other indications for trans- consumption, other known causes of fatty liver disease (Table 336-1),
plantation. In general, transplant candidacy should be reevaluated viral hepatitis, or drug-induced or congenital liver diseases. Because
after a defined period of sobriety. Patients presenting with alcoholic the prevalence of such “cryptogenic” ALT elevations increases with
hepatitis have been largely excluded from transplant candidacy
because of the perceived risk of increased surgical mortality and
high rates of recidivism following transplantation. A European TABLE 336-1 Alternative Causes of Hepatic Steatosis
multidisciplinary group has reported excellent long-term transplant • Alcoholic liver disease
outcomes in highly selected patients with florid alcoholic hepatitis. • Hepatitis C (particularly genotype 3)
General application of transplantation in such patients must await • Inborn errors of metabolism
confirmatory outcomes. • Abetalipoproteinemia
• Cholesterol ester storage disease
■■FURTHER READING • Galactosemia
Mathurin P et al: Corticosteroids improves short-term survival in • Glycogen storage disease
patients with severe alcoholic hepatitis (AH): Individual data analysis • Hereditary fructose intolerance
of the last three randomized placebo controlled double blind trials of • Homocystinuria
corticosteroids in severe AH. J Hepatol 36:480, 2002. • Systemic carnitine deficiency
Sanyal AJ et al: Alcoholic and nonalcoholic fatty liver disease. • Tyrosinemia
Gastroenterology 150:8 (suppl), 2016. • Weber-Christian syndrome
Thurz MR et al: Prednisolone or pentoxifylline for alcoholic hepatitis.
• Wilson’s disease
N Engl J Med 372:1619, 2015.
• Wolman’s disease
• Medications (see Table 336-2)
• Miscellaneous
• Industrial exposure to petrochemical
336 Nonalcoholic
• Inflammatory bowel disease
Fatty Liver • Lipodystrophy
Diseases and Nonalcoholic • Bacterial overgrowth
• Starvation
Steatohepatitis • Parenteral nutrition
• Surgical procedures
Manal F. Abdelmalek, Anna Mae Diehl • Bilopancreatic diversion
• Extensive small-bowel resection
• Gastric bypass
■■INCIDENCE, PREVALENCE, AND NATURAL HISTORY • Jejunoileal bypass
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic • Reye’s syndrome
liver disease in many parts of the world, including the United States.
• Acute fatty liver of pregnancy
Population-based abdominal imaging studies have demonstrated fatty
• HELLP syndrome (hemolytic anemia, elevated liver enzymes,
liver in at least 25% of American adults. Because the vast majority of
low platelet count)
these subjects deny hazardous levels of alcohol consumption (defined

2402 body mass index, it is presumed that they are due to NASH. Hence, at morphologic manifestation of lipotoxicity and resultant wound healing
any given point in time, NASH is present in about 25% of individuals responses. Because the severity and duration of lipotoxic liver injury
who have NAFLD (i.e., about 6% of the general U.S. adult population dictate the intensity and duration of repair, the histologic features and
has NASH). Smaller cross-sectional studies in which liver biopsies outcomes of NASH are variable. Cirrhosis and liver cancer are potential
have been performed on NASH patients at tertiary referral centers outcomes of chronic NASH. Cirrhosis results from futile repair, i.e.,
consistently demonstrate advanced fibrosis or cirrhosis in about 25% of progressive accumulation of wound healing cells, fibrous matrix, and
those cohorts. By extrapolation, therefore, cirrhosis develops in about abnormal vasculature (scarring), rather than efficient reconstruction/
6% of individuals with NAFLD (i.e., in about 1.5–2% of the general U.S. regeneration of healthy hepatic parenchyma. Primary liver cancers
population). The risk for advanced liver fibrosis is highest in individ- develop when malignantly transformed liver cells escape mechanisms
uals with NASH who are aged >45–50 years and overweight/obese or that normally control regenerative growth. The mechanisms respon-
afflicted with type 2 diabetes. sible for futile repair (cirrhosis) and liver carcinogenesis are not well
Heritable factors clearly impact susceptibility to hepatic steatosis, understood. Because normal liver regeneration is a very complex
NASH, liver fibrosis, and liver cancer. Indeed, recent twin studies process, there are multiple opportunities for deregulation and, thus,
suggest that inheritance accounts for about half the risk for developing pathogenic heterogeneity. To date, this heterogeneity has confounded
cirrhosis. Certain variants in PNPLA3 (a gene that encodes an enzyme development of both diagnostic tests and treatments for defective/
involved in intracellular trafficking of lipids) consistently correlates deregulated liver repair (i.e., cirrhosis and cancer). Hence, current strat-
with susceptibility to hepatic steatosis, cirrhosis, and liver cancer. Poly- egies focus on circumventing misrepair by preventing and/or reducing
morphisms in other genes involved in lipid homeostasis (e.g., TM6SF2 lipotoxic liver injury.
and MBOAT7) are also emerging as potential genetic risk factors for
NAFLD. Epigenetic factors (i.e., heritable traits that do not result from ■■DIAGNOSIS
direct changes in DNA) may also influence NAFLD pathogenesis and/ Diagnosing NAFLD requires demonstration of increased liver fat in
or progression based on evidence that intra-uterine exposures influence the absence of hazardous levels of alcohol consumption. Thresholds
susceptibility to obesity and the metabolic syndrome in adolescence. for potentially dangerous alcohol ingestion have been set at more than
Experts have predicted that NAFLD will be the leading indica- one drink per day in women and two drinks per day in men based on
tion for liver transplantation in the United States by 2020. Similar to epidemiologic evidence that the prevalence of serum aminotransferase
cirrhosis caused by other liver diseases, cirrhosis caused by NAFLD elevations increases when alcohol consumption habitually exceeds
increases the risk for primary liver cancer. Both hepatocellular car- these levels. In those studies, one drink was defined as having 10 g of
cinoma and intrahepatic cholangiocarcinoma (ICC) have also been ethanol and, thus, is equivalent to one can of beer, 4 ounces of wine,
reported to occur in NAFLD patients without cirrhosis, suggesting that or 1.5 ounces (one shot) of distilled spirits. Other causes of liver fat
PART 10
NAFLD per se may be a premalignant condition. NAFLD, NASH, and accumulation (particularly exposure to certain drugs; Table 336-2) and
NAFLD-related cirrhosis are not limited to adults. All have been well liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or cop-
documented in children. As in adults, obesity and insulin resistance are per overload, α1 antitrypsin deficiency) must also be excluded. Thus,
the main risk factors for pediatric NAFLD. Thus, the rising incidence
and prevalence of childhood obesity suggests that NAFLD is likely to
become an even greater contributor to society’s burden of liver disease TABLE 336-2 Medications Associated with Hepatic Steatosis
in the future. • Cytotoxic and cytostatic drugs
• l-Asparaginase
■■PATHOGENESIS • Azacitidine
The mechanisms underlying the pathogenesis and progression of • Azaserine
NAFLD are not entirely clear. The best-understood mechanisms per- • Bleomycin
tain to hepatic steatosis. This is proven to result when hepatocyte • Methotrexate
mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo • Puromycin
lipogenesis) overwhelm mechanisms for triglyceride disposal (e.g.,
• Tetracycline
degradative metabolism and lipoprotein export), leading to accumu-
• Doxycycline
lation of fat (i.e., triglyceride) within hepatocytes. Obesity stimulates
hepatocyte triglyceride accumulation by altering the intestinal microbi- • Metals
ota to enhance both energy harvest from dietary sources and intestinal • Antimony
permeability. Reduced intestinal barrier function increases hepatic • Barium salts
exposure to gut-derived products, which stimulate liver cells to gener- • Chromates
ate inflammatory mediators that inhibit insulin actions. Obese adipose • Phosphorus
depots also produce excessive soluble factors (adipokines) that inhibit • Rare earths of low atomic number
tissue insulin sensitivity. Insulin resistance promotes hyperglycemia. • Thallium compounds
This drives the pancreas to produce more insulin to maintain glucose • Uranium compounds
homeostasis. However, hyperinsulinemia also promotes lipid uptake, • Other drugs and toxins
fat synthesis, and fat storage. The net result is hepatic triglyceride accu- • Amiodarone
mulation (i.e., steatosis).
• 4,4′-Diethylaminoethoxyhexesterol
Triglyceride per se is not hepatotoxic. However, its precursors (e.g.,
• Ethionine
fatty acids and diacylglycerols) and metabolic by-products (e.g., reac-
tive oxygen species) may damage hepatocytes, leading to hepatocyte • Ethyl bromide
lipotoxicity. Lipotoxicity also triggers the generation of other factors • Estrogens
(e.g., inflammatory cytokines, hormonal mediators) that deregulate • Glucocorticoids
systems that normally maintain hepatocyte viability. The net result is • Highly active antiretroviral therapy
increased hepatocyte death. Dying hepatocytes, in turn, release vari- • Hydralazine
ous factors that trigger wound healing responses that aim to replace • Hypoglycin
(regenerate) lost hepatocytes. Such repair involves transient expansion • Orotate
of other cell types, such as myofibroblasts and progenitor cells, that • Perhexiline maleate
make and degrade matrix, remodel the vasculature, and generate • Safrole
replacement hepatocytes, as well as the recruitment of immune cells • Tamoxifen
that release factors that modulate liver injury and repair. NASH is the

establishing the diagnosis of NAFLD does not require invasive testing: ■■CLINICAL FEATURES OF NAFLD 2403
it can be accomplished by history and physical examination, liver Most subjects with NAFLD are asymptomatic. The diagnosis is often
imaging (ultrasound is an acceptable first-line test; computed tomog- made when abnormal liver aminotransferases or features of fatty liver
raphy [CT] or magnetic resonance imaging [MRI] enhances sensitivity are noted during an evaluation performed for other reasons. NAFLD
for liver fat detection but adds expense), and blood tests to exclude may also be diagnosed during the workup of vague right upper
other liver diseases. It is important to emphasize that the liver may quadrant abdominal pain, hepatomegaly, or an abnormal-appearing
not be enlarged, and serum aminotransferases and liver function tests liver at time of abdominal surgery. Obesity is present in 50–90% of sub-
(e.g., bilirubin, albumin, prothrombin time) may be completely normal, jects. Most patients with NAFLD also have other features of the meta-
in individuals with NAFLD. Because there is yet no one specific blood bolic syndrome (Chap. 401). Some have subtle stigmata of chronic liver
test for NAFLD, confidence in the diagnosis of NAFLD is increased disease, such as spider angiomata, palmer erythema, or splenomegaly.
by identification of NAFLD risk factors. The latter include increased In a small minority of patients with advanced NAFLD, complications
body mass index, insulin resistance/type 2 diabetes mellitus, and other of end-stage liver disease (e.g., jaundice, features of portal hyperten-
parameters indicative of the metabolic syndrome (e.g., systemic hyper- sion such as ascites or variceal hemorrhage) may be the initial findings.
tension, dyslipidemia, hyperuricemia/gout, cardiovascular disease; The association of NAFLD with obesity, diabetes, hypertriglyceri-
Chap. 401) in the patient or family members. demia, hypertension, and cardiovascular disease is well known. Other
Establishing the severity of NAFLD-related liver injury and related associations include chronic fatigue, mood alterations, obstructive
scarring (i.e., staging NAFLD) is more difficult than simply diagnosing sleep apnea, thyroid dysfunction, and chronic pain syndrome. NAFLD
NAFLD. Staging is critically important, however, because it is neces- is an independent risk factor for metabolic syndrome (Chap. 401).
sary to define prognosis and thereby determine treatment recommen- Longitudinal studies suggest that patients with NASH are at two- to
dations. The goal of staging is to distinguish patients with NASH from threefold increased risk for the development of metabolic syndrome.
those with simple steatosis and to identify which of the NASH patients Similarly, studies have shown that patients with NASH have a higher
have advanced fibrosis. The 10-year probability of developing liver- risk for the development of hypertension and diabetes mellitus. The
related morbidity or mortality in steatosis is negligible, and hence, this presence of NAFLD is also independently associated with endothe-
subgroup of NAFLD patients tends to be managed conservatively (see lial dysfunction, increased carotid intimal thickness, and the number
below). In contrast, more intensive follow-up and therapy are justified of plaques in carotid and coronary arteries. Such data indicate that
in NASH patients, and the subgroup with advanced fibrosis merits the NAFLD has many deleterious effects on health in general.
most intensive scrutiny and intervention because their 10-year risk of
liver-related morbidity and mortality is clearly increased. ■■TREATMENT OF NAFLD
CHAPTER 336 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis

Staging approaches can be separated into noninvasive testing Treatment of NAFLD can be divided into three components: (1) specific
(i.e., blood testing, physical examination, and imaging) and invasive therapy of NAFLD-related liver disease; (2) treatment of NAFLD-
approaches (i.e., liver biopsy). Blood test evidence of hepatic dys- associated comorbidities; and (3) treatment of the complications of
function (e.g., hyperbilirubinemia, hypoalbuminemia, prothrombin advanced NAFLD. The subsequent discussion focuses on specific ther-
time prolongation) or portal hypertension (e.g., thrombocytopenia) apies for NAFLD, with some mention of their impact on major NAFLD
and stigmata of portal hypertension on physical examination (e.g., comorbidities (insulin resistance/diabetes, obesity, and dyslipidemia).
spider angiomata, palmar erythema, splenomegaly, ascites, clubbing, Treatment of the complications of advanced NAFLD involves manage-
encephalopathy) suggest a diagnosis of advanced NAFLD. Currently, ment of the complications of cirrhosis and portal hypertension, includ-
however, liver biopsy is the gold standard for establishing the severity ing primary liver cancers. Approaches to accomplish these objectives
of liver injury and fibrosis because it is both more sensitive and specific are similar to those used in other chronic liver diseases and are covered
than these other tests for establishing NAFLD severity. Although inva- elsewhere in the textbook (Chaps. 337 and 78).
sive, liver biopsy is seldom complicated by serious adverse sequelae At present, there are no Food and Drug Administration (FDA)-
such as significant bleeding, pain, or inadvertent puncture of other approved therapies for the treatment of NAFLD. Thus, the current
organs and thus is relatively safe. However, biopsy suffers from poten- approach to NAFLD management focuses on treatment to improve
tial sampling error unless tissue cores of 2 cm or longer are acquired. the risk factors for NASH (i.e., obesity, insulin resistance, metabolic
Also, examination of tissue at a single point in time is not reliable syndrome, dyslipidemia). Based on our understanding of the natural
for determining whether the pathologic processes are progressing or history of NAFLD, only patients with NASH or those with features of
regressing. The risk of serial liver biopsies within short time intervals hepatic fibrosis on liver biopsy are considered currently for targeted
is generally deemed as unacceptable outside of research studies. These pharmacologic therapies. This approach may change as our under-
limitations of liver biopsy have stimulated efforts to develop nonin- standing of disease pathophysiology improves and potential targets of
vasive approaches to stage NAFLD. As is true for many other types therapy evolve.
of chronic liver disease, in NAFLD the levels of serum aminotransfer- Diet and Exercise Lifestyle changes and dietary modification are
ases (aspartate aminotransferase [AST] and alanine aminotransferase the foundation for NAFLD treatment. Many studies indicate that life-
[ALT]) do not reliably reflect the severity of liver cell injury, extent of style modification can improve serum aminotransferases and hepatic
liver cell death, or related liver inflammation and fibrosis. Thus, they steatosis, with loss of at least 3–5% of body weight improving steatosis,
are imperfect for determining which individuals with NAFLD have but greater weight loss (up to 10%) necessary to improve steatohep-
NASH. This has prompted efforts to identify superior markers of atitis. The benefits of different dietary macronutrient contents (e.g.,
NASH, and particularly liver fibrosis, because fibrosis stage predicts low-carbohydrate vs low-fat diets, saturated vs unsaturated fat diets)
eventual liver outcomes and mortality in NASH. Algorithms that and different intensities of calorie restriction appear to be comparable.
combine various laboratory tests (e.g., ELF score, BARD Score, NAFLD In adults with NAFLD, exercise regimens that improve fitness may be
Fibrosis Score, APRI score) are somewhat helpful in separating NASH sufficient to reduce hepatic steatosis, but their impact on other aspects
patients with advanced versus mild liver fibrosis. Combining these of liver histology remains unknown. Unfortunately, most NAFLD
tests with new imaging approaches that permit noninvasive quantifica- patients are unable to achieve sustained weight loss. Although phar-
tion of liver fat (e.g., MRI using proton density fat fraction [MRI-PDFF]) macologic therapies such as orlistat, topiramate, and phentermine to
and liver stiffness, a surrogate marker of liver fibrosis (e.g., magnetic facilitate weight loss are available, their role in the treatment of NAFLD
resonance elastography, MRE, and transient elastography, FibroScan) remains experimental.
improves their predictive power (Chap. 330). Increasingly, these new
tools are being used serially to monitor fibrosis progression and regres- Pharmacologic Therapies Several drug therapies have been
sion in NAFLD patients. As a result, liver biopsy staging is becoming tried in both research and clinical settings. No agent has yet been
restricted to patients who cannot be stratified reliably using these non- approved by the FDA for the treatment of NAFLD. Hence, this remains
invasive assessments. an area of active research. Because NAFLD is strongly associated with

2404 the metabolic syndrome and type 2 diabetes (Chaps. 396 and 397), or patients with other chronic liver diseases. Moreover, several stud-
the efficacy of various insulin-sensitizing agents has been examined. ies have suggested that statins may improve aminotransferases and
Metformin, an agent that mainly improves hepatic insulin sensitivity, histology in patients with NASH. Yet, there is continued reluctance to
has been evaluated in several small, open-label studies in adults and use statins in patients with NAFLD. The lack of evidence that statins
a recent larger, prospectively randomized trial in children (dubbed the harm the liver in NAFLD patients, combined with the increase risk for
TONIC study). Although several of the adult NASH studies suggested cardiovascular morbidity and mortality in NAFLD patients, warrants
improvements in aminotransferases and/or liver histology, metfor- the use of statins to treat dyslipidemia in patients with NAFLD/NASH.
min did not improve liver histology in the TONIC study of children
with NASH. Thus, it is not currently recommended as a treatment for Bariatric Surgery Although interest in bariatric surgery as a
NASH. Uncontrolled open-label studies have also investigated thiazoli- treatment for NAFLD exists, a recently published Cochrane review
dinediones (pioglitazone and rosiglitazone) in adults with NASH. This class concluded that lack of randomized clinical trials or adequate clinical
of drugs is known to improve systemic insulin resistance. Both pioglita- studies prevents definitive assessment of benefits and harms of bariat-
zone and rosiglitazone reduced aminotransferases and improved some ric surgery as a treatment for NASH. Most studies of bariatric surgery
of the histologic features of NASH in small, uncontrolled studies. A have shown that bariatric surgery is generally safe in individuals with
large, National Institutes of Health–sponsored, randomized placebo- well-compensated chronic liver disease and improves hepatic steatosis
controlled clinical trial, the PIVENS Study (Pioglitazone vs Vitamin E and necroinflammation (i.e., features of NAFLD/NASH); however,
vs Placebo for the Treatment of 247 Nondiabetic Adults with NASH), effects on hepatic fibrosis have been variable. Concern lingers because
demonstrated that resolution of histologic NASH occurred more often some of the largest prospective studies suggest that hepatic fibrosis
in subjects treated with pioglitazone (30 mg/d) than with placebo for might progress after bariatric surgery. Thus, the Cochrane review
18 months (47 vs 21%, p = .001). However, many subjects in the piogli- deemed it premature to recommend bariatric surgery as a primary
tazone group gained weight, and liver fibrosis did not improve. Also, treatment for NASH. This opinion was challenged by a recently study
it should be noted that the long-term safety and efficacy of thiazoli- which demonstrated that fibrosis stage had improved by 5 years after
dinediones in patients with NASH has not been established. Five-year surgery in about half the patients in one large bariatric surgery cohort.
follow-up of subjects treated with rosiglitazone demonstrated no However, most of those individuals had relatively mild fibrosis initially
reduction in liver fibrosis, and rosiglitazone has been associated with and thus, it is unclear if similar outcomes would occur in individuals
increased long-term risk for cardiovascular mortality. Hence, it is not with more advanced liver disease. Indeed there is general agreement
recommended as a treatment for NAFLD. Pioglitazone may be safer that patients with NAFLD-related cirrhosis and portal hypertension
because in a recent large meta-analysis it was associated with reduced should be excluded as candidates for bariatric surgery. However, given
overall morality, myocardial infarction, and stroke. However, caution growing evidence for the benefits of bariatric surgery on metabolic
must be exercised when considering its use in patients with impaired syndrome complications in individuals with refractory obesity, it is not
PART 10
myocardial function. contraindicated in otherwise eligible patients with NAFLD or NASH.

Antioxidants have also been evaluated for the treatment of NAFLD
because oxidant stress is thought to contribute to the pathogenesis Liver Transplantation Patients with NAFLD in whom end-stage
of NASH. Vitamin E, an inexpensive yet potent antioxidant, has liver disease develops should be evaluated for liver transplantation
(Chap. 338). The outcomes of liver transplantation in well-selected
been examined in several small pediatric and adult studies with

varying results. In all of those studies, vitamin E was well tolerated, patients with NAFLD are generally good, but comorbid medical con-
and most showed modest improvements in aminotransferase levels, ditions associated with NAFLD, such as diabetes mellitus, obesity, and
radiographic features of hepatic steatosis, and/or histologic features cardiovascular disease, often limit transplant candidacy. NAFLD may
of NASH. Vitamin E (800 IU/d) was also compared to placebo in the recur after liver transplantation. The risk factors for recurrent or de
PIVENS and TONIC studies. In PIVENS, vitamin E was the only agent novo NAFLD after liver transplantation are multifactorial and include
that achieved the predetermined primary endpoint (i.e., improvement hypertriglyceridemia, obesity, diabetes mellitus, and immunosuppres-
in steatohepatitis, lobular inflammation, and steatosis score, without an sive therapies, particularly glucocorticoids.
increase in the fibrosis score). This endpoint was met in 43% of patients
in the vitamin E group (p = .001 vs placebo), 34% in the pioglitazone ■■GLOBAL HEALTH CONSIDERATIONS
group (p = .04 vs placebo), and 19% in the placebo group. Vitamin The epidemic of obesity is now a global and accelerating phe-
E also improved NASH histology in pediatric patients with NASH nomenon. Worldwide, there are >1 billion overweight adults, of
(TONIC trial). However, a recent population-based study suggested whom at least 300 million are obese. The worldwide prevalence
that chronic vitamin E therapy may increase the risk for cardiovascular of obesity has more than doubled since 1980. In the wake of the obesity
mortality. Thus, vitamin E should only be considered as a first-line epidemic follow numerous comorbidities, including NAFLD. NAFLD is
pharmacotherapy for nondiabetic NASH patients. Also, given its the most common liver disease identified in Western countries and the
potentially negative effects on cardiovascular health, caution should be fastest rising form of chronic liver disease worldwide. The economic
exercised until the risk-to-benefit ratio and long-term therapeutic effi- burden directly attributable to NAFLD is already enormous (estimated
cacy of vitamin E are better defined. Ursodeoxycholic acid (a bile acid as $103 billion/year in the United States and nearly 35 billion Euros/
that improves certain cholestatic liver diseases) and betaine (metabolite year for four European Union countries) and predicted to increase ten-
of choline that raises SAM levels and decreases cellular oxidative dam- fold by the year 2025. Present understanding of NAFLD natural history
age) offer no histologic benefit over placebo in patients with NASH. is based mainly on studies in whites who became overweight/obese
Experimental evidence to support the use of omega-3 fatty acids in and developed the metabolic syndrome in adulthood. The impact of
NAFLD exists; however, a recent large, multicenter, placebo-controlled the global childhood obesity epidemic on NAFLD pathogenesis/pro-
study failed to demonstrate a histologic benefit. Other pharmacother- gression is unknown. Emerging evidence demonstrates that advanced
apies are also being evaluated in NAFLD (e.g., probiotics, farnesoid X NAFLD, including cirrhosis and primary liver cancer, can occur in
receptor agonists, intestinal bile acid transport inhibitors, fibroblast growth children, prompting concerns that childhood-onset NAFLD might fol-
factor agonists, anticytokine agents, glucagon-like peptide agonists, dipeptidyl low a more aggressive course than typical adult-acquired NAFLD.
IV antagonists, dual PPAR-alpha/PPAR-delta agonists, modulators of liver Some of the most populated parts of the world are in the midst of
fibrosis); however, sufficient data do not yet exist to justify their use as industrial revolutions, and certain environmental pollutants seem to
NASH treatments in standard clinical practice. exacerbate NAFLD. Some studies also suggest that the risk for NASH
Statins are an important class of agents to treat dyslipidemia and and NAFLD-related cirrhosis may be higher in certain ethnic groups
decrease cardiovascular risk. There is no evidence to suggest that such as Asians, certain Hispanics, and Native Americans and lower in
statins cause liver failure in patients with any chronic liver disease, others such as African Americans, compared with whites. Although all
including NAFLD. The incidence of liver enzyme elevations in NAFLD of these variables confound efforts to predict the net impact of this
patients taking statins is also no different than that of healthy controls obesity-related liver disease on global health, it seems likely that

NAFLD will remain a major cause of chronic liver disease worldwide TABLE 337-1 Causes of Cirrhosis 2405
for the foreseeable future. Alcoholism Cardiac cirrhosis
■■FURTHER READING Chronic viral hepatitis Inherited metabolic liver disease
Angulo P et al: Fibrosis in nonalcoholic fatty liver disease: Mecha- Hepatitis B Hemochromatosis
nisms and clinical implications. Semin Liver Dis 35:132, 2015. Hepatitis C Wilson’s disease
Chalasani N et al: The diagnosis and management of non-alcoholic Autoimmune hepatitis α1 Antitrypsin deficiency
fatty liver disease: Practice guideline by the American Gastroentero- Nonalcoholic steatohepatitis Cystic fibrosis
logical Association, American Association for the Study of Liver Dis- Biliary cirrhosis Cryptogenic cirrhosis
eases, and American College of Gastroenterology. Gastroenterology Primary biliary cholangitis
142:1592, 2012. Primary sclerosing cholangitis
European Association for the Study of the Liver (EASL); Euro-
Autoimmune cholangiopathy
pean Association for the Study of Diabetes (EASD); European
Association for the Study of Obesity (EASO): EASL-EASD-EASO
Clinical Practice Guidelines for the management of non-alcoholic
fatty liver disease. J Hepatol 64:1388, 2016. The complications of cirrhosis are basically the same regardless of the
Sanyal AJ et al: Pioglitazone, vitamin E, or placebo for nonalcoholic etiology. Nonetheless, it is useful to classify patients by the cause of
steatohepatitis. N Engl J Med 362:1675, 2010. their liver disease (Table 337-1); patients can be divided into broad
groups with alcoholic cirrhosis, cirrhosis due to chronic viral hepatitis,
biliary cirrhosis, and other, less common causes such as cardiac cirrho-
sis, cryptogenic cirrhosis, and other miscellaneous causes.
ALCOHOLIC CIRRHOSIS
Excessive chronic alcohol use can cause several different types of
chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis,
337 Cirrhosis and Its and alcoholic cirrhosis. Furthermore, use of excessive alcohol can con-
tribute to liver damage in patients with other liver diseases, such as
Complications hepatitis C, hemochromatosis, and fatty liver disease related to obesity.
Chronic alcohol use can produce fibrosis in the absence of accompa-
CHAPTER 337 Cirrhosis and Its Complications

Bruce R. Bacon nying inflammation and/or necrosis. Fibrosis can be centrilobular,
pericellular, or periportal. When fibrosis reaches a certain degree,
there is disruption of the normal liver architecture and replacement of
liver cells by regenerative nodules. In alcoholic cirrhosis, the nodules
Cirrhosis is a condition that is defined histopathologically and has a
are usually <3 mm in diameter; this form of cirrhosis is referred to as
variety of clinical manifestations and complications, some of which
micronodular. With cessation of alcohol use, larger nodules may form,
can be life-threatening. In the past, it has been thought that cirrhosis
resulting in a mixed micronodular and macronodular cirrhosis.
was never reversible; however, it has become apparent that when the
underlying insult that has caused the cirrhosis has been removed, there Pathogenesis Alcohol is the most commonly used drug in the
can be reversal of fibrosis. This is most apparent with the successful United States, and more than two-thirds of adults drink alcohol each
treatment of chronic hepatitis C; however, reversal of fibrosis is also year. Thirty percent have had a binge within the past month, and
seen in patients with hemochromatosis who have been successfully over 7% of adults regularly consume more than two drinks per day.
treated and in patients with alcoholic liver disease who have discon- Unfortunately, more than 14 million adults in the United States meet
tinued alcohol use. the diagnostic criteria for alcohol abuse or dependence. In the United
Regardless of the cause of cirrhosis, the pathologic features consist States, chronic liver disease is the tenth most common cause of death
of the development of fibrosis to the point that there is architectural in adults, and alcoholic cirrhosis accounts for ~40% of deaths due to
distortion with the formation of regenerative nodules. This results in a cirrhosis.
decrease in hepatocellular mass, and thus function, and an alteration of Ethanol is mainly absorbed by the small intestine and, to a lesser
blood flow. The induction of fibrosis occurs with activation of hepatic degree, through the stomach. Gastric alcohol dehydrogenase (ADH)
stellate cells, resulting in the formation of increased amounts of col- initiates alcohol metabolism. Three enzyme systems account for metab-
lagen and other components of the extracellular matrix. olism of alcohol in the liver. These include cytosolic ADH, the microso-
Clinical features of cirrhosis are the result of pathologic changes mal ethanol oxidizing system (MEOS), and peroxisomal catalase. The
and mirror the severity of the liver disease. Most hepatic pathologists majority of ethanol oxidation occurs via ADH to form acetaldehyde,
provide an assessment of grading and staging when evaluating liver which is a highly reactive molecule that may have multiple effects. Ulti-
biopsy samples. These grading and staging schemes vary between mately, acetaldehyde is metabolized to acetate by aldehyde dehydro-
disease states and have been developed for most conditions, including genase (ALDH). Intake of ethanol increases intracellular accumulation
chronic viral hepatitis, nonalcoholic fatty liver disease, and primary of triglycerides by increasing fatty acid uptake and by reducing fatty
biliary cholangitis. Advanced fibrosis usually includes bridging fibrosis acid oxidation and lipoprotein secretion. Protein synthesis, glycosy-
with nodularity designated as stage 3 and cirrhosis designated as stage lation, and secretion are impaired. Oxidative damage to hepatocyte
4. Patients who have cirrhosis have varying degrees of compensated membranes occurs due to the formation of reactive oxygen species;
liver function, and clinicians need to differentiate between those who acetaldehyde is a highly reactive molecule that combines with proteins
have stable, compensated cirrhosis and those who have decompen- to form protein-acetaldehyde adducts. These adducts may interfere
sated cirrhosis. Patients who have developed complications of their with specific enzyme activities, including microtubular formation and
liver disease and have become decompensated should be considered hepatic protein trafficking. With acetaldehyde-mediated hepatocyte
for liver transplantation. Many of the complications of cirrhosis will damage, certain reactive oxygen species can result in Kupffer cell acti-
require specific therapy. Portal hypertension is a significant complicating vation. As a result, profibrogenic cytokines are produced that initiate
feature of decompensated cirrhosis and is responsible for the develop- and perpetuate stellate cell activation, with the resultant production of
ment of ascites and bleeding from esophagogastric varices, two com- excess collagen and extracellular matrix. Connective tissue appears in
plications that signify decompensated cirrhosis. Loss of hepatocellular both periportal and pericentral zones and eventually connects portal
function results in jaundice, coagulation disorders, and hypoalbumine- triads with central veins forming regenerative nodules. Hepatocyte
mia and contributes to the causes of portosystemic encephalopathy. loss occurs, and with increased collagen production and deposition,

2406 Laboratory tests may be completely normal in patients with early
compensated alcoholic cirrhosis. Alternatively, in advanced liver
disease, many abnormalities usually are present. Patients may be
anemic either from chronic GI blood loss, nutritional deficiencies, or
hypersplenism related to portal hypertension, or as a direct suppres-
sive effect of alcohol on the bone marrow. A unique form of hemolytic
anemia (with spur cells and acanthocytes) called Zieve’s syndrome can
occur in patients with severe alcoholic hepatitis. Platelet counts are
often reduced early in the disease, reflective of portal hypertension
with hypersplenism. Serum total bilirubin can be normal or elevated
with advanced disease. Direct bilirubin is frequently mildly elevated
in patients with a normal total bilirubin, but the abnormality typically
progresses as the disease worsens. Prothrombin times are often pro-
longed and usually do not respond to administration of parenteral
vitamin K. Serum sodium levels are usually normal unless patients
FIGURE 337-1 Palmar erythema. This figure shows palmar erythema in a patient
have ascites and then can be depressed, largely due to ingestion of
with alcoholic cirrhosis. The erythema is peripheral over the palm with central excess free water. Serum alanine and aspartate aminotransferases
pallor. (ALT, AST) are typically elevated, particularly in patients who con-
tinue to drink, with AST levels being higher than ALT levels, usually
by a 2:1 ratio.
together with continuing hepatocyte destruction, the liver contracts Diagnosis Patients who have any of the above-mentioned clinical
and shrinks in size. This process generally takes from years to decades features, physical examination findings, or laboratory studies should
to occur and requires repeated insults. be considered to have alcoholic liver disease. The diagnosis, however,
Clinical Features The diagnosis of alcoholic liver disease requires requires accurate knowledge that the patient is continuing to use and
an accurate history regarding both amount and duration of alcohol abuse alcohol. Furthermore, other forms of chronic liver disease (e.g.,
consumption. Patients with alcoholic liver disease can present with chronic viral hepatitis or metabolic or autoimmune liver diseases) must
nonspecific symptoms such as vague right upper quadrant abdominal be considered or ruled out, or if present, an estimate of relative causal-
pain, fever, nausea and vomiting, diarrhea, anorexia, and malaise. ity along with the alcohol use should be determined. Liver biopsy can
PART 10
Alternatively, they may present with more specific complications of be helpful to confirm a diagnosis, but generally when patients present
chronic liver disease, including ascites, edema, or upper gastrointes- with alcoholic hepatitis and are still drinking, liver biopsy is withheld
tinal (GI) hemorrhage. Many cases present incidentally at the time of until abstinence has been maintained for at least 6 months to determine
autopsy or elective surgery. Other clinical manifestations include the residual, nonreversible disease.
development of jaundice or encephalopathy. The abrupt onset of any In patients who have had complications of cirrhosis and who
of these complications may be the first event prompting the patient continue to drink, there is a <50% 5-year survival. In contrast, in
to seek medical attention. Other patients may be identified in the patients who are able to remain abstinent, the prognosis is significantly

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Harrisons_20e_Part6_p1649-p1942.

indd 1942 6/1/18 12:55 PM

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CHAPTER 279 Disturbances of Respiratory Function

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–80 –60 –40 –20 0 20 40 60 80

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CHAPTER 279 Disturbances of Respiratory Function

as asthma, chronic bronchitis, emphy-

dynamic hyperinflation. In this sce-

insufficient to allow complete exha-

repetition of incomplete exhalations

TLC. At these high lung volumes,

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stopped. During the ensuing inhalation, fresh gas immediately enters

strives to maintain arterial Pco (Paco ) at ~40 mmHg, the adequacy of 2

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CHAPTER 279 Disturbances of Respiratory Function

. . FIO2 = 0.21 FIO2 = 1

58 mmHg 350 mmHg

Restriction due to Restriction due to Restriction due to Obstruction Obstruction due to

TLC 60% 95% 75% 100% 130%

DLCO 60% 95% 80% 120% 40%

Volume Volume Volume Volume Volume

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CHAPTER 280 Diagnostic Procedures in Respiratory Disease

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analysis of images to improve diagnostic information; and (3) ability

Diagnostic ultrasound (US) produces images using echoes or reflection

■■NUCLEAR MEDICINE TECHNIQUES

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CHAPTER 280 Diagnostic Procedures in Respiratory Disease

masses from vascular structures primarily in the mediastinum, and

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■■VIRTUAL BRONCHOSCOPY ■■MAGNETIC RESONANCE IMAGING

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CHAPTER 280 Diagnostic Procedures in Respiratory Disease

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ture. In addition, immunofluorescent staining with antibodies and/or

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CHAPTER 281 Asthma

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the more widespread use of inhaled corticosteroids (ICS) in patients

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CHAPTER 281 Asthma

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through the release of sulfur dioxide gas in the stom-

AIR POLLUTION Increased ambient levels of sul-

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CHAPTER 281 Asthma

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Inflammatory Mediators Multiple inflammatory mediators

effects, the role of individual mediators in the pathophysiology of

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CHAPTER 281 Asthma

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Expired volume (liters)

Time (seconds) Volume (liters)

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CHAPTER 281 Asthma

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• Congestive heart failure