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Harrison Gastroenterology and Hepatology 2013 Ed 18 - Compress
Harrison Gastroenterology and Hepatology 2013 Ed 18 - Compress
HARRISON’S
TM
Gastroenterology
and Hepatology
Derived from Harrison’s Principles of Internal Medicine, 18th Edition
Editors
Dan L. Longo, md Anthony S. Fauci, md
Professor of Medicine, Harvard Medical School; Chief, Laboratory of Immunoregulation;
Senior Physician, Brigham and Women’s Hospital; Director, National Institute of Allergy and Infectious Diseases,
Deputy Editor, New England Journal of Medicine, National Institutes of Health, Bethesda, Maryland
Boston, Massachusetts
HARRISON’S
TM
Gastroenterology
and Hepatology
Editors
Dan L. Longo, MD
Professor of Medicine, Harvard Medical School;
Senior Physician, Brigham and Women’s Hospital;
Deputy Editor, New England Journal of Medicine
Boston, Massachusetts
Anthony S. Fauci, MD
Chief, Laboratory of Immunoregulation;
Director, National Institute of Allergy and Infectious
Diseases, National Institutes of Health
Bethesda, Maryland
Associate Editor
Carol A. Langford, MD, MHS
Harold C. Schott Chair
Associate Professor of Medicine
Cleveland Clinic, Cleveland, Ohio
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
Copyright © 2013 by McGraw-Hill Education, LLC. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may
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ISBN: 9780-07-181489-8
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Dr. Fauci’s work as an editor and author was performed outside the scope of his employment as a U.S. government employee. This work represents his personal and
professional views and not necessarily those of the U.S. government.
This book was set in Bembo by Cenveo Publisher Services. The editors were James F. Shanahan and Kim J. Davis. The production supervisor was Catherine H. Saggese.
Project management was provided by Sandhya Gola of Cenveo® Publisher Services. The cover design was by Thomas DePierro. Cover illustration, villi in the small intestine
mucosa, © Visuals Unlimited/Corbis.
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Contents
37 The Hyperbilirubinemias. . . . . . . . . . . . . . . . . 348 50 Tumors of the Liver and Biliary Tree. . . . . . . . 535
Allan W. Wolkoff Brian I. Carr
54 Vitamin and Trace Mineral Deficiency 58 Evaluation and Management of Obesity. . . . . . 634
and Excess. . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 Robert F. Kushner
Robert M. Russell, Paolo M. Suter 59 Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . 643
55 Malnutrition and Nutritional Assessment . . . . . 601 B. Timothy Walsh, Evelyn Attia
Douglas C. Heimburger
60 The Metabolic Syndrome . . . . . . . . . . . . . . . . 650
56 Enteral and Parenteral Nutrition Robert H. Eckel
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Appendix
Bruce R. Bistrian, David F. Driscoll Laboratory Values of Clinical Importance. . . . . . . . 659
Alexander Kratz, Michael A. Pesce,
Robert C. Basner, Andrew J. Einstein
SECTION XI
Review and Self-Assessment. . . . . . . . . . . . . . . 685
Obesity and Eating Disorders Charles Wiener, Cynthia D. Brown, Anna R. Hemnes
57 Biology of Obesity . . . . . . . . . . . . . . . . . . . . . 624
Jeffrey S. Flier, Eleftheria Maratos-Flier Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
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CONTRIBUTORS
ix
x Contributors
Harrison’s Principles of Internal Medicine (HPIM) has long gastroenterology and hepatology in a conveniently sized
been a major source of information related to the book for a focused study of this medical subspecialty.
principles and practice of medicine for many practitioners The book is organized into 60 chapters and eleven
and trainees. Yet, in its aim to cover the broad spectrum sections: (I) Cardinal Manifestations of Gastrointestinal
of medicine, the book has become more than 3000 pages Disease; (II) Evaluation of the Patient with Alimentary
in length and is pushing the envelope of “portability.” Tract Symptoms; (III) Disorders of the Alimentary Tract;
HPIM has spawned several offspring tailored to diverse (IV) Infections of the Alimentary Tract; (V) Evaluation
uses for sources of medical information. The entire book of the Patient with Liver Disease; (VI) Disorders of
plus a large cache of supplemental visual and textual the Liver and Biliary Tree; (VII) Liver Transplantation;
information are available as Harrison’s Online, a component (VIII) Disorders of the Pancreas; (IX) Neoplastic Diseases
of McGraw-Hill’s Access Medicine offering. In addition, of the Gastrointestinal System; (X) Nutrition; and (XI)
the 18th edition of HPIM is now available on iPad. A Obesity and Eating Disorders.
condensed version of HPIM, called Harrison’s Manual of The information presented here is contributed by
Medicine, has been published in print format suitable for physician/authors who have personally made notable
carrying in a white coat pocket and in several electronic advances in the fields of their expertise. The chapters
formats (PDA, Blackberry, iPhone). A companion to reflect authoritative analyses by individuals who have
HPIM that serves as a study guide for standardized tests been active participants in the extraordinary surge of new
in medicine, HPIM Self-Assessment and Board Review, is information on genetics, cell biology, pathophysiology,
an effective teaching tool that highlights important areas and treatment that has characterized all of medicine in
of medicine discussed in HPIM. All of these products the last 20 years. In addition to the didactic value of the
retain the broad spectrum of topics presented in the chapters, a section of test questions, answers, and an
HPIM “mother book” in variable degrees of depth. explanation of the correct answers is provided to facilitate
In 2006, for the first time, the Editors of HPIM learning and assist the reader in preparing for standardized
experimented with extracting portions of HPIM that were examinations.
focused on a specific subspecialty of internal medicine. Gastroenterology and hepatology, like many other
The products of that effort, Harrison’s Endocrinology, areas of medicine, are changing rapidly. Novel technol-
Harrison’s Rheumatology, and Harrison’s Neurology, were ogies of imaging, development of new drugs, and the
very well-received by audiences keenly interested in the application of molecular pathogenesis information to detect
respective subspecialties of internal medicine. Accord- disease early and prevent disease in people at risk are just
ingly, we extended the concept of sectional publication a few of the advances that have made an impact on the
2009 with the publication of books in other internal practice of gastroenterology. Physicians are now applying
medicine subspecialties including Harrison’s Gastroenterology endoscopic techniques in ways that were once unimagina-
and Hepatology based on the 17th edition of HPIM. These ble including performing operations successfully without
volumes, too, appeared to serve the needs of many readers. an incision; operations that once required major surgery
Therefore, we are continuing the publication of books with attendant morbidity and expense. The pace of
with a subspecialty focus. discovery demands that physicians undertake nearly
According to a report from the National Institute continuous self-education. It is our hope that this book
of Diabetes and Digestive and Kidney Diseases, for will help physicians in this process.
every 100 residents of the United States, there were 35 We are grateful to Kim Davis and James Shanahan at
ambulatory care contacts and 5 overnight hospital stays at McGraw-Hill for their help in producing this book.
which a digestive disease diagnosis was noted. In 2004, We thank Chung Owyang, MD, from the University
digestive diseases accounted for more than 236,000 of Michigan, Jay Hoofnagle, MD, from the National
deaths. Thus, training in the disciplines of gastroenter- Institutes of Health, and Dennis Kasper, MD, from
ology and hepatology are essential to any primary care Harvard Medical School, for helpful discussions in shaping
physician or general internist and even to practitioners of the content of this volume.
other internal medicine subspecialties.
This book is aimed at bringing together the chapters Dan L. Longo, MD
of the current and 18th edition of HPIM related to Anthony S. Fauci, MD
xiii
NOTICE
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher of this work have checked with
sources believed to be reliable in their efforts to provide information that is
complete and generally in accord with the standards accepted at the time of
publication. However, in view of the possibility of human error or changes
in medical sciences, neither the authors nor the publisher nor any other party
who has been involved in the preparation or publication of this work
warrants that the information contained herein is in every respect accurate or
complete, and they disclaim all responsibility for any errors or omissions or
for the results obtained from use of the information contained in this work.
Readers are encouraged to confirm the information contained herein with
other sources. For example and in particular, readers are advised to check the
product information sheet included in the package of each drug they plan to
administer to be certain that the information contained in this work is
accurate and that changes have not been made in the recommended dose or in
the contraindications for administration. This recommendation is of particular
importance in connection with new or infrequently used drugs.
Review and self-assessment questions and answers were taken from Wiener CM,
Brown CD, Hemnes AR (eds). Harrison’s Self-Assessment and Board Review, 18th ed.
New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.
The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine
throughout the world.
The genetic icons identify a clinical issue with an explicit genetic relationship.
SECTION I
Cardinal
Manifestations of
Gastrointestinal
Disease
CHAPTER 1
ABDOMINAL PAIN
William silen
The correct interpretation of acute abdominal pain contamination, such as in pelvic inflammatory disease,
is challenging. Few other clinical situations demand the pain is frequently of low intensity early in the illness
greater judgment, because the most catastrophic of until bacterial multiplication has caused the elaboration
events may be forecast by the subtlest of symptoms and of irritating substances.
signs. A meticulously executed, detailed history and The rate at which the irritating material is applied
physical examination are of the greatest importance. to the peritoneum is important. Perforated peptic ulcer
The etiologic classification in Table 1-1, although may be associated with entirely different clinical pictures
not complete, forms a useful basis for the evaluation of dependent only on the rapidity with which the gastric
patients with abdominal pain. juice enters the peritoneal cavity.
The diagnosis of “acute or surgical abdomen” is not The pain of peritoneal inflammation is invariably accen-
an acceptable one because of its often misleading and tuated by pressure or changes in tension of the peritoneum,
erroneous connotation. The most obvious of “acute whether produced by palpation or by movement, as in
abdomens” may not require operative intervention, and coughing or sneezing. The patient with peritonitis lies
the mildest of abdominal pains may herald an urgently quietly in bed, preferring to avoid motion, in contrast
correctable lesion. Any patient with abdominal pain of to the patient with colic, who may writhe incessantly.
recent onset requires early and thorough evaluation and Another characteristic feature of peritoneal irrita-
accurate diagnosis. tion is tonic reflex spasm of the abdominal musculature,
localized to the involved body segment. The inten-
sity of the tonic muscle spasm accompanying perito-
SOmE mECHaNISmS Of paIN OrIgINaTINg neal inflammation is dependent on the location of the
IN THE abdOmEN inflammatory process, the rate at which it develops, and
Inflammation of the parietal peritoneum the integrity of the nervous system. Spasm over a per-
forated retrocecal appendix or perforated ulcer into the
The pain of parietal peritoneal inflammation is steady lesser peritoneal sac may be minimal or absent because
and aching in character and is located directly over the of the protective effect of overlying viscera. A slowly
inflamed area, its exact reference being possible because developing process often greatly attenuates the degree
it is transmitted by somatic nerves supplying the pari- of muscle spasm. Catastrophic abdominal emergencies
etal peritoneum. The intensity of the pain is dependent such as a perforated ulcer may be associated with mini-
on the type and amount of material to which the peri- mal or no detectable pain or muscle spasm in obtunded,
toneal surfaces are exposed in a given time period. For seriously ill, debilitated elderly patients or in psychotic
example, the sudden release into the peritoneal cav- patients.
ity of a small quantity of sterile acid gastric juice causes
much more pain than the same amount of grossly con-
taminated neutral feces. Enzymatically active pancre-
Obstruction of hollow viscera
atic juice incites more pain and inflammation than does
the same amount of sterile bile containing no potent The pain of obstruction of hollow abdominal viscera
enzymes. Blood and urine are often so bland as to go is classically described as intermittent, or colicky. Yet
undetected if their contact with the peritoneum has the lack of a truly cramping character should not be
not been sudden and massive. In the case of bacterial misleading, because distention of a hollow viscus may
2
Table 1-1 3
Some Important Causes of Abdominal Pain
Pain Originating in the Abdomen
CHAPTER 1
Parietal peritoneal inflammation Vascular disturbances
Bacterial contamination Embolism or thrombosis
Perforated appendix or other perforated viscus Vascular rupture
Pelvic inflammatory disease Pressure or torsional occlusion
Chemical irritation Sickle cell anemia
Perforated ulcer Abdominal wall
Abdominal Pain
Pancreatitis Distortion or traction of mesentery
Mittelschmerz Trauma or infection of muscles
Mechanical obstruction of hollow viscera Distention of visceral surfaces, e.g., by hemorrhage
Obstruction of the small or large intestine Hepatic or renal capsules
Obstruction of the biliary tree Inflammation of a viscus
Obstruction of the ureter Appendicitis
Typhoid fever
Typhlitis
Pain Referred from Extraabdominal Source
Cardiothoracic Pleurodynia
Acute myocardial infarction Pneumothorax
Myocarditis, endocarditis, pericarditis Empyema
Congestive heart failure Esophageal disease, spasm, rupture, inflammation
Pneumonia Genitalia
Pulmonary embolus Torsion of the testis
Metabolic Causes
Diabetes Acute adrenal insufficiency
Uremia Familial Mediterranean fever
Hyperlipidemia Porphyria
Hyperparathyroidism C′1 esterase inhibitor deficiency (angioneurotic edema)
Neurologic/Psychiatric Causes
Herpes zoster Spinal cord or nerve root compression
Tabes dorsalis Functional disorders
Causalgia Psychiatric disorders
Radiculitis from infection or arthritis
Toxic Causes
Lead poisoning
Insect or animal envenomations
Black widow spiders
Snake bites
Uncertain Mechanisms
Narcotic withdrawal
Heat stroke
produce steady pain with only very occasional exacer- The colicky pain of colonic obstruction is of lesser
bations. It is not nearly as well localized as the pain of intensity than that of the small intestine and is often
parietal peritoneal inflammation. located in the infraumbilical area. Lumbar radiation of
The colicky pain of obstruction of the small intes- pain is common in colonic obstruction.
tine is usually periumbilical or supraumbilical and is Sudden distention of the biliary tree produces a steady
poorly localized. As the intestine becomes progressively rather than colicky type of pain; hence, the term biliary
dilated with loss of muscular tone, the colicky nature of colic is misleading. Acute distention of the gallbladder
the pain may diminish. With superimposed strangulat- usually causes pain in the right upper quadrant with
ing obstruction, pain may spread to the lower lumbar radiation to the right posterior region of the thorax or
region if there is traction on the root of the mesentery. to the tip of the right scapula, but is not uncommonly
4 midline. Distention of the common bile duct is often frequently encountered in association with anticoagulant
associated with pain in the epigastrium radiating to the therapy, a mass may be present in the lower quadrants
upper part of the lumbar region. Considerable variation of the abdomen. Simultaneous involvement of muscles
is common, however, so that differentiation between in other parts of the body usually serves to differentiate
SECTION I
these may be impossible. The typical subscapular pain myositis of the abdominal wall from an intraabdominal
or lumbar radiation is frequently absent. Gradual dila- process that might cause pain in the same region.
tation of the biliary tree, as in carcinoma of the head
of the pancreas, may cause no pain or only a mild ach- Referred Pain in Abdominal Diseases
ing sensation in the epigastrium or right upper quadrant.
The pain of distention of the pancreatic ducts is simi- Pain referred to the abdomen from the thorax, spine,
Cardinal Manifestations of Gastrointestinal Disease
lar to that described for distention of the common bile or genitalia may prove a vexing diagnostic problem,
duct but, in addition, is very frequently accentuated by because diseases of the upper part of the abdominal cav-
recumbency and relieved by the upright position. ity such as acute cholecystitis or perforated ulcer are
Obstruction of the urinary bladder results in dull frequently associated with intrathoracic complications.
suprapubic pain, usually low in intensity. Restlessness A most important, yet often forgotten, dictum is that
without specific complaint of pain may be the only the possibility of intrathoracic disease must be consid-
sign of a distended bladder in an obtunded patient. In ered in every patient with abdominal pain, especially if
contrast, acute obstruction of the intravesicular portion the pain is in the upper part of the abdomen. Systematic
of the ureter is characterized by severe suprapubic and questioning and examination directed toward detecting
flank pain that radiates to the penis, scrotum, or inner myocardial or pulmonary infarction, pneumonia, peri-
aspect of the upper thigh. Obstruction of the uretero- carditis, or esophageal disease (the intrathoracic diseases
pelvic junction is felt as pain in the costovertebral angle, that most often masquerade as abdominal emergencies)
whereas obstruction of the remainder of the ureter is will often provide sufficient clues to establish the proper
associated with flank pain that often extends into the diagnosis. Diaphragmatic pleuritis resulting from pneu-
same side of the abdomen. monia or pulmonary infarction may cause pain in the
right upper quadrant and pain in the supraclavicular
area, the latter radiation to be distinguished from the
Vascular disturbances referred subscapular pain caused by acute distention of
A frequent misconception, despite abundant expe- the extrahepatic biliary tree. The ultimate decision as
rience to the contrary, is that pain associated with to the origin of abdominal pain may require deliberate
intraabdominal vascular disturbances is sudden and cata- and planned observation over a period of several hours,
strophic in nature. The pain of embolism or thrombosis during which repeated questioning and examination
of the superior mesenteric artery or that of impend- will provide the diagnosis or suggest the appropriate
ing rupture of an abdominal aortic aneurysm certainly studies.
may be severe and diffuse. Yet, just as frequently, the Referred pain of thoracic origin is often accompanied
patient with occlusion of the superior mesenteric artery by splinting of the involved hemithorax with respira-
has only mild continuous or cramping diffuse pain tory lag and decrease in excursion more marked than
for 2 or 3 days before vascular collapse or findings of that seen in the presence of intraabdominal disease. In
peritoneal inflammation appear. The early, seemingly addition, apparent abdominal muscle spasm caused
insignificant discomfort is caused by hyperperistalsis by referred pain will diminish during the inspiratory
rather than peritoneal inflammation. Indeed, absence phase of respiration, whereas it is persistent through-
of tenderness and rigidity in the presence of continu- out both respiratory phases if it is of abdominal origin.
ous, diffuse pain in a patient likely to have vascular dis- Palpation over the area of referred pain in the abdomen
ease is quite characteristic of occlusion of the superior also does not usually accentuate the pain and in many
mesenteric artery. Abdominal pain with radiation to instances actually seems to relieve it. Thoracic disease
the sacral region, flank, or genitalia should always signal and abdominal disease frequently coexist and may be
the possible presence of a rupturing abdominal aortic difficult or impossible to differentiate. For example, the
aneurysm. This pain may persist over a period of several patient with known biliary tract disease often has epi-
days before rupture and collapse occur. gastric pain during myocardial infarction, or biliary
colic may be referred to the precordium or left shoul-
der in a patient who has suffered previously from angina
Abdominal wall
pectoris.
Pain arising from the abdominal wall is usually constant Referred pain from the spine, which usually involves
and aching. Movement, prolonged standing, and pres- compression or irritation of nerve roots, is character-
sure accentuate the discomfort and muscle spasm. In istically intensified by certain motions such as cough,
the case of hematoma of the rectus sheath, now most sneeze, or strain and is associated with hyperesthesia
over the involved dermatomes. Pain referred to the abdominal distention, or changes in respiration. Severe 5
abdomen from the testes or seminal vesicles is generally muscle spasm, as in the gastric crises of tabes dorsalis,
accentuated by the slightest pressure on either of these is common but is either relieved or is not accentuated
CHAPTER 1
organs. The abdominal discomfort is of dull, aching by abdominal palpation. The pain is made worse by
character and is poorly localized. movement of the spine and is usually confined to a few
dermatomes. Hyperesthesia is very common.
Pain due to functional causes conforms to none of
Metabolic Abdominal Crises the aforementioned patterns. Mechanism is hard to
Pain of metabolic origin may simulate almost any other define. Irritable bowel syndrome (IBS) is a functional
gastrointestinal disorder characterized by abdominal
Abdominal Pain
type of intraabdominal disease. Several mechanisms may
be at work. In certain instances, such as hyperlipidemia, pain and altered bowel habits. The diagnosis is made on
the metabolic disease itself may be accompanied by an the basis of clinical criteria (Chap. 18) and after exclu-
intraabdominal process such as pancreatitis, which can sion of demonstrable structural abnormalities. The epi-
lead to unnecessary laparotomy unless recognized. C′1 sodes of abdominal pain are often brought on by stress,
esterase deficiency associated with angioneurotic edema and the pain varies considerably in type and location.
is often associated with episodes of severe abdominal Nausea and vomiting are rare. Localized tenderness and
pain. Whenever the cause of abdominal pain is obscure, muscle spasm are inconsistent or absent. The causes of
a metabolic origin always must be considered. Abdomi- IBS or related functional disorders are not known.
nal pain is also the hallmark of familial Mediterranean
fever. APPROACH TO THE
The problem of differential diagnosis is often not PATIENT Abdominal Pain
readily resolved. The pain of porphyria and of lead colic
is usually difficult to distinguish from that of intestinal Few abdominal conditions require such urgent opera-
obstruction, because severe hyperperistalsis is a promi- tive intervention that an orderly approach need be
nent feature of both. The pain of uremia or diabetes abandoned, no matter how ill the patient. Only those
is nonspecific, and the pain and tenderness frequently patients with exsanguinating intraabdominal hemor-
shift in location and intensity. Diabetic acidosis may be rhage (e.g., ruptured aneurysm) must be rushed to the
precipitated by acute appendicitis or intestinal obstruc- operating room immediately, but in such instances only
tion, so if prompt resolution of the abdominal pain a few minutes are required to assess the critical nature
does not result from correction of the metabolic abnor- of the problem. Under these circumstances, all obstacles
malities, an underlying organic problem should be sus- must be swept aside, adequate venous access for fluid
pected. Black widow spider bites produce intense pain replacement obtained, and the operation begun. Many
and rigidity of the abdominal muscles and back, an area patients of this type have died in the radiology depart-
infrequently involved in intraabdominal disease. ment or the emergency room while awaiting such
unnecessary examinations as electrocardiograms or CT
scans. There are no contraindications to operation when
Neurogenic Causes massive intraabdominal hemorrhage is present. Fortu-
nately, this situation is relatively rare. These comments
Causalgic pain may occur in diseases that injure sensory do not pertain to gastrointestinal hemorrhage, which
nerves. It has a burning character and is usually limited can often be managed by other means (Chap. 7).
to the distribution of a given peripheral nerve. Normal Nothing will supplant an orderly, painstakingly
stimuli such as touch or change in temperature may be detailed history, which is far more valuable than any
transformed into this type of pain, which is frequently laboratory or radiographic examination. This kind of
present in a patient at rest. The demonstration of irreg- history is laborious and time-consuming, making it not
ularly spaced cutaneous pain spots may be the only indi- especially popular, even though a reasonably accu-
cation of an old nerve lesion underlying causalgic pain. rate diagnosis can be made on the basis of the history
Even though the pain may be precipitated by gentle alone in the majority of cases. Computer-aided diag-
palpation, rigidity of the abdominal muscles is absent, nosis of abdominal pain provides no advantage over
and the respirations are not disturbed. Distention of the clinical assessment alone. In cases of acute abdominal
abdomen is uncommon, and the pain has no relation- pain, a diagnosis is readily established in most instances,
ship to the intake of food. whereas success is not so frequent in patients with
Pain arising from spinal nerves or roots comes chronic pain. IBS is one of the most common causes
and goes suddenly and is of a lancinating type. It may of abdominal pain and must always be kept in mind
be caused by herpes zoster, impingement by arthri- (Chap. 18). The location of the pain can assist in nar-
tis, tumors, herniated nucleus pulposus, diabetes, rowing the differential diagnosis (Table 1-2); however,
or syphilis. It is not associated with food intake,
6 Table 1-2
Differential Diagnoses of Abdominal Pain by Location
Right Upper Quadrant Epigastric Left Upper Quadrant
SECTION I
the chronological sequence of events in the patient’s and localizing. Asking the patient to cough will elicit true
history is often more important than emphasis on the rebound tenderness without the need for placing a hand
location of pain. If the examiner is sufficiently open- on the abdomen. Furthermore, the forceful demonstra-
minded and unhurried, asks the proper questions, and tion of rebound tenderness will startle and induce pro-
listens, the patient will usually provide the diagnosis. tective spasm in a nervous or worried patient in whom
Careful attention should be paid to the extraabdominal true rebound tenderness is not present. A palpable gall-
regions that may be responsible for abdominal pain. An bladder will be missed if palpation is so brusque that vol-
accurate menstrual history in a female patient is essen- untary muscle spasm becomes superimposed on invol-
tial. Narcotics or analgesics should not be withheld until untary muscular rigidity.
a definitive diagnosis or a definitive plan has been for- As with history taking, sufficient time should be
mulated; obfuscation of the diagnosis by adequate anal- spent in the examination. Abdominal signs may be
gesia is unlikely. minimal but nevertheless, if accompanied by consistent
In the examination, simple critical inspection of the symptoms, may be exceptionally meaningful. Abdomi-
patient, e.g., of facies, position in bed, and respiratory nal signs may be virtually or totally absent in cases of
activity, provides valuable clues. The amount of infor- pelvic peritonitis, so careful pelvic and rectal examina-
mation to be gleaned is directly proportional to the tions are mandatory in every patient with abdominal
gentleness and thoroughness of the examiner. Once a pain. Tenderness on pelvic or rectal examination in the
patient with peritoneal inflammation has been examined absence of other abdominal signs can be caused by
brusquely, accurate assessment by the next examiner operative indications such as perforated appendicitis,
becomes almost impossible. Eliciting rebound tender- diverticulitis, twisted ovarian cyst, and many others.
ness by sudden release of a deeply palpating hand in a Much attention has been paid to the presence or
patient with suspected peritonitis is cruel and unneces- absence of peristaltic sounds, their quality, and their
sary. The same information can be obtained by gentle frequency. Auscultation of the abdomen is one of the
percussion of the abdomen (rebound tenderness on a least revealing aspects of the physical examination of
miniature scale), a maneuver that can be far more precise a patient with abdominal pain. Catastrophes such as
strangulating small intestinal obstruction or perforated ditions. They are usually unnecessary in patients with 7
appendicitis may occur in the presence of normal peri- acute appendicitis or strangulated external hernias. In
staltic sounds. Conversely, when the proximal part of rare instances, barium or water-soluble contrast study
CHAPTER 1
the intestine above an obstruction becomes markedly of the upper part of the gastrointestinal tract may dem-
distended and edematous, peristaltic sounds may lose onstrate partial intestinal obstruction that may elude
the characteristics of borborygmi and become weak or diagnosis by other means. If there is any question of
absent, even when peritonitis is not present. It is usually obstruction of the colon, oral administration of barium
the severe chemical peritonitis of sudden onset that is sulfate should be avoided. On the other hand, in cases
associated with the truly silent abdomen. Assessment of of suspected colonic obstruction (without perforation),
Abdominal Pain
the patient’s state of hydration is important. contrast enema may be diagnostic.
Laboratory examinations may be valuable in assessing In the absence of trauma, peritoneal lavage has been
the patient with abdominal pain, yet, with few exceptions, replaced as a diagnostic tool by ultrasound, CT, and lap-
they rarely establish a diagnosis. Leukocytosis should aroscopy. Ultrasonography has proved to be useful in
never be the single deciding factor as to whether or not detecting an enlarged gallbladder or pancreas, the pres-
operation is indicated. A white blood cell count >20,000/μL ence of gallstones, an enlarged ovary, or a tubal preg-
may be observed with perforation of a viscus, but pan- nancy. Laparoscopy is especially helpful in diagnosing
creatitis, acute cholecystitis, pelvic inflammatory disease, pelvic conditions, such as ovarian cysts, tubal pregnan-
and intestinal infarction may be associated with marked cies, salpingitis, and acute appendicitis. Radioisotopic
leukocytosis. A normal white blood cell count is not rare hepatobiliary iminodiacetic acid scans (HIDAs) may help
in cases of perforation of abdominal viscera. The diagnosis differentiate acute cholecystitis from acute pancreatitis.
of anemia may be more helpful than the white blood cell A CT scan may demonstrate an enlarged pancreas, rup-
count, especially when combined with the history. tured spleen, or thickened colonic or appendiceal wall
The urinalysis may reveal the state of hydration and streaking of the mesocolon or mesoappendix char-
or rule out severe renal disease, diabetes, or urinary acteristic of diverticulitis or appendicitis.
infection. Blood urea nitrogen, glucose, and serum Sometimes, even under the best circumstances with
bilirubin levels may be helpful. Serum amylase levels all available aids and with the greatest of clinical skill, a
may be increased by many diseases other than pan- definitive diagnosis cannot be established at the time of
creatitis, e.g., perforated ulcer, strangulating intestinal the initial examination. Nevertheless, despite lack of a
obstruction, and acute cholecystitis; thus, elevations of clear anatomic diagnosis, it may be abundantly clear to
serum amylase do not rule out the need for an opera- an experienced and thoughtful physician and surgeon
tion. The determination of the serum lipase may have that on clinical grounds alone operation is indicated.
greater accuracy than that of the serum amylase. Should that decision be questionable, watchful waiting
Plain and upright or lateral decubitus radiographs with repeated questioning and examination will often
of the abdomen may be of value in cases of intestinal elucidate the true nature of the illness and indicate the
obstruction, perforated ulcer, and a variety of other con- proper course of action.
chaPter 2
Samuel C. Durso
As primary care physicians and consultants, internists are unattached or free gingiva (1–3 mm) overlap the base
often asked to evaluate patients with disease of the oral of the crown, forming a shallow sulcus along the gum
soft tissues, teeth, and pharynx. Knowledge of the oral tooth margin.
milieu and its unique structures is necessary to guide
preventive services and recognize oral manifestations of Dental caries, pulpal and periapical disease,
local or systemic disease (Chap. 3). Furthermore, inter and complications
nists frequently collaborate with dentists in the care of
patients who have a variety of medical conditions that Dental caries begin asymptomatically as a destruc
affect oral health or who undergo dental procedures that tive process of the hard surface of the tooth. Streptococcus
increase their risk of medical complications. mutans, principally, along with other bacteria colo
nize the organic buffering film on the tooth surface to
produce plaque. If not removed by brushing or the
natural cleaning action of saliva and oral soft tissues,
Diseases of the teeth aND bacterial acids demineralize the enamel. Fissures and
PerioDoNtal structures pits on the occlusion surfaces are the most frequent
sites of decay. Surfaces adjacent to tooth restorations
tooth and Periodontal structure
and exposed roots are also vulnerable, particularly as
Tooth formation begins during the sixth week of teeth are retained in an aging population. Over time,
embryonic life and continues through the first 17 years dental caries extend to the underlying dentin, leading
of age. Tooth development begins in utero and contin to cavitation of the enamel and, ultimately, penetra
ues until after the tooth erupts. Normally, all 20 decidu tion to the tooth pulp, producing acute pulpitis. At this
ous teeth have erupted by age 3 and have been shed by early stage, when the pulp infection is limited, the tooth
age 13. Permanent teeth, eventually totaling 2, begin to becomes sensitive to percussion and hot or cold, and
erupt by age 6 and have completely erupted by age 14, pain resolves immediately when the irritating stimulus
though third molars (wisdom teeth) may erupt later. is removed. Should the infection spread throughout the
The erupted tooth consists of the visible crown cov pulp, irreversible pulpitis occurs, leading to pulp necro
ered with enamel and the root submerged below the sis. At this late stage, pain is severe and has a sharp or
gum line and covered with bonelike cementum. Dentin, throbbing visceral quality that may be worse when the
a material that is denser than bone and exquisitely sensi patient lies down. Once pulp necrosis is complete, pain
tive to pain, forms the majority of the tooth substance. may be constant or intermittent, but cold sensitivity is
Dentin surrounds a core of myxomatous pulp containing lost.
the vascular and nerve supply. The tooth is held firmly Treatment of caries involves removal of the softened
in the alveolar socket by the periodontium, supporting and infected hard tissue; sealing the exposed dentin; and
structures that consist of the gingivae, alveolar bone, restoration of the tooth structure with silver amalgam,
cementum, and periodontal ligament. The periodontal composite resin, gold, or porcelain. Once irrevers
ligament tenaciously binds the tooth’s cementum to the ible pulpitis occurs, root canal therapy is necessary, and
alveolar bone. Above this ligament is a collar of attached the contents of the pulp chamber and root canals are
gingiva just below the crown. A few millimeters of removed, followed by thorough cleaning, antisepsis, and
8
filling with an inert material. Alternatively, the tooth ANUG in some patients or a more destructive form of 9
may be extracted. adult chronic periodontitis in others. It may also pro
Pulpal infection, if it does not egress through the duce a gangrene-like destructive process of the oral soft
CHAPTER 2
decayed enamel, leads to periapical abscess formation, tissues and bone that resembles noma, seen in severely
which produces pain on chewing. If the infection malnourished children in developing nations.
is mild and chronic, a periapical granuloma or eventu
ally a periapical cyst forms, either of which produces Prevention of tooth decay and
radiolucency at the root apex. When unchecked, a periodontal infection
periapical abscess can erode into the alveolar bone
producing osteomyelitis, penetrate and drain through Despite the reduced prevalence of dental caries and
is seen with age, bruxism, or excessive acid exposure acute ulcers are painful and self-limited. Recurrent
(e.g., chronic gastric reflux or bulimia). aphthous ulcers and herpes simplex infection consti
Premature tooth loss resulting from periodontitis is tute the majority. Persistent and deep aphthous ulcers
seen with cyclic neutropenia, Papillon-Lefèvre syn can be idiopathic or seen with HIV/AIDS. Aphthous
drome, Chédiak-Higashi syndrome, and leukemia. lesions are often the presenting symptom in Behçet’s
Rapid focal tooth loosening is most often due to infec syndrome. Similar-appearing, though less painful, lesions
tion, but rarer causes include Langerhans cell histio may occur with reactive arthritis (formerly known as
cytosis, Ewing’s sarcoma, osteosarcoma, or Burkitt’s Reiter’s syndrome), and aphthous ulcers are occasion
lymphoma. Early loss of primary teeth is a feature of ally present during phases of discoid or systemic lupus
hypophosphatasia, a rare inborn error of metabolism. erythematosus. Aphthous-like ulcers are seen in Crohn’s
Pregnancy may produce severe gingivitis and localized disease (Chap. 17), but unlike the common aphthous
pyogenic granulomas. Severe periodontal disease occurs variety, they may exhibit granulomatous inflammation
with Down’s syndrome and diabetes mellitus. Gingival histologically. Recurrent aphthae in some patients with
hyperplasia may be caused by phenytoin, calcium channel celiac disease have been reported to remit with elimina
blockers (e.g., nifedipine), and cyclosporine. Idiopathic tion of gluten.
familial gingival fibromatosis and several syndrome-related Of major concern are chronic, relatively painless
disorders appear similar. Removal of the medication ulcers and mixed red/white patches (erythroplakia and
often reverses the drug-induced form, though surgery leukoplakia) of more than 2 weeks’ duration. Squa
may be needed to control both. Linear gingival erythema mous cell carcinoma and premalignant dysplasia should
is variably seen in patients with advanced HIV infec be considered early and a diagnostic biopsy obtained.
tion and probably represents immune deficiency and The importance is underscored because early-stage
decreased neutrophil activity. Diffuse or focal gingival malignancy is vastly more treatable than late-stage
swelling may be a feature of early or late acute myelo disease. High-risk sites include the lower lip, floor of
monocytic leukemia (AMML) as well as of other lym the mouth, ventral and lateral tongue, and soft pal
phoproliferative disorders. A rare, but pathognomonic, ate–tonsillar pillar complex. Significant risk factors for
sign of Wegener’s granulomatosis is a red-purplish, oral cancer in Western countries include sun expo
granular gingivitis (strawberry gums). sure (lower lip) and tobacco and alcohol use. In India
and some other Asian countries, smokeless tobacco
mixed with betel nut, slaked lime, and spices is a com
mon cause of oral cancer. Less common etiologies
Diseases of the Oral Mucosa include syphilis and Plummer-Vinson syndrome (iron
Infection deficiency).
Rarer causes of chronic oral ulcer such as tubercu
Most oral mucosal diseases involve microorganisms losis, fungal infection, granulomatosis with polyangiitis
(Table 2-1). (Wegener’s), and midline granuloma may look identical
to carcinoma. Making the correct diagnosis depends on
Pigmented lesions recognizing other clinical features and biopsy of the
lesion. The syphilitic chancre is typically painless and
See Table 2-2. therefore easily missed. Regional lymphadenopathy is
invariably present. Confirmation is achieved using appro
Dermatologic diseases priate bacterial and serologic tests.
See Tables 2-1, 2-2, and 2-3. Disorders of mucosal fragility often produce pain
ful oral ulcers that fail to heal within 2 weeks. Mucous
membrane pemphigoid and pemphigus vulgaris are the major
Diseases of the tongue acquired disorders. While clinical features are often dis
See Table 2-4. tinctive, immunohistochemical examination should be
Table 2-1 11
Vesicular, Bullous, or Ulcerative Lesions of the Oral Mucosa
CHAPTER 2
Condition Usual Location Clinical Features Course
Viral Diseases
Primary acute herpetic gingi- Lip and oral mucosa Labial vesicles that rupture and Heals spontaneously in
vostomatitis [herpes simplex (buccal, gingival, crust, and intraoral vesicles that 10–14 days. Unless second-
virus (HSV) type 1, rarely lingual mucosa) quickly ulcerate; extremely painful; arily infected, lesions lasting
type 2] acute gingivitis, fever, malaise, foul >3 weeks are not due to
odor, and cervical lymphadenopa- primary HSV infection
Prenatal (congenital) syphilis Palate, jaws, tongue, Gummatous involvement of palate, Tooth deformities in perma-
and teeth jaws, and facial bones; Hutchinson’s nent dentition irreversible
incisors, mulberry molars, glossitis,
mucous patches, and fissures on
corner of mouth
Primary syphilis (chancre) Lesion appears where Small papule developing rapidly Healing of chancre in
organism enters body; into a large, painless ulcer with 1–2 months, followed by
may occur on lips, indurated border; unilateral lymph- secondary syphilis in
tongue, or tonsillar adenopathy; chancre and lymph 6–8 weeks
area nodes containing spirochetes;
serologic tests positive by third to
fourth weeks
Secondary syphilis Oral mucosa frequently Maculopapular lesions of oral Lesions may persist from sev-
involved with mucous mucosa, 5–10 mm in diameter with eral weeks to a year
patches, primarily on central ulceration covered by
palate, also at com- grayish membrane; eruptions
missures of mouth occurring on various mucosal
surfaces and skin accompanied by
fever, malaise, and sore throat
Tertiary syphilis Palate and tongue Gummatous infiltration of palate or Gumma may destroy palate,
tongue followed by ulceration and causing complete
fibrosis; atrophy of tongue papil- perforation
lae produces characteristic bald
tongue and glossitis
Gonorrhea Lesions may occur in Most pharyngeal infection is asymp- More difficult to eradicate
mouth at site of inocu- tomatic; may produce burning or than urogenital infection,
lation or secondarily itching sensation; oropharynx and though pharyngitis usually
by hematogenous tonsils may be ulcerated and ery- resolves with appropriate
spread from a primary thematous; saliva viscous and fetid antimicrobial treatment
focus elsewhere
Tuberculosis Tongue, tonsillar area, A painless, solitary, 1–5 cm, irregu- Autoinoculation from pulmo-
soft palate lar ulcer covered with a persistent nary infection usual; lesions
exudate; ulcer has a firm under- resolve with appropriate
mined border antimicrobial therapy
Cervicofacial actinomycosis Swellings in region of Infection may be associated with Typically, swelling is hard and
face, neck, and floor an extraction, jaw fracture, or grows painlessly; multiple
of mouth eruption of molar tooth; in acute abscesses with draining
form resembles an acute pyogenic tracts develop; penicillin
abscess, but contains yellow first choice; surgery usually
“sulfur granules” (gram-positive necessary
mycelia and their hyphae)
Histoplasmosis Any area of the mouth, Nodular, verrucous, or granuloma- Systemic antifungal therapy
particularly tongue, tous lesions; ulcers are indurated necessary to treat
gingiva, or palate and painful; usual source hema-
togenous or pulmonary, but may
be primary
Candidiasis (Table 2-3)
(continued )
Table 2-1 13
Vesicular, Bullous, or Ulcerative Lesions of the Oral Mucosa (Continued )
CHAPTER 2
Condition Usual Location Clinical Features Course
Dermatologic Diseases
Mucous membrane Typically produces Painful, grayish-white collapsed Protracted course with remis-
pemphigoid marked gingival ery- vesicles or bullae of full-thickness sions and exacerbations;
thema and ulceration; epithelium with peripheral ery- involvement of different
other areas of oral thematous zone; gingival lesions sites occurs slowly; gluco-
cavity, esophagus, desquamate, leaving ulcerated corticoids may temporarily
Acute myeloid leukemia Gingiva Gingival swelling and superficial Usually responds to systemic
(usually monocytic) ulceration followed by hyperplasia treatment of leukemia;
of gingiva with extensive necrosis occasionally requires local
and hemorrhage; deep ulcers may radiation therapy
occur elsewhere on the mucosa
complicated by secondary
Cardinal Manifestations of Gastrointestinal Disease
infection
Lymphoma Gingiva, tongue, palate Elevated, ulcerated area that may Fatal if untreated; may
and tonsillar area proliferate rapidly, giving the indicate underlying HIV
appearance of traumatic infection
inflammation
Chemical or thermal burns Any area in mouth White slough due to contact with Lesion heals in several weeks
corrosive agents (e.g., aspirin, hot if not secondarily infected
cheese) applied locally; removal of
slough leaves raw, painful surface
Table 2-2
Pigmented Lesions of the Oral Mucosa
Condition Usual Location Clinical Features Course
Oral melanotic macule Any area of the mouth Discrete or diffuse localized, Remains indefinitely; no
brown to black macule growth
Diffuse melanin Any area of the mouth Diffuse pale to dark-brown Remains indefinitely
pigmentation pigmentation; may be physiologic
(“racial”) or due to smoking
Nevi Any area of the mouth Discrete, localized, brown to black Remains indefinitely
pigmentation
Malignant melanoma Any area of the mouth Can be flat and diffuse, painless, Expands and invades early;
brown to black, or can be raised and metastasis leads to death
nodular
Addison’s disease Any area of the mouth, Blotches or spots of bluish-black to Condition controlled by adre-
but mostly buccal dark-brown pigmentation occurring nal steroid replacement
mucosa early in the disease, accompanied
by diffuse pigmentation of skin;
other symptoms of adrenal
insufficiency
Peutz-Jeghers syndrome Any area of the mouth Dark-brown spots on lips, buccal Oral pigmented lesions
mucosa, with characteristic distribu- remain indefinitely; gastroin-
tion of pigment around lips, nose, testinal polyps may become
eyes, and on hands; concomitant malignant
intestinal polyposis
Drug ingestion (neurolep- Any area of the mouth Brown, black, or gray areas of Gradually disappears follow-
tics, oral contraceptives, pigmentation ing cessation of drug
minocycline, zidovudine,
quinine derivatives)
Amalgam tattoo Gingiva and alveolar Small blue-black pigmented areas Remains indefinitely
mucosa associated with embedded amalgam
particles in soft tissues; these may
show up on radiographs as radi-
opaque particles in some cases
(continued )
Table 2-2 15
Pigmented Lesions of the Oral Mucosa (Continued )
CHAPTER 2
Condition Usual Location Clinical Features Course
Heavy metal pigmentation Gingival margin Thin blue-black pigmented line along Indicative of systemic absorp-
(bismuth, mercury, lead) gingival margin; rarely seen except tion; no significance for oral
for children exposed to lead-based health
paint
Black hairy tongue Dorsum of tongue Elongation of filiform papillae of Improves within 1–2 weeks
tongue, which become stained by with gentle brushing of
Table 2-3
White Lesions of Oral Mucosa
Condition Usual Location Clinical Features Course
Lichen planus Buccal mucosa, tongue, Striae, white plaques, red areas, Protracted; responds to
gingiva, and lips; skin ulcers in mouth; purplish papules on topical glucocorticoids
skin; may be asymptomatic, sore,
or painful; lichenoid drug reactions
may look similar
White sponge nevus Oral mucosa, vagina, anal Painless white thickening of epithe- Benign and permanent
mucosa lium; adolescent/early adult onset;
familial
Smoker’s leukoplakia Any area of oral mucosa, White patch that may become firm, May or may not resolve with
and smokeless sometimes related to rough, or red-fissured and ulcer- cessation of habit; 2%
tobacco lesions location of habit ated; may become sore and painful develop squamous cell
but usually painless carcinoma; early biopsy
essential
Erythroplakia with Floor of mouth common in Velvety, reddish plaque; occasionally High risk of squamous
or without white men; tongue and buccal mixed with white patches or smooth cell cancer; early biopsy
patches mucosa in women red areas essential
Candidiasis Any area in mouth Pseudomembranous type (“thrush”): Responds favorably to
creamy white curdlike patches antifungal therapy and
that reveal a raw, bleeding surface correction of predisposing
when scraped; found in sick infants, causes where possible
debilitated elderly patients
receiving high doses of glucocorti-
coids or broad-spectrum antibiotics,
or in patients with AIDS
(continued )
16 Table 2-3
White Lesions of Oral Mucosa (Continued )
Condition Usual Location Clinical Features Course
SECTION I
Table 2-4
Alterations of the Tongue
Type of Change Clinical Features
CHAPTER 2
Lesion Morphology Etiologies
a
Strongly associated with HIV infection.
performed for diagnosis and to distinguish these entities burning tongue may occur with pernicious anemia.
from lichen planus and drug reactions. B-group vitamin deficiencies produce many of these
same symptoms as well as oral ulceration and cheilosis.
Hematologic and nutritional disease Swollen, bleeding gums, ulcers, and loosening of the
teeth are a consequence of scurvy.
Internists are more likely to encounter patients with
acquired, rather than congenital, bleeding disorders.
Bleeding after minor trauma should stop after 15 min
and within an hour of tooth extraction if local pres Nondental Causes of Oral Pain
sure is applied. More prolonged bleeding, if not due
to continued injury or rupture of a large vessel, should Most, but not all, oral pain emanates from inflamed or
lead to investigation for a clotting abnormality. In addi injured tooth pulp or periodontal tissues. Nonodon
tion to bleeding, petechiae and ecchymoses are prone togenic causes may be overlooked. In most instances,
to occur at the line of vibration between the soft and toothache is predictable and proportional to the stimulus
hard palates in patients with platelet dysfunction or applied, and an identifiable condition (e.g., caries,
thrombocytopenia. abscess) is found. Local anesthesia eliminates pain origi
All forms of leukemia, but particularly acute myelo nating from dental or periodontal structures, but not
monocyticleukemia, can produce gingival bleeding, referred pains. The most common nondental origin
ulcers, and gingival enlargement. Oral ulcers are a fea is myofascial pain referred from muscles of mastica
ture of agranulocytosis, and ulcers and mucositis are tion, which become tender and ache with increased
often severe complications of chemotherapy and radia use. Many sufferers exhibit bruxism (the grinding of
tion therapy for hematologic and other malignancies. teeth, often during sleep) that is secondary to stress and
Plummer-Vinson syndrome (iron deficiency, angular anxiety. Temporomandibular disorder is closely related. It
stomatitis, glossitis, and dysphagia) raises the risk of affects both sexes with a higher prevalence in women.
oral squamous cell cancer and esophageal cancer at the Features include pain, limited mandibular movement,
postcricoidal tissue web. Atrophic papillae and a red, and temporomandibular joint sounds. The etiologies are
18 complex, and malocclusion does not play the primary some. Some cases associated with ACE inhibitors have
role once attributed to it. Osteoarthritis is a common remitted when the drug was discontinued.
cause of masticatory pain. Anti-inflammatory medica
tion, jaw rest, soft foods, and heat provide relief. The
SECTION I
cause and absence of relief with local anesthesia are (e.g., lysozyme, lactoperoxidase, secretory IgA), epider
important clues. Trigeminal neuralgia (tic douloureux) may mal growth factor, minerals, and buffering systems. The
involve the entire branch or part of the mandibular or major salivary glands secrete intermittently in response
maxillary branches of the fifth cranial nerve and pro to autonomic stimulation, which is high during a meal
duce pain in one or a few teeth. Pain may occur spon but low otherwise. Hundreds of minor glands in the lips
taneously or may be triggered by touching the lip or and cheeks secrete mucus continuously. Consequently,
gingiva, brushing the teeth, or chewing. Glossopharyngeal oral function becomes impaired when salivary function
neuralgia produces similar acute neuropathic symptoms is reduced. Dry mouth (xerostomia) is perceived when
in the distribution of the ninth cranial nerve. Swallow salivary flow is reduced by 50%. The most common eti
ing, sneezing, coughing, or pressure on the tragus of the ology is medication, especially drugs with anticholiner
ear triggers pain that is felt in the base of the tongue, gic properties, but also alpha and beta blockers, calcium
pharynx, and soft palate and may be referred to the channel blockers, and diuretics. Other causes include
temporomandibular joint. Neuritis involving the max Sjögren’s syndrome, chronic parotitis, salivary duct obs
illary and mandibular divisions of the trigeminal nerve truction, diabetes mellitus, HIV/AIDS, and radiation
(e.g., maxillary sinusitis, neuroma, and leukemic infil therapy that includes the salivary glands in the field
trate) is distinguished from ordinary toothache by the (Hodgkin’s disease and head and neck cancer). Man
neuropathic quality of the pain. Occasionally, phantom agement involves eliminating or limiting drying medi
pain follows tooth extraction. Often the earliest symp cations, preventive dental care, and supplementing oral
tom of Bell’s palsy in the day or so before facial weak liquid. Sugarless mints or chewing gum may stimulate
ness develops is pain and hyperalgesia behind the ear salivary secretion if dysfunction is mild. When sufficient
and side of the face. Likewise, similar symptoms may exocrine tissue remains, pilocarpine or cevimeline has
precede visible lesions of herpes zoster infecting the been shown to increase secretions. Commercial saliva
seventh nerve (Ramsey-Hunt syndrome) or trigemi substitutes or gels relieve dryness but must be supple
nal nerve. Postherpetic neuralgia may follow either con mented with fluoride applications to prevent caries.
dition. Coronary ischemia may produce pain exclusively Sialolithiasis presents most often as painful swelling
in the face and jaw and, like typical angina pectoris, is but in some instances as just swelling or pain. Con
usually reproducible with increased myocardial demand. servative therapy consists of local heat, massage, and
Aching in several upper molar or premolar teeth that hydration. Promotion of salivary secretion with mints
is unrelieved by anesthetizing the teeth may point to or lemon drops may flush out small stones. Antibi
maxillary sinusitis. otic treatment is necessary when bacterial infection in
Giant cell arteritis is notorious for producing head suspected. In adults, acute bacterial parotitis is typically
ache, but it may also produce facial pain or sore throat unilateral and most commonly affects postoperative,
without headache. Jaw and tongue claudication with dehydrated, and debilitated patients. Staphylococcus aureus
chewing or talking is relatively common. Tongue including methicillin-resistant forms and anaerobic bac
infarction is rare. Patients with subacute thyroiditis teria are the most common pathogens. Chronic bacte
often experience pain referred to the face or jaw before rial sialadenitis results from lowered salivary secretion
the tender thyroid gland and transient hyperthyroidism and recurrent bacterial infection. When suspected bac
are appreciated. terial infection is not responsive to therapy, the differ
Burning mouth syndrome (glossodynia) is present in ential diagnosis should be expanded to include benign
the absence of an identifiable cause (e.g., vitamin B12 and malignant neoplasms, lymphoproliferative disorders,
deficiency, iron deficiency, diabetes mellitus, low-grade Sjögren’s syndrome, sarcoidosis, tuberculosis, lymphad
Candida infection, food sensitivity, or subtle xerostomia) enitis, actinomycosis, and granulomatosis with polyan
and predominantly affects postmenopausal women. The giitis (Wegener’s). Bilateral nontender parotid enlarge
etiology may be neuropathic. Clonazepam, alpha-lipoic ment occurs with diabetes mellitus, cirrhosis, bulimia,
acid, and cognitive behavioral therapy have benefited HIV/AIDS, and drugs (e.g., iodide, propylthiouracil).
Pleomorphic adenoma comprises two-thirds of all sali Hematogenous bacterial seeding from oral infection 19
vary neoplasms. The parotid is the principal salivary can undoubtedly produce late prosthetic joint infection
gland affected, and the tumor presents as a firm, slow- and therefore requires removal of the infected
CHAPTER 2
growing mass. Though benign, recurrence is com tissue (e.g., drainage, extraction, root canal) and appro
mon if resection is incomplete. Malignant tumors such priate antibiotic therapy. However, evidence that late
as mucoepidermoid carcinoma, adenoid cystic carci prosthetic joint infection occurs following routine
noma, and adenocarcinoma tend to grow relatively fast, dental procedures is lacking. For this reason, antibiotic
depending upon grade. They may ulcerate and invade prophylaxis is not recommended before dental surgery
nerves, producing numbness and facial paralysis. Surgi in patients with orthopedic pins, screws, and plates.
cal resection is the primary treatment. Radiation ther It is, however, advised within the first 2 years after
Xerostomia can produce and exacerbate halitosis. Pockets tion wane. These factors occur in an increasing propor
of decay in the tonsillar crypts, esophageal diverticulum, tion of persons over age 75 who retain teeth that have
esophageal stasis (e.g., achalasia, stricture), sinusitis, and extensive restorations and exposed roots. Without assid
lung abscess account for some instances. A few systemic uous care, decay can become quite advanced yet remain
diseases produce distinctive odors: renal failure (ammo asymptomatic. Consequently, much or the entire tooth
niacal), hepatic (fishy), and ketoacidosis (fruity). Helico- can be destroyed before the process is detected.
Cardinal Manifestations of Gastrointestinal Disease
bacter pylori gastritis can also produce ammoniac breath. Periodontal disease, a leading cause of tooth loss, is
If no odor is detectable, then pseudohalitosis or even indicated by loss of alveolar bone height. Over 90% of
halitophobia must be considered. These conditions rep Americans have some degree of periodontal disease by
resent varying degrees of psychiatric illness. age 50. Healthy adults who have not experienced signifi
cant alveolar bone loss by the sixth decade do not typi
cally develop significant worsening with advancing age.
Complete edentulousness with advanced age, though
Aging and Oral Health
less common than in previous decades, is still present in
While tooth loss and dental disease are not normal con approximately 50% of Americans age ≥85. Speech, mas
sequences of aging, a complex array of structural and tication, and facial contours are dramatically affected.
functional changes occurs with age that can affect oral Edentulousness may also worsen obstructive sleep apnea,
health. Subtle changes in tooth structure (e.g., dimin particularly in those without symptoms while wear
ished pulp space and volume, sclerosis of dentinal ing dentures. Dentures can improve speech articulation
tubules, and altered proportions of nerve and vascular and restore diminished facial contours. Mastication is
pulp content) result in diminished or altered pain sen restored less predictably, and those expecting dentures
sitivity, reduced reparative capacity, and increased tooth to improve oral intake are often disappointed. Dentures
brittleness. In addition, age-associated fatty replacement require periodic adjustment to accommodate inevitable
of salivary acini may reduce physiologic reserve, thus remodeling that leads to a diminished volume of the
increasing the risk of xerostomia. alveolar ridge. Pain can result from friction or traumatic
Poor oral hygiene often results when vision fails or lesions produced by loose dentures. Poor fit and poor
when patients lose manual dexterity and upper-extremity oral hygiene may permit candidiasis to develop. This
flexibility. This is particularly common for nursing may be asymptomatic or painful and is indicated by ery
home residents and must be emphasized because regu thematous smooth or granular tissue conforming to an
lar oral cleaning and dental care have been shown to area covered by the appliance.
CHAPTER 3
Figure 3-2
Oral lichen planus.
Figure 3-1
Gingival overgrowth secondary to calcium channel blocker
use.
Figure 3-3
Erosive lichen planus.
21
22
SECTION I
Cardinal Manifestations of Gastrointestinal Disease
Figure 3-4 A
Stevens-Johnson syndrome—reaction to nevirapine.
CHAPTER 3
Atlas of Oral Manifestations of Disease
Figure 3-11
Oral leukoplakia, subtype homogenous leukoplakia.
Figure 3-9
A. Epulis (gingival hypertrophy) under denture. B. Epulis
fissuratum.
Figure 3-12
Oral carcinoma.
Figure 3-17
Heavy calculus and gingival inflammation.
Figure 3-14
Geographic tongue.
Figure 3-18
Severe gingival inflammation and heavy calculus.
Figure 3-15
Moderate gingivitis.
CHAPTER 3
Atlas of Oral Manifestations of Disease
Figure 3-20 Figure 3-23
Ulcer on lateral border of tongue—potential carcinoma. Salivary stone.
Figure 3-24
A. Calculus. B. Teeth cleaned.
Figure 3-21
Osteonecrosis.
the materials have been carried over into the 18th edition.
Cardinal Manifestations of Gastrointestinal Disease
Figure 3-26
Fissured tongue.
Figure 3-27
White coated tongue—likely candidiasis.
CHAPTER 4
DYSPHAGIA
Dysphagia—difficulty with swallowing—refers to prob- residue from the pharynx and through the esophagus.
lems with the transit of food or liquid from the mouth The lower esophageal sphincter (LES) relaxes as the
to the hypopharynx or through the esophagus. Severe food enters the esophagus and remains relaxed until the
dysphagia can compromise nutrition, cause aspiration, peristaltic contraction has delivered the bolus into the
and reduce quality of life. Additional terminology per- stomach. Peristaltic contractions elicited in response
taining to swallowing dysfunction is as follows. Aphagia to a swallow are called primary peristalsis and involve
denotes complete esophageal obstruction, most com- sequenced inhibition followed by contraction of the
monly encountered in the acute setting of a food bolus musculature along the entire length of the esophagus.
or foreign body impaction. Odynophagia refers to pain- The inhibition that precedes the peristaltic contrac-
ful swallowing, typically resulting from mucosal ulcer- tion is called deglutitive inhibition. Local distention of
ation within the oropharynx or esophagus. It commonly the esophagus anywhere along its length, as may occur
is accompanied by dysphagia, but the converse is not with gastroesophageal reflux, activates secondary peristal-
true. Globus pharyngeus is a foreign body sensation local- sis that begins at the point of distention and proceeds
ized in the neck that does not interfere with swallowing distally. Tertiary esophageal contractions are nonperi-
and sometimes is relieved by swallowing. Transfer dyspha- staltic, disordered esophageal contractions that may be
gia frequently results in nasal regurgitation and pulmo- observed to occur spontaneously during fluoroscopic
nary aspiration during swallowing and is characteristic of observation.
oropharyngeal dysphagia. Phagophobia (fear of swallow- The musculature of the oral cavity, pharynx, UES,
ing) and refusal to swallow may be psychogenic or related and cervical esophagus is striated and directly inner-
to anticipatory anxiety about food bolus obstruction, vated by lower motor neurons carried in cranial nerves
odynophagia, or aspiration. (Fig. 4-1). Oral cavity muscles are innervated by the
fifth (trigeminal) and seventh (facial) cranial nerves; the
tongue, by the twelfth (hypoglossal) cranial nerve. Pha-
Physiology of sWalloWiNg
ryngeal muscles are innervated by the ninth (glossopha-
Swallowing begins with a voluntary (oral) phase that ryngeal) and tenth (vagus) cranial nerves.
includes preparation during which food is masticated Physiologically, the UES consists of the cricopharyn-
and mixed with saliva. This is followed by a transfer geus muscle, the adjacent inferior pharyngeal constrictor,
phase during which the bolus is pushed into the phar- and the proximal portion of the cervical esophagus. UES
ynx by the tongue. Bolus entry into the hypopharynx innervation is derived from the vagus nerve, whereas
initiates the pharyngeal swallow response, which the innervation to the musculature acting on the UES
is centrally mediated and involves a complex series to facilitate its opening during swallowing comes from
of actions, the net result of which is to propel food the fifth, seventh, and twelfth cranial nerves. The UES
through the pharynx into the esophagus while prevent- remains closed at rest owing to both its inherent elastic
ing its entry into the airway. To accomplish this, the properties and neurogenically mediated contraction of
larynx is elevated and pulled forward, actions that also the cricopharyngeus muscle. UES opening during swal-
facilitate upper esophageal sphincter (UES) opening. lowing involves both cessation of vagal excitation to the
Tongue pulsion then propels the bolus through the cricopharyngeus and simultaneous contraction of the
UES, followed by a peristaltic contraction that clears suprahyoid and geniohyoid muscles that pull open the
27
28 Sagittal view of the pharynx Musculature of the pharynx
SECTION I
Figure 4-1
Sagittal and diagrammatic views of the musculature such that the esophageal inlet is open and the laryngeal
involved in enacting oropharyngeal swallowing. Note the inlet closed during swallowing. (Adapted from PJ Kahrilas, in
dominance of the tongue in the sagittal view and the intimate DW Gelfand and JE Richter [eds]: Dysphagia: Diagnosis and
relationship between the entrance to the larynx (airway) and Treatment. New York: Igaku-Shoin Medical Publishers, 1989,
the esophagus. In the resting configuration illustrated, the pp. 11–28.)
esophageal inlet is closed. This is transiently reconfigured
UES in conjunction with the upward and forward dis- its intrinsic myogenic tone, a property that distinguishes
placement of the larynx. it from the adjacent esophagus. The function of the LES
The neuromuscular apparatus for peristalsis is dis- is supplemented by the surrounding muscle of the right
tinct in proximal and distal parts of the esophagus. The diaphragmatic crus, which acts as an external sphincter
cervical esophagus, like the pharyngeal musculature, during inspiration, cough, or abdominal straining.
consists of striated muscle and is directly innervated by
lower motor neurons of the vagus nerve. Peristalsis in
Pathophysiology of Dysphagia
the proximal esophagus is governed by the sequential
activation of the vagal motor neurons in the nucleus Dysphagia can be subclassified both by location and
ambiguus. In contrast, the distal esophagus and LES by the circumstances in which it occurs. With respect
are composed of smooth muscle and are controlled by to location, distinct considerations apply to oral, pha-
excitatory and inhibitory neurons within the esopha- ryngeal, or esophageal dysphagia. Normal transport of
geal myenteric plexus. Medullary preganglionic neurons an ingested bolus depends on the consistency and size
from the dorsal motor nucleus of the vagus trigger peri- of the bolus, the caliber of the lumen, the integrity of
stalsis via these ganglionic neurons during primary peri- peristaltic contraction, and deglutitive inhibition of both
stalsis. Neurotransmitters of the excitatory ganglionic the UES and the LES. Dysphagia caused by an oversized
neurons are acetylcholine and substance P; those of the bolus or a narrow lumen is called structural dysphagia,
inhibitory neurons are vasoactive intestinal peptide and whereas dysphagia due to abnormalities of peristalsis or
nitric oxide. Peristalsis results from the patterned acti- impaired sphincter relaxation after swallowing is called
vation of inhibitory followed by excitatory ganglionic propulsive or motor dysphagia. More than one mechanism
neurons, with progressive dominance of the inhibitory may be operative in a patient with dysphagia. Sclero-
neurons distally. Similarly, LES relaxation occurs with derma commonly presents with absent peristalsis as well
the onset of deglutitive inhibition and persists until the as a weakened LES that predisposes patients to peptic
peristaltic sequence is complete. At rest, the LES is con- stricture formation. Likewise, radiation therapy for head
tracted because of excitatory ganglionic stimulation and and neck cancer may compound the functional deficits
in the oropharyngeal swallow attributable to the tumor is a common radiographic finding, and most patients 29
and cause cervical esophageal stenosis. with transient cricopharyngeal bars are asymptomatic,
making it important to rule out alternative etiologies
CHAPTER 4
of dysphagia before treatment. Furthermore, cricopha-
Oral and pharyngeal (oropharyngeal) ryngeal bars may be secondary to other neuromuscular
dysphagia disorders.
Oral-phase dysphagia is associated with poor bolus for- Since the pharyngeal phase of swallowing occurs in
mation and control so that food has prolonged retention less than a second, rapid-sequence fluoroscopy is neces-
within the oral cavity and may seep out of the mouth. sary to evaluate for functional abnormalities. Adequate
fluoroscopic examination requires that the patient be
Dysphagia
Drooling and difficulty in initiating swallowing are
other characteristic signs. Poor bolus control also may conscious and cooperative. The study incorporates
lead to premature spillage of food into the hypopharynx recordings of swallow sequences during ingestion of
with resultant aspiration into the trachea or regurgita- food and liquids of varying consistencies. The pharynx
tion into the nasal cavity. Pharyngeal-phase dysphagia is is examined to detect bolus retention, regurgitation into
associated with retention of food in the pharynx due to the nose, or aspiration into the trachea. Timing and
poor tongue or pharyngeal propulsion or obstruction at integrity of pharyngeal contraction and opening of the
the UES. Signs and symptoms of concomitant hoarse- UES with a swallow are analyzed to assess both aspira-
ness or cranial nerve dysfunction may be associated with tion risk and the potential for swallow therapy. Struc-
oropharyngeal dysphagia. tural abnormalities of the oropharynx, especially those
Oropharyngeal dysphagia may be due to neuro- which may require biopsies, also should be assessed by
logic, muscular, structural, iatrogenic, infectious, and direct laryngoscopic examination.
metabolic causes. Iatrogenic, neurologic, and struc-
tural pathologies are most common. Iatrogenic causes
Esophageal dysphagia
include surgery and radiation, often in the setting of
head and neck cancer. Neurogenic dysphagia resulting The adult esophagus measures 18–26 cm in length
from cerebrovascular accidents, Parkinson’s disease, and and is anatomically divided into the cervical esopha-
amyotrophic lateral sclerosis is a major source of mor- gus, extending from the pharyngoesophageal junction
bidity related to aspiration and malnutrition. Medullary to the suprasternal notch, and the thoracic esophagus,
nuclei directly innervate the oropharynx. Lateralization which continues to the diaphragmatic hiatus. When dis-
of pharyngeal dysphagia implies either a structural pha- tended, the esophageal lumen has internal dimensions
ryngeal lesion or a neurologic process that selectively of about 2 cm in the anteroposterior plane and 3 cm
targeted the ipsilateral brainstem nuclei or cranial nerve. in the lateral plane. Solid food dysphagia becomes com-
Advances in functional brain imaging have elucidated mon when the lumen is narrowed to <13 mm but also
an important role of the cerebral cortex in swallow can occur with larger diameters in the setting of poorly
function and dysphagia. Asymmetry in the cortical rep- masticated food or motor dysfunction. Circumferen-
resentation of the pharynx provides an explanation for tial lesions are more likely to cause dysphagia than are
the dysphagia that occurs as a consequence of unilateral lesions that involve only a partial circumference of the
cortical cerebrovascular accidents. esophageal wall. The most common structural causes of
Oropharyngeal structural lesions causing dysphagia dysphagia are Schatzki’s rings, eosinophilic esophagitis,
include Zenker’s diverticulum, cricopharyngeal bar, and and peptic strictures. Dysphagia also occurs in the set-
neoplasia. Zenker’s diverticulum typically is encoun- ting of gastroesophageal reflux disease without a stric-
tered in elderly patients, with an estimated prevalence ture, perhaps on the basis of altered esophageal sensation,
between 1:1000 and 1:10,000. In addition to dysphagia, distensibility, or motor function.
patients may present with regurgitation of particulate Propulsive disorders leading to esophageal dysphagia
food debris, aspiration, and halitosis. The pathogenesis result from abnormalities of peristalsis and/or degluti-
is related to stenosis of the cricopharyngeus that causes tive inhibition, potentially affecting the cervical or tho-
diminished opening of the UES and results in increased racic esophagus. Since striated muscle pathology usually
hypopharyngeal pressure during swallowing with devel- involves both the oropharynx and the cervical esopha-
opment of a pulsion diverticulum immediately above gus, the clinical manifestations usually are dominated
the cricopharyngeus in a region of potential weakness by oropharyngeal dysphagia. Diseases affecting smooth
known as Killian’s dehiscence. A cricopharyngeal bar, muscle involve both the thoracic esophagus and the
appearing as a prominent indentation behind the lower LES. A dominant manifestation of this, absent peristal-
third of the cricoid cartilage, is related to Zenker’s sis, refers to either the complete absence of swallow-
diverticulum in that it involves limited distensibility of induced contraction or the presence of nonperistaltic,
the cricopharyngeus and can lead to the formation of a disordered contractions. Absent peristalsis and failure of
Zenker’s diverticulum. However, a cricopharyngeal bar deglutitive LES relaxation are the defining features of
30 achalasia. In diffuse esophageal spasm (DES), LES func- dysphagia or a tracheoesophageal fistula. The pres-
tion is normal, with the disordered motility restricted to ence of hoarseness may be another important diag-
the esophageal body. Absent peristalsis combined with nostic clue. When hoarseness precedes dysphagia,
severe weakness of the LES is a nonspecific pattern
SECTION I
Dysphagia localized
Dysphagia localized
to neck, nasal
to chest or
regurgitation, aspiration,
neck, food impaction
associated ENT symptoms
Odynophagia
Figure 4-2
Aproach to the patient with dysphagia. Etiologies in bold print are the most common. ENT, ear, nose, and throat; GERD,
gastroesophageal reflux disease.
it is related to motor disorders, structural disorders, or esophagitis as a common cause of dysphagia in adults has 31
reflux disease. A prolonged history of heartburn pre- led to the recommendation that esophageal mucosal biop-
ceding the onset of dysphagia is suggestive of peptic sies be obtained routinely in the evaluation of unexplained
CHAPTER 4
stricture and, less commonly, esophageal adenocarci- dysphagia even if no endoscopic lesions are evident. For
noma. A history of prolonged nasogastric intubation, cases of suspected esophageal motility disorders, esopha-
esophageal or head and neck surgery, ingestion of caus- gogastroscopy is still the primary examination as neoplas-
tic agents or pills, previous radiation or chemotherapy, tic and inflammatory conditions can secondarily produce
or associated mucocutaneous diseases may help isolate patterns of either achalasia or esophageal spasm. Esopha-
the cause of dysphagia. With accompanying odyno- geal manometry is done if dysphagia is not adequately
Dysphagia
phagia, which usually is indicative of ulceration, infec- explained by endoscopy or to confirm the diagnosis of a
tious or pill-induced esophagitis should be suspected. suspected esophageal motor disorder. Barium radiography
In patients with AIDS or other immunocompromised can provide useful adjunctive information in cases of subtle
states, esophagitis due to opportunistic infections or complex esophageal strictures, esophageal diverticula,
such as Candida, herpes simplex virus, or cytomegalo- or paraesophageal herniation. In specific cases, CT exami-
virus and to tumors such as Kaposi’s sarcoma and lym- nation and endoscopic ultrasonography may be useful.
phoma should be considered. A strong history of atopy
Treatment Treatment of dysphagia depends on
increases concerns for eosinophilic esophagitis.
both the locus and the specific etiology. Oropharyn-
Physical Examination Physical examination geal dysphagia most commonly results from functional
is important in the evaluation of oral and pharyngeal dys- deficits caused by neurologic disorders. In such circum-
phagia because dysphagia is usually only one of many stances, the treatment focuses on utilizing postures or
manifestations of a more global disease process. Signs of maneuvers devised to reduce pharyngeal residue and
bulbar or pseudobulbar palsy, including dysarthria, dys- enhance airway protection learned under the direc-
phonia, ptosis, tongue atrophy, and hyperactive jaw jerk, tion of a trained swallow therapist. Aspiration risk may
in addition to evidence of generalized neuromuscular be reduced by altering the consistency of ingested
disease, should be elicited. The neck should be examined food and liquid. Dysphagia resulting from a cerebrovas-
for thyromegaly. A careful inspection of the mouth and cular accident usually, but not always, spontaneously
pharynx should disclose lesions that may interfere with improves within the first few weeks after the event. More
passage of food. Physical examination is less helpful in severe and persistent cases may require gastrostomy
the evaluation of esophageal dysphagia as most relevant and enteral feeding. Patients with myasthenia gravis
pathology is restricted to the esophagus. The notable and polymyositis may respond to medical treatment of
exception is skin disease. Changes in the skin may sug- the primary neuromuscular disease. Surgical intervention
gest a diagnosis of scleroderma or mucocutaneous dis- with cricopharyngeal myotomy is usually not helpful, with
eases such as pemphigoid and epidermolysis bullosa, all the exception of specific disorders such as the idiopathic
of which can involve the esophagus. cricopharyngeal bar, Zenker’s diverticulum, and oculopha-
ryngeal muscular dystrophy. Chronic neurologic disorders
Diagnostic Procedures Although most
such as Parkinson’s disease and amyotrophic lateral scle-
instances of dysphagia are attributable to benign disease
rosis may manifest with severe oropharyngeal dysphagia.
processes, dysphagia is also a cardinal symptom of several
Feeding by a nasogastric tube or an endoscopically placed
malignancies, making it an important symptom to evalu-
gastrostomy tube may be considered for nutritional sup-
ate. Even when not attributable to malignancy, dyspha-
port; however, these maneuvers do not provide protec-
gia is usually a manifestation of an identifiable and treat-
tion against aspiration of salivary secretions or refluxed
able disease entity, making its evaluation beneficial to the
gastric contents.
patient and gratifying to the practitioner. The specific diag-
Treatment of esophageal dysphagia is covered in
nostic algorithm to pursue is guided by the details of the
detail in Chap. 13. The majority of causes of esophageal
history. If oral or pharyngeal dysphagia is suspected, a fluo-
dysphagia are effectively managed by means of esopha-
roscopic swallow study, usually done by a swallow thera-
geal dilatation using bougie or balloon dilators. Cancer
pist, is the procedure of choice. Otolaryngoscopic and neu-
and achalasia are often managed surgically, although
rologic evaluation also can be important, depending on
endoscopic techniques are available for both palliation
the circumstances. For suspected esophageal dysphagia,
and primary therapy, respectively. Infectious etiologies
endoscopy is the single most useful test. Endoscopy allows
respond to antimicrobial medications or treatment of
better visualization of mucosal lesions than does barium
the underlying immunosuppressive state. Finally, eosino-
radiography and also allows one to obtain mucosal biop-
philic esophagitis has emerged as an important cause of
sies. Furthermore, therapeutic intervention with esopha-
dysphagia that is amenable to treatment by elimination
geal dilatation can be done as part of the procedure if it is
of dietary allergens or topical glucocorticoids.
deemed necessary. Of note, the emergence of eosinophilic
CHAPteR 5
William L. Hasler
Nausea is the subjective feeling of a need to vomit. Vom- initiation of emesis. Neurotransmitters involved in this
iting (emesis) is the oral expulsion of gastrointestinal coordination are uncertain, but neurokinin NK1, sero-
contents resulting from contractions of gut and thora- tonin 5-HT3, and vasopressin pathways may participate.
coabdominal wall musculature. Vomiting is contrasted Somatic and visceral muscles exhibit stereotypic
with regurgitation, the effortless passage of gastric contents responses during emesis. Inspiratory thoracic and abdomi-
into the mouth. Rumination is the repeated regurgita- nal wall muscles contract, producing high intrathoracic
tion of stomach contents, which may be rechewed and and intraabdominal pressures that facilitate expulsion of
reswallowed. In contrast to vomiting, these phenomena gastric contents. The gastric cardia herniates across the
often exhibit volitional control. Indigestion is a nonspe- diaphragm and the larynx moves upward to promote
cific term that encompasses a variety of upper abdomi- oral propulsion of the vomitus. Under normal condi-
nal complaints including nausea, vomiting, heartburn, tions, distally migrating gut contractions are regulated by
regurgitation, and dyspepsia (the presence of symptoms an electrical phenomenon, the slow wave, which cycles
thought to originate in the gastroduodenal region). at 3 cycles/min in the stomach and 11 cycles/min in the
Some individuals with dyspepsia report predominantly duodenum. With emesis, there is slow-wave abolition and
epigastric burning, gnawing discomfort, or pain. Others initiation of orally propagating spikes that evoke retro-
with dyspepsia experience a constellation of symptoms grade contractions that assist in oral expulsion of intestinal
including postprandial fullness, early satiety (an inability contents.
to complete a meal due to premature fullness), bloating,
eructation (belching), and anorexia. Activators of emesis
Emetic stimuli act at several sites. Emesis provoked by
unpleasant thoughts or smells originates in the cerebral
nAUseA And VoMItIng cortex, whereas cranial nerves mediate vomiting after
gag reflex activation. Motion sickness and inner ear dis-
meChanisms orders act on the labyrinthine apparatus, whereas gastric
Vomiting is coordinated by the brainstem and is effected irritants and cytotoxic agents such as cisplatin stimulate
by responses in the gut, pharynx, and thoracoabdomi- gastroduodenal vagal afferent nerves. Nongastric visceral
nal wall. The mechanisms underlying nausea are poorly afferents are activated by intestinal and colonic obstruc-
understood but likely involve the cerebral cortex, because tion and mesenteric ischemia. The area postrema, a med-
nausea requires conscious perception. This is supported ullary nucleus, responds to bloodborne emetic stimuli
by electroencephalographic studies showing activation of and is termed the chemoreceptor trigger zone. Many emeto-
temporofrontal regions during nausea. genic drugs act on the area postrema, as do bacterial
toxins and metabolic factors produced during uremia,
hypoxia, and ketoacidosis.
Coordination of emesis Neurotransmitters that mediate induction of vomit-
Brainstem nuclei—including the nucleus tractus soli- ing are selective for these anatomic sites. Labyrinthine
tarius; dorsal vagal and phrenic nuclei; medullary nuclei disorders stimulate vestibular muscarinic M1 and hista-
that regulate respiration; and nuclei that control pha- minergic H1 receptors, whereas vagal afferent stimuli
ryngeal, facial, and tongue movements—coordinate the activate serotonin 5-HT3 receptors. The area postrema
32
is richly served by nerves acting on 5-HT3, M1, H1, ileus. Enteric infections with viruses or bacteria such as 33
and dopamine D2 subtypes. Transmitters in the cerebral Staphylococcus aureus and Bacillus cereus commonly cause
cortex are poorly understood, although cannabinoid vomiting, especially in children. Opportunistic infec-
CHAPTER 5
CB1 pathways may participate. Optimal pharmacologic tions such as cytomegalovirus or herpes simplex virus
therapy of vomiting requires understanding of these induce emesis in immunocompromised individuals.
pathways. Disordered gut sensorimotor function commonly
causes nausea and vomiting. Gastroparesis is defined as
a delay in gastric emptying of food and occurs after vago
Differential Diagnosis tomy, with pancreatic adenocarcinoma, with mesen
teric vascular insufficiency, or in systemic diseases such
Table 5-1
Causes of Nausea and Vomiting
Intraperitoneal Extraperitoneal Medications/Metabolic Disorders
unknown etiology that produces periodic discrete epi- history helps define the etiology of unexplained nau-
sodes of relentless nausea and vomiting. The syndrome sea and vomiting. Drugs, toxins, and gastrointestinal
shows a strong association with migraine headaches, infections commonly cause acute symptoms, whereas
suggesting that some cases may be migraine variants. established illnesses evoke chronic complaints. Pyloric
Cyclic vomiting is most common in children, although obstruction and gastroparesis produce vomiting within
adult cases have been described in association with rapid 1 h of eating, whereas emesis from intestinal obstruc-
Cardinal Manifestations of Gastrointestinal Disease
gastric emptying and with chronic cannabis use. tion occurs later. In severe cases of gastroparesis, the
vomitus may contain food residue ingested hours or
Extraperitoneal disorders days previously. Hematemesis raises suspicion of an
ulcer, malignancy, or Mallory-Weiss tear, whereas fecu-
Myocardial infarction and congestive heart failure may lent emesis is noted with distal intestinal or colonic
cause nausea and vomiting. Postoperative emesis occurs obstruction. Bilious vomiting excludes gastric obstruc-
after 25% of surgeries, most commonly laparotomy and tion, while emesis of undigested food is consistent with
orthopedic surgery, and is more prevalent in women. a Zenker’s diverticulum or achalasia. Relief of abdomi-
Increased intracranial pressure from tumors, bleed- nal pain by emesis characterizes intestinal obstruc-
ing, abscess, or obstruction to cerebrospinal fluid out- tion, whereas vomiting has no effect on pancreatitis or
flow produces prominent vomiting with or without cholecystitis pain. Pronounced weight loss raises con-
nausea. Motion sickness, labyrinthitis, and Ménière’s cern about malignancy or obstruction. Fevers suggest
disease evoke emesis via labyrinthine pathways. Patients inflammation; an intracranial source is considered if
with psychiatric illnesses including anorexia nervosa, there are headaches or visual field changes. Vertigo or
bulimia nervosa, anxiety, and depression may report tinnitus indicates labyrinthine disease.
significant nausea that may be associated with delayed The physical examination complements informa-
gastric emptying. tion from the history. Orthostatic hypotension and
reduced skin turgor indicate intravascular fluid loss.
Medications and metabolic disorders Pulmonary abnormalities raise concern for aspira-
tion of vomitus. Abdominal auscultation may reveal
Drugs evoke vomiting by action on the stomach (anal- absent bowel sounds with ileus. High-pitched rushes
gesics, erythromycin) or area postrema (digoxin, opiates, suggest bowel obstruction, while a succussion splash
anti-Parkinsonian drugs). Emetogenic agents include anti- upon abrupt lateral movement of the patient is found
biotics, cardiac antiarrhythmics, antihypertensives, oral with gastroparesis or pyloric obstruction. Tenderness or
hypoglycemics, and contraceptives. Cancer chemotherapy involuntary guarding raises suspicion of inflammation,
causes vomiting that is acute (within hours of adminis- whereas fecal blood suggests mucosal injury from ulcer,
tration), delayed (after 1 or more days), or anticipatory. ischemia, or tumor. Neurologic disease presents with
Acute emesis resulting from highly emetogenic agents papilledema, visual field loss, or focal neural abnormali-
such as cisplatin is mediated by 5-HT3 pathways, whereas ties. Neoplasm is suggested by palpation of masses or
delayed emesis is 5-HT3-independent. Anticipatory nau- adenopathy.
sea often responds better to anxiolytic therapy than to
antiemetics. Diagnostic Testing For intractable symptoms
Several metabolic disorders elicit nausea and vomit- or an elusive diagnosis, selected screening tests can
ing. Pregnancy is the most prevalent endocrinologic direct clinical care. Electrolyte replacement is indicated
cause of nausea, which affects 70% of women in the for hypokalemia or metabolic alkalosis. Detection of
first trimester. Hyperemesis gravidarum is a severe form iron-deficiency anemia mandates a search for mucosal
of nausea of pregnancy that can produce significant fluid injury. Pancreaticobiliary disease is indicated by abnor-
loss and electrolyte disturbances. Uremia, ketoacidosis, mal pancreatic or liver biochemistries, whereas endo-
and adrenal insufficiency, as well as parathyroid and thy- crinologic, rheumatologic, or paraneoplastic etiologies
roid disease, are other metabolic causes of emesis. are suggested by hormone or serologic abnormalities.
Circulating toxins evoke emesis via effects on the If bowel obstruction is suspected, supine and upright
area postrema. Endogenous toxins are generated in ful- abdominal radiographs may show intestinal air-fluid
minant liver failure, whereas exogenous enterotoxins levels with reduced colonic air. Ileus is characterized by
may be produced by enteric bacterial infection. Ethanol diffusely dilated air-filled bowel loops.
intoxication is a common toxic etiology of nausea and Anatomic studies may be indicated if initial test-
vomiting. ing is nondiagnostic. Upper endoscopy detects ulcers
or malignancy, while small-bowel barium radiography and granisetron exhibit utility in postoperative vomit- 35
diagnoses partial intestinal obstruction. Colonoscopy or ing, after radiation therapy, and for preventing cancer
contrast enema radiography can detect colonic obstruc- chemotherapy–induced emesis. The usefulness of 5-HT3
CHAPTER 5
tion. Ultrasound or CT defines intraperitoneal inflam- antagonists for other causes of emesis is less well estab-
matory processes, while CT or MRI of the head can lished. Low-dose tricyclic antidepressant agents provide
delineate intracranial disease. Advances in CT and MRI symptomatic benefit in patients with chronic idiopathic
enterography have improved definition of bowel inflam- nausea and functional vomiting as well as in diabetic
mation, as in Crohn’s disease. Mesenteric angiography, patients with nausea and vomiting whose disease is of
CT, or MRI is useful for suspected ischemia. long standing. Other antidepressants such as mirtazap-
ine also may exhibit antiemetic effects.
CHAPTER 5
of the LES, whereas impaired esophageal body motility symptoms. Alkaline reflux esophagitis produces GERD-
and reduced salivary secretion prolong fluid exposure. like symptoms most often in patients who have had
The role of hiatal hernias is controversial—although most surgery for peptic ulcer disease. Approximately 10% of
reflux patients exhibit hiatal hernias, most individuals patients with heartburn of a functional nature exhibit
with hiatal hernias do not have excess heartburn. normal degrees of esophageal acid exposure and no
increase in nonacidic reflux.
cause odynophagia. Other causes of esophageal inflam- acid regurgitation may cause poor dentition. Func-
mation include eosinophilic esophagitis and pill esoph- tional dyspeptics may report epigastric tenderness or
agitis. Biliary colic is in the differential diagnosis of distention.
dyspepsia, but most patients with true biliary colic Discrimination between functional and organic causes
report discrete episodes of right upper quadrant or epi- of indigestion mandates exclusion of selected historic
gastric pain rather than chronic burning discomfort, and examination features. Odynophagia suggests
Cardinal Manifestations of Gastrointestinal Disease
nausea, and bloating. Intestinal lactase deficiency pro- esophageal infection, while dysphagia is worrisome
duces gas, bloating, discomfort, and diarrhea after lac- for a benign or malignant esophageal blockage. Other
tose ingestion. Lactase deficiency occurs in 15–25% of alarming features include unexplained weight loss,
whites of northern European descent but is more com- recurrent vomiting, occult or gross gastrointestinal
mon in blacks and Asians. Intolerance of other car- bleeding, jaundice, a palpable mass or adenopathy,
bohydrates (e.g., fructose, sorbitol) produces similar and a family history of gastrointestinal malignancy.
symptoms. Small-intestinal bacterial overgrowth may Diagnostic Testing Because indigestion is
produce dyspepsia, often with bowel dysfunction, dis- prevalent and most cases result from GERD or func-
tention, and malabsorption. Eosinophilic infiltration tional dyspepsia, a general principle is to perform only
of the duodenal mucosa is described in some cases of limited and directed diagnostic testing of selected indi-
dyspepsia. Pancreatic disease (chronic pancreatitis and viduals.
malignancy), hepatocellular carcinoma, celiac disease, Once alarm factors are excluded (Table 5-3), patients
Ménétrier’s disease, infiltrative diseases (sarcoidosis and with typical GERD do not need further evaluation and
eosinophilic gastroenteritis), mesenteric ischemia, thy- are treated empirically. Upper endoscopy is indicated
roid and parathyroid disease, and abdominal wall strain to exclude mucosal injury in cases with atypical symp-
cause dyspepsia. Extraperitoneal etiologies of indigestion toms, symptoms unresponsive to acid suppressing
include congestive heart failure and tuberculosis. Inves- drugs, or alarm factors. For heartburn >5 years in dura-
tigation is ongoing into genetic markers that predispose tion, especially in patients >50 years old, endoscopy
to developing functional dyspepsia. is recommended to screen for Barrett’s metaplasia.
However, the clinical benefits and cost-effectiveness
of this approach have not been validated in controlled
APPROACH TO THE
PATIENt Indigestion studies. Ambulatory esophageal pH testing using a
catheter method or an implanted esophageal capsule
History and Physical Examination device is considered for drug-refractory symptoms and
Care of the patient with indigestion requires a thorough atypical symptoms like unexplained chest pain. Esoph-
interview. GERD classically produces heartburn, a sub- ageal manometry most commonly is ordered when
sternal warmth in the epigastrium that moves toward surgical treatment of GERD is considered. A low LES
the neck. Heartburn often is exacerbated by meals and pressure may predict failure of drug therapy and helps
may awaken the patient. Associated symptoms include select patients who may require surgery. Demonstra-
regurgitation of acid or nonacidic fluid and water brash, tion of disordered esophageal body peristalsis may
the reflex release of salty salivary secretions into the affect the decision to operate or modify the type
mouth. Atypical symptoms include pharyngitis, asthma,
cough, bronchitis, hoarseness, and chest pain that
mimics angina. Some patients with acid reflux on
esophageal pH testing do not report heartburn, but Table 5-3
note abdominal pain or other symptoms. Alarm Symptoms in GERD
Some patients with dyspepsia report a predomi-
Odynophagia
nance of epigastric pain or burning that is intermittent
Unexplained weight loss
and not generalized or localized to other regions. Others
experience a postprandial distress syndrome charac- Recurrent vomiting
terized by fullness occurring after normal-sized meals Occult or gross gastrointestinal bleeding
and early satiety that prevents completion of regular Jaundice
meals, with associated bloating, belching, or nausea.
Palpable mass or adenopathy
Functional dyspepsia overlaps with other functional
disorders such as IBS. Family history of gastrointestinal malignancy
of operation chosen. High-resolution manometric 39
Treatment General Principles
methods improve characterization of ineffective esoph-
ageal propulsion, which may contribute to impaired For mild indigestion, reassurance that a careful evalua-
CHAPTER 5
esophageal acid clearance in some GERD patients. tion revealed no serious organic disease may be the only
Manometry with provocative testing may clarify the intervention needed. Drugs that cause gastroesophageal
diagnosis in patients with atypical symptoms. Blind reflux or dyspepsia should be stopped, if possible. Patients
perfusion of saline and then acid into the esophagus, with GERD should limit ethanol, caffeine, chocolate, and
known as the Bernstein test, can delineate whether unex- tobacco use because of their effects on the LES. Other mea-
plained chest discomfort results from acid reflux. Non- sures in GERD include ingesting a low-fat diet, avoiding
ulcer and mucosa-associated lymphoid tissue gastric cal symptoms and those who have esophageal body
lymphoma. The utility of eradication therapy in func- motor disturbances. Fundoplications are performed
tional dyspepsia is less well established, but <15% of laparoscopically when possible and include the Nissen
cases relate to this infection. Meta-analysis of 13 con- and Toupet procedures in which the proximal stom-
trolled trials calculated a risk ratio of 0.91, with a 95% ach is partly or completely wrapped around the distal
confidence interval of 0.87–0.96, favoring H. pylori esophagus to increase LES pressure. Dysphagia, gas-
eradication therapy over placebo. Several drug com- bloat syndrome, and gastroparesis may be long-term
binations show efficacy in eliminating the infection complications of these procedures. The utility and safety
(Chap. 14); most include 10–14 days of a proton pump of endoscopic therapies for increasing the barrier func-
inhibitor or bismuth subsalicylate in concert with two tion of the gastroesophageal junction, including radio-
antibiotics. H. pylori infection is associated with reduced frequency energy delivery and gastroplication, have not
prevalence of GERD, especially in the elderly. However, been fully investigated for patients with refractory GERD.
eradication of the infection does not worsen GERD Some patients with functional heartburn and func-
symptoms. To date, no consensus recommendations tional dyspepsia refractory to standard therapies may
regarding H. pylori eradication in GERD patients have respond to low-dose antidepressants in tricyclic and
been offered. other classes. Their mechanism of action is unknown but
may involve blunting of visceral pain processing in the
Agents that Modify Gastrointestinal brain. Gas and bloating are among the most troubling
Motor Activity Motor stimulants (also known symptoms in some patients with indigestion and can
as prokinetics) such as metoclopramide, erythromy- be difficult to treat. Dietary exclusion of gas-producing
cin, and domperidone have limited utility in GERD. foods such as legumes and use of simethicone or acti-
Several studies have evaluated the effectiveness vated charcoal provide benefits in some cases. Therapies
of motor-stimulating drugs in functional dyspep- that modify gut flora, including antibiotics and probiotic
sia; however, convincing evidence of their benefits preparations containing active bacterial cultures, are use-
has not been found. Some clinicians suggest that ful for cases of bacterial overgrowth and functional lower
patients with symptoms resembling postprandial dis- gastrointestinal disorders, but their utility in functional
tress may respond preferentially to prokinetic drugs. dyspepsia is unproven. Psychological treatments may be
The γ-aminobutyric acid B (GABA-B) agonist baclofen offered for refractory functional dyspepsia, but no con-
reduces esophageal exposure to acid and non acidic vincing data suggest their efficacy.
Chapter 6
tylcholine, vasoactive intestinal peptide (VIP), opi- influence colonic absorption, reflecting the common
oids, norepinephrine, serotonin, adenosine triphosphate embryologic development of the distal colonic epithe-
(ATP), and nitric oxide (NO). The myenteric plexus lium and the renal tubules.
regulates smooth-muscle function, and the submucosal
plexus affects secretion, absorption, and mucosal blood
flow. Small-Intestinal Motility
Cardinal Manifestations of Gastrointestinal Disease
The extrinsic innervations of the small intestine and During fasting, the motility of the small intestine is char-
colon are part of the autonomic nervous system and acterized by a cyclical event called the migrating motor
also modulate motor and secretory functions. The para- complex (MMC), which serves to clear nondigestible
sympathetic nerves convey visceral sensory and excit- residue from the small intestine (the intestinal “house-
atory pathways to the colon. Parasympathetic fibers via keeper”). This organized, propagated series of contrac-
the vagus nerve reach the small intestine and proximal tions last, on average, 4 min, occur every 60–90 min,
colon along the branches of the superior mesenteric and usually involve the entire small intestine. After food
artery. The distal colon is supplied by sacral parasym- ingestion, the small intestine produces irregular, mixing
pathetic nerves (S2–4) via the pelvic plexus; these fibers contractions of relatively low amplitude, except in the
course through the wall of the colon as ascending intra- distal ileum where more powerful contractions occur
colonic fibers as far as, and in some instances including, intermittently and empty the ileum by bolus transfers.
the proximal colon. The chief excitatory neurotransmit-
ters controlling motor function are acetylcholine and
the tachykinins, such as substance P. The sympathetic Ileocolonic Storage and Salvage
nerve supply modulates motor functions and reaches The distal ileum acts as a reservoir, emptying intermit-
the small intestine and colon alongside their arterial ves- tently by bolus movements. This action allows time for
sels. Sympathetic input to the gut is generally excitatory salvage of fluids, electrolytes, and nutrients. Segmenta-
to sphincters and inhibitory to nonsphincteric muscle. tion by haustra compartmentalizes the colon and facili-
Visceral afferents convey sensation from the gut to the tates mixing, retention of residue, and formation of
central nervous system (CNS); initially, they course solid stools. There is increased appreciation of the inti-
along sympathetic fibers, but as they approach the spi- mate interaction between the colonic function and the
nal cord they separate, have cell bodies in the dorsal luminal ecology. The resident bacteria in the colon are
root ganglion, and enter the dorsal horn of the spinal necessary for the digestion of unabsorbed carbohydrates
cord. Afferent signals are conveyed to the brain along that reach the colon even in health, thereby providing a
the lateral spinothalamic tract and the nociceptive dor- vital source of nutrients to the mucosa. Normal colonic
sal column pathway and are then projected beyond the flora also keeps pathogens at bay by a variety of mecha-
thalamus and brainstem to the insula and cerebral cor- nisms. In health, the ascending and transverse regions
tex to be perceived. Other afferent fibers synapse in of colon function as reservoirs (average transit, 15 h),
the prevertebral ganglia and reflexly modulate intestinal and the descending colon acts as a conduit (average
motility. transit, 3 h). The colon is efficient at conserving sodium
and water, a function that is particularly important in
Intestinal Fluid Absorption sodium-depleted patients in whom the small intestine
and Secretion alone is unable to maintain sodium balance. Diarrhea or
constipation may result from alteration in the reservoir
On an average day, 9 L of fluid enter the gastrointestinal
function of the proximal colon or the propulsive func-
(GI) tract, ∼1 L of residual fluid reaches the colon, and
tion of the left colon. Constipation may also result from
the stool excretion of fluid constitutes about 0.2 L/d.
disturbances of the rectal or sigmoid reservoir, typically
The colon has a large capacitance and functional reserve
as a result of dysfunction of the pelvic floor, the anal
and may recover up to four times its usual volume of
sphincters, or the coordination of defecation.
0.8 L/d, provided the rate of flow permits reabsorption
to occur. Thus, the colon can partially compensate for
excess fluid delivery to the colon because of intestinal
absorptive or secretory disorders. Colonic Motility and Tone
In the colon, sodium absorption is predominantly The small intestinal MMC only rarely continues into
electrogenic, and uptake takes place at the apical mem- the colon. However, short duration or phasic con
brane; it is compensated for by the export functions of tractions mix colonic contents, and high-amplitude
(>75 mmHg) propagated contractions (HAPCs) are Distention of the rectum results in transient relaxation 43
sometimes associated with mass movements through of the internal anal sphincter via intrinsic and reflex
the colon and normally occur approximately five times sympathetic innervation. As sigmoid and rectal con-
CHAPTER 6
per day, usually on awakening in the morning and post- tractions increase the pressure within the rectum, the
prandially. Increased frequency of HAPCs may result in rectosigmoid angle opens by >15°. Voluntary relax-
diarrhea or urgency. The predominant phasic contrac- ation of the external anal sphincter (striated muscle
tions in the colon are irregular and nonpropagated and innervated by the pudendal nerve) in response to the
serve a “mixing” function. sensation produced by distention permits the evac-
Colonic tone refers to the background contractil- uation of feces; this evacuation process can be
ity upon which phasic contractile activity (typically augmented by an increase in intraabdominal pressure
Pubis
Puborectalis
Coccyx
Anorectal Anorectal
External anal angle angle
sphincter Internal anal
A B
sphincter
Descent of the pelvic floor
Figure 6-1
Sagittal view of the anorectum (A) at rest and (B) during (including the puborectalis) relax, allowing the anorec-
straining to defecate. Continence is maintained by normal tal angle to straighten by at least 15°, and the perineum
rectal sensation and tonic contraction of the internal anal descends by 1–3.5 cm. The external anal sphincter
sphincter and the puborectalis muscle, which wraps around also relaxes and reduces pressure on the anal canal.
the anorectum, maintaining an anorectal angle between (Reproduced with permission from A Lembo, M Camilleri:
80° and 110°. During defecation, the pelvic floor muscles N Engl J Med 349:1360, 2003.)
44 disorders or structural anorectal problems. Diarrhea and may suggest infection with Salmonella, Campylobacter,
urgency, especially if severe, may aggravate or cause or Shigella from chicken; enterohemorrhagic E. coli
incontinence. Pseudodiarrhea and fecal incontinence (O157:H7) from undercooked hamburger; Bacillus
occur at prevalence rates comparable to or higher than cereus from fried rice or other reheated food; Staph-
SECTION I
that of chronic diarrhea and should always be consid- ylococcus aureus or Salmonella from mayonnaise or
ered in patients complaining of “diarrhea.” Overflow creams; Salmonella from eggs; Listeria from uncooked
diarrhea may occur in nursing home patients due to foods or soft cheeses; and Vibrio species, Salmonella,
fecal impaction that is readily detectable by rectal exam- or acute hepatitis A from seafood, especially if raw.
ination. A careful history and physical examination gen- 3. Immunodeficient persons. Individuals at risk for diar-
erally allow these conditions to be discriminated from rhea include those with either primary immunodefi-
Cardinal Manifestations of Gastrointestinal Disease
CHAPTER 6
Incubation Abdominal
Pathobiology/Agents Period Vomiting Pain Fever Diarrhea
Toxin producers
Preformed toxin
Bacillus cereus, Staphylococcus aureus, 1–8 h 3–4+ 1–2+ 0–1+ 3–4+, watery
Clostridium perfringens 8–24 h
Source: Adapted from DW Powell, in T Yamada (ed): Textbook of Gastroenterology and Hepatology, 4th ed. Philadelphia, Lippincott Williams &
Wilkins, 2003.
especially severe abdominal pain with tenderness mim- may be suggested by a temporal association between use
icking acute appendicitis. and symptom onset. Although innumerable medica-
Finally, infectious diarrhea may be associated with tions may produce diarrhea, some of the more frequently
systemic manifestations. Reactive arthritis (formerly incriminated include antibiotics, cardiac antidysrhythmics,
known as Reiter’s syndrome), arthritis, urethritis, and antihypertensives, nonsteroidal anti-inflammatory drugs
conjunctivitis may accompany or follow infections (NSAIDs), certain antidepressants, chemotherapeutic
by Salmonella, Campylobacter, Shigella, and Yersinia. agents, bronchodilators, antacids, and laxatives. Occlusive
Yersiniosis may also lead to an autoimmune-type thy- or nonocclusive ischemic colitis typically occurs in persons
roiditis, pericarditis, and glomerulonephritis. Both >50 years; often presents as acute lower abdominal pain
enterohemorrhagic E. coli (O157:H7) and Shigella can preceding watery, then bloody diarrhea; and generally
lead to the hemolytic-uremic syndrome with an attendant results in acute inflammatory changes in the sigmoid or
high mortality rate. The syndrome of postinfectious IBS left colon while sparing the rectum. Acute diarrhea may
has now been recognized as a complication of infectious accompany colonic diverticulitis and graft-versus-host disease.
diarrhea. Acute diarrhea can also be a major symptom Acute diarrhea, often associated with systemic compro-
of several systemic infections including viral hepatitis, mise, can follow ingestion of toxins including organo-
listeriosis, legionellosis, and toxic shock syndrome. phosphate insecticides; amanita and other mushrooms;
arsenic; and preformed environmental toxins in seafood,
Other causes such as ciguatera and scombroid. Acute anaphylaxis to
food ingestion can have a similar presentation. Conditions
Side effects from medications are probably the most com- causing chronic diarrhea can also be confused with acute
mon noninfectious causes of acute diarrhea, and etiology diarrhea early in their course. This confusion may occur
46 with inflammatory bowel disease (IBD) and some of the
the leukocyte proteins) or with gross blood, a diagnos-
other inflammatory chronic diarrheas that may have an
tic evaluation might be avoided in favor of an empirical
abrupt rather than insidious onset and exhibit features that
antibiotic trial discussed later.
mimic infection.
SECTION I
its severity and duration and on various host factors antigens (Giardia, E. histolytica). The aforementioned
(Fig. 6-2). Most episodes of acute diarrhea are mild clinical and epidemiologic associations may assist in
and self-limited and do not justify the cost and poten- focusing the evaluation. If a particular pathogen or set
tial morbidity rate of diagnostic or pharmacologic of possible pathogens is so implicated, then either the
interventions. Indications for evaluation include profuse whole panel of routine studies may not be necessary
diarrhea with dehydration, grossly bloody stools, fever or, in some instances, special cultures may be appropri-
≥38.5°C (≥101°F), duration >48 h without improvement, ate as for enterohemorrhagic and other types of E. coli,
recent antibiotic use, new community outbreaks, associ- Vibrio species, and Yersinia. Molecular diagnosis of
ated severe abdominal pain in patients >50 years, and pathogens in stool can be made by identification of
elderly (≥70 years) or immunocompromised patients. In unique DNA sequences; and evolving microarray tech-
some cases of moderately severe febrile diarrhea asso- nologies could lead to a more rapid, sensitive, specific,
ciated with fecal leukocytes (or increased fecal levels of and cost-effective diagnostic approach in the future.
Persistent diarrhea is commonly due to Giardia
(Chap. 32), but additional causative organisms that
should be considered include C. difficile (especially
if antibiotics had been administered), E. histolytica,
Acute Diarrhea Cryptosporidium, Campylobacter, and others. If stool
studies are unrevealing, flexible sigmoidoscopy with
biopsies and upper endoscopy with duodenal aspi-
History and Likely noninfectious
physical exam rates and biopsies may be indicated. Brainerd diarrhea
is an increasingly recognized entity characterized by an
Evaluate and abrupt-onset diarrhea that persists for at least 4 weeks,
Likely infectious treat accordingly
but may last 1–3 years, and is thought to be of infec-
tious origin. It may be associated with subtle inflamma-
Mild Moderate Severe tion of the distal small intestine or proximal colon.
(unrestricted) (activities altered) (incapacitated)
Structural examination by sigmoidoscopy, colo-
Institute fluid and electrolyte replacement noscopy, or abdominal CT scanning (or other imag-
ing approaches) may be appropriate in patients with
Observe Fever ≥38.5°C, bloody stools, fecal WBCs,
uncharacterized persistent diarrhea to exclude IBD or as
immunocompromised or elderly host an initial approach in patients with suspected noninfec-
tious acute diarrhea such as might be caused by isch-
Resolves Persists* Stool microbiology
No Yes† studies emic colitis, diverticulitis, or partial bowel obstruction.
Antidiarrheal
agents
Pathogen found
Resolves Persists* Treatment Acute Diarrhea
No Yes†
Fluid and electrolyte replacement are of central impor-
Empirical Select specific
tance to all forms of acute diarrhea. Fluid replacement
treatment + further treatment alone may suffice for mild cases. Oral sugar-electrolyte
evaluation
solutions (sport drinks or designed formulations) should
be instituted promptly with severe diarrhea to limit
Figure 6-2
dehydration, which is the major cause of death. Pro-
Algorithm for the management of acute diarrhea.
foundly dehydrated patients, especially infants and the
Consider empirical Rx before evaluation with (*) metronida-
elderly, require IV rehydration.
zole and with (†) quinolone. WBCs, white blood cells.
In moderately severe nonfebrile and nonbloody diar- may reduce the frequency of traveler’s diarrhea. Antibiotic 47
rhea, antimotility and antisecretory agents such as lop- prophylaxis is only indicated for certain patients travel-
eramide can be useful adjuncts to control symptoms. ing to high-risk countries in whom the likelihood or seri-
CHAPTER 6
Such agents should be avoided with febrile dysentery, ousness of acquired diarrhea would be especially high,
which may be exacerbated or prolonged by them. including those with immunocompromise, IBD, hemo-
Bismuth subsalicylate may reduce symptoms of vomiting chromatosis, or gastric achlorhydria. Use of ciprofloxacin
and diarrhea but should not be used to treat immuno- or rifaximin may reduce bacterial diarrhea in such trav-
compromised patients or those with renal impairment elers by 90%, though rifaximin is not suitable for inva-
because of the risk of bismuth encephalopathy. sive disease, but rather as treatment for uncomplicated
Table 6-3
Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism
Secretory causes Inflammatory causes
Exogenous stimulant laxatives Idiopathic inflammatory bowel disease (Crohn’s, chronic
Chronic ethanol ingestion ulcerative colitis)
Other drugs and toxins Lymphocytic and collagenous colitis
Endogenous laxatives (dihydroxy bile acids) Immune-related mucosal disease (1° or 2°
Idiopathic secretory diarrhea immunodeficiencies, food allergy, eosinophilic
Certain bacterial infections gastroenteritis, graft-vs-host disease)
Bowel resection, disease, or fistula (↓ absorption) Infections (invasive bacteria, viruses, and parasites,
Partial bowel obstruction or fecal impaction Brainerd diarrhea)
Hormone-producing tumors (carcinoid, VIPoma, medullary Radiation injury
cancer of thyroid, mastocytosis, gastrinoma, colorectal Gastrointestinal malignancies
villous adenoma) Dysmotile causes
Addison’s disease Irritable bowel syndrome (including postinfectious IBS)
Congenital electrolyte absorption defects Visceral neuromyopathies
Osmotic causes Hyperthyroidism
Osmotic laxatives (Mg2+, PO4−3, SO4−2) Drugs (prokinetic agents)
Lactase and other disaccharide deficiencies Postvagotomy
Nonabsorbable carbohydrates (sorbitol, lactulose, Factitial causes
polyethylene glycol) Munchausen
Steatorrheal causes Eating disorders
Intraluminal maldigestion (pancreatic exocrine insufficiency, Iatrogenic causes
bacterial overgrowth, bariatric surgery, liver disease) Cholecystectomy
Mucosal malabsorption (celiac sprue, Whipple’s disease, Ileal resection
infections, abetalipoproteinemia, ischemia) Bariatric surgery
Postmucosal obstruction (1° or 2° lymphatic obstruction) Vagotomy, fundoplication
48 Secretory causes heart disease. Diarrhea is due to the release into the
circulation of potent intestinal secretagogues including
Secretory diarrheas are due to derangements in fluid and serotonin, histamine, prostaglandins, and various kinins.
electrolyte transport across the enterocolonic mucosa. Pellagra-like skin lesions may rarely occur as the result
SECTION I
They are characterized clinically by watery, large- of serotonin overproduction with niacin depletion.
volume fecal outputs that are typically painless and per- Gastrinoma, one of the most common neuroendocrine
sist with fasting. Because there is no malabsorbed solute, tumors, most typically presents with refractory peptic
stool osmolality is accounted for by normal endogenous ulcers, but diarrhea occurs in up to one-third of cases
electrolytes with no fecal osmotic gap. and may be the only clinical manifestation in 10%.
While other secretagogues released with gastrin may
Cardinal Manifestations of Gastrointestinal Disease
Medications
Side effects from regular ingestion of drugs and toxins play a role, the diarrhea most often results from fat mal-
are the most common secretory causes of chronic diar- digestion owing to pancreatic enzyme inactivation by
rhea. Hundreds of prescription and over-the-counter low intraduodenal pH. The watery diarrhea hypokale-
medications (see “Acute Diarrhea, Other Causes”) mia achlorhydria syndrome, also called pancreatic cholera,
may produce diarrhea. Surreptitious or habitual use of is due to a non-β cell pancreatic adenoma, referred to
stimulant laxatives [e.g., senna, cascara, bisacodyl, ricin- as a VIPoma, that secretes VIP and a host of other pep-
oleic acid (castor oil)] must also be considered. Chronic tide hormones including pancreatic polypeptide, secre-
ethanol consumption may cause a secretory-type diar- tin, gastrin, gastrin-inhibitory polypeptide (also called
rhea due to enterocyte injury with impaired sodium glucose-dependent insulinotropic peptide), neurotensin,
and water absorption as well as rapid transit and other calcitonin, and prostaglandins. The secretory diarrhea is
alterations. Inadvertent ingestion of certain environmen- often massive with stool volumes >3 L/d; daily volumes
tal toxins (e.g., arsenic) may lead to chronic rather than as high as 20 L have been reported. Life-threatening
acute forms of diarrhea. Certain bacterial infections may dehydration; neuromuscular dysfunction from associ-
occasionally persist and be associated with a secretory- ated hypokalemia, hypomagnesemia, or hypercalcemia;
type diarrhea. flushing; and hyperglycemia may accompany a VIPoma.
Medullary carcinoma of the thyroid may present with watery
owel resection, mucosal disease,
B diarrhea caused by calcitonin, other secretory peptides,
or enterocolic fistula or prostaglandins. Prominent diarrhea is often associated
These conditions may result in a secretory-type diar- with metastatic disease and poor prognosis. Systemic mas-
rhea because of inadequate surface for reabsorption of tocytosis, which may be associated with the skin lesion
secreted fluids and electrolytes. Unlike other secretory urticaria pigmentosa, may cause diarrhea that is either
diarrheas, this subset of conditions tends to worsen with secretory and mediated by histamine or inflammatory
eating. With disease (e.g., Crohn’s ileitis) or resection of due to intestinal infiltration by mast cells. Large colorectal
<100 cm of terminal ileum, dihydroxy bile acids may villous adenomas may rarely be associated with a secretory
escape absorption and stimulate colonic secretion (chol- diarrhea that may cause hypokalemia, can be inhibited by
orrheic diarrhea). This mechanism may contribute to NSAIDs, and are apparently mediated by prostaglandins.
so-called idiopathic secretory diarrhea, in which bile acids
are functionally malabsorbed from a normal-appearing Congenital defects in ion absorption
terminal ileum. This idiopathic bile acid malabsorption may Rarely, defects in specific carriers associated with ion
account for an average of 40% of unexplained chronic absorption cause watery diarrhea from birth. These dis-
diarrhea. Reduced negative feedback regulation of bile orders include defective Cl−/HCO3− exchange (congenital
acid synthesis by fibroblast growth factor 19 produced chloridorrhea) with alkalosis (which results from a mutated
by enterocytes results in a degree of bile-acid synthesis DRA [down-regulated in adenoma] gene) and defec-
that exceeds the normal capacity for ileal reabsorption, tive Na+/H+ exchange (congential sodium diarrhea), which
producing bile acid diarrhea. results from a mutation in the NHE3 (sodium-hydrogen
Partial bowel obstruction, ostomy stricture, or fecal exchanger) gene and results in acidosis.
impaction may paradoxically lead to increased fecal out- Some hormone deficiencies may be associated with
put due to fluid hypersecretion. watery diarrhea, such as occurs with adrenocortical
insufficiency (Addison’s disease) that may be accompa-
Hormones nied by skin hyperpigmentation.
Although uncommon, the classic examples of secretory
diarrhea are those mediated by hormones. Metastatic Osmotic causes
gastrointestinal carcinoid tumors or, rarely, primary bron-
chial carcinoids may produce watery diarrhea alone or as Osmotic diarrhea occurs when ingested, poorly absorb-
part of the carcinoid syndrome that comprises episodic able, osmotically active solutes draw enough fluid into
flushing, wheezing, dyspnea, and right-sided valvular the lumen to exceed the reabsorptive capacity of the
colon. Fecal water output increases in proportion to deconjugate bile acids and alter micelle formation, 49
such a solute load. Osmotic diarrhea characteristically impairing fat digestion; it occurs with stasis from a
ceases with fasting or with discontinuation of the caus- blind-loop, small-bowel diverticulum or dysmotility
CHAPTER 6
ative agent. and is especially likely in the elderly. Finally, cirrhosis or
biliary obstruction may lead to mild steatorrhea due to
Osmotic laxatives
deficient intraluminal bile acid concentration.
Ingestion of magnesium-containing antacids, health
supplements, or laxatives may induce osmotic diarrhea Mucosal malabsorption
typified by a stool osmotic gap (>50 mosmol/L): Mucosal malabsorption occurs from a variety of enter-
serum osmolarity (typically 290 mosmol/kg) - [2 × opathies, but it most commonly occurs from celiac
older person with chronic inflammatory-type diarrhea, glandins, prokinetic agents) may produce hypermotility
especially with blood, should be carefully evaluated to with resultant diarrhea. Primary visceral neuromyopa-
exclude a colorectal tumor. thies or idiopathic acquired intestinal pseudoobstruction
may lead to stasis with secondary bacterial overgrowth
Idiopathic inflammatory bowel disease
causing diarrhea. Diabetic diarrhea, often accompanied
The illnesses in this category, which include Crohn’s by peripheral and generalized autonomic neuropathies,
Cardinal Manifestations of Gastrointestinal Disease
disease and chronic ulcerative colitis, are among the most may occur in part because of intestinal dysmotility.
common organic causes of chronic diarrhea in adults The exceedingly common IBS (10% point preva-
and range in severity from mild to fulminant and life- lence, 1–2% per year incidence) is characterized by
threatening. They may be associated with uveitis, disturbed intestinal and colonic motor and sensory
polyarthralgias, cholestatic liver disease (primary scleros- responses to various stimuli. Symptoms of stool fre-
ing cholangitis), and skin lesions (erythema nodosum, quency typically cease at night, alternate with periods
pyoderma gangrenosum). Microscopic colitis, includ- of constipation, are accompanied by abdominal pain
ing both lymphocytic and collagenous colitis, is an relieved with defecation, and rarely result in weight loss.
increasingly recognized cause of chronic watery diar-
rhea, especially in middle-aged women and those on
NSAIDs, statins, proton pump inhibitors (PPIs), and Factitial causes
selective serotonin reuptake inhibitors (SSRIs); biopsy
of a normal-appearing colon is required for histologic Factitial diarrhea accounts for up to 15% of unexplained
diagnosis. It may coexist with symptoms suggesting diarrheas referred to tertiary care centers. Either as a
IBS or with celiac sprue. It typically responds well to form of Munchausen syndrome (deception or self-injury
anti-inflammatory drugs (e.g., bismuth), to the opioid for secondary gain) or eating disorders, some patients
agonist loperamide, or to budesonide. covertly self-administer laxatives alone or in combina-
tion with other medications (e.g., diuretics) or surrepti-
rimary or secondary forms
P tiously add water or urine to stool sent for analysis. Such
of immunodeficiency patients are typically women, often with histories of
Immunodeficiency may lead to prolonged infectious psychiatric illness, and disproportionately from careers in
diarrhea. With selective IgA deficiency or common health care. Hypotension and hypokalemia are common
variable hypogammaglobulinemia, diarrhea is particularly co-presenting features. The evaluation of such patients
prevalent and often the result of giardiasis, bacterial may be difficult: contamination of the stool with water
overgrowth, or sprue. or urine is suggested by very low or high stool osmolar-
ity, respectively. Such patients often deny this possibility
Eosinophilic gastroenteritis when confronted, but they do benefit from psychiatric
Eosinophil infiltration of the mucosa, muscularis, or counseling when they acknowledge their behavior.
serosa at any level of the GI tract may cause diarrhea,
pain, vomiting, or ascites. Affected patients often have an
APPROACH TO THE
atopic history, Charcot-Leyden crystals due to extruded PATIENT Chronic Diarrhea
eosinophil contents may be seen on microscopic inspec-
tion of stool, and peripheral eosinophilia is present in The laboratory tools available to evaluate the very
50–75% of patients. While hypersensitivity to certain common problem of chronic diarrhea are extensive,
foods occurs in adults, true food allergy causing chronic and many are costly and invasive. As such, the diag-
diarrhea is rare. nostic evaluation must be rationally directed by a
careful history and physical examination (Fig. 6-3A).
Other causes When this strategy is unrevealing, simple triage tests
Chronic inflammatory diarrhea may be caused by radia- are often warranted to direct the choice of more com-
tion enterocolitis, chronic graft-versus-host disease, Behçet’s plex investigations (Fig. 6-3B). The history, physical
syndrome, and Cronkhite-Canada syndrome, among others. examination (Table 6-4), and routine blood studies
should attempt to characterize the mechanism of diar-
Dysmotility causes rhea, identify diagnostically helpful associations, and
assess the patient’s fluid/electrolyte and nutritional
Rapid transit may accompany many diarrheas as a sec-
status. Patients should be questioned about the onset,
ondary or contributing phenomenon, but primary dys-
duration, pattern, aggravating (especially diet) and
motility is an unusual etiology of true diarrhea. Stool
51
Chronic diarrhea
CHAPTER 6
medication, surgery
Chronic diarrhea
Opioid Rx +
Colonoscopy + Small bowel: X-ray, Stool vol, OSM, pH; follow-up
biopsy biopsy, aspirate; Laxative screen;
stool 48-h fat Hormonal screen
Persistent
chronic diarrhea
Normal and
Stool fat >20 g/day stool fat Titrate Rx to
Pancreatic function <14 g/day Full gut transit speed of transit
Figure 6-3
Chronic diarrhea. A. Initial management based on accom- bowel syndrome; Hb, hemoglobin; Alb, albumin; MCV, mean
panying symptoms or features. B. Evaluation based on corpuscular volume; MCH, mean corpuscular hemoglobin;
findings from a limited age-appropriate screen for organic OSM, osmolality. (Reprinted from M Camilleri: Clin Gastro
disease. pr, per rectum; bm, bowel movement; IBS, irritable enterol Hepatol 2:198, 2004.)
relieving factors, and stool characteristics of their abnormalities, perianal fistulas, or anal sphincter
diarrhea. The presence or absence of fecal inconti- laxity. Peripheral blood leukocytosis, elevated sedimen-
nence, fever, weight loss, pain, certain exposures (travel, tation rate, or C-reactive protein suggests inflammation;
medications, contacts with diarrhea), and common anemia reflects blood loss or nutritional deficiencies; or
extraintestinal manifestations (skin changes, arthral- eosinophilia may occur with parasitoses, neoplasia, col-
gias, oral aphthous ulcers) should be noted. A family lagen-vascular disease, allergy, or eosinophilic gastroen-
history of IBD or sprue may indicate those possibili- teritis. Blood chemistries may demonstrate electrolyte,
ties. Physical findings may offer clues such as a thyroid hepatic, or other metabolic disturbances. Measuring tis-
mass, wheezing, heart murmurs, edema, hepatomegaly, sue transglutaminase antibodies may help detect celiac
abdominal masses, lymphadenopathy, mucocutaneous disease.
52 Table 6-4
laxative use should be reconsidered. Microbiologic studies
Physical Examination in Patients With should be done including fecal bacterial cultures (includ-
Chronic Diarrhea
ing media for Aeromonas and Pleisiomonas), inspection
SECTION I
1. Are there general features to suggest malabsorption for ova and parasites, and Giardia antigen assay (the
or inflammatory bowel disease (IBD) such as anemia,
most sensitive test for giardiasis). Small-bowel bacte-
dermatitis herpetiformis, edema, or clubbing?
2. Are there features to suggest underlying autonomic rial overgrowth can be excluded by intestinal aspirates
neuropathy or collagen-vascular disease in the pupils, with quantitative cultures or with glucose or lactulose
orthostasis, skin, hands, or joints? breath tests involving measurement of breath hydro-
3. Is there an abdominal mass or tenderness? gen, methane, or other metabolite (e.g., 14CO2). However,
Cardinal Manifestations of Gastrointestinal Disease
4. Are there any abnormalities of rectal mucosa, rectal interpretation of these breath tests may be confounded by
defects, or altered anal sphincter functions? disturbances of intestinal transit. Upper endoscopy and colo-
5. Are there any mucocutaneous manifestations of sys-
noscopy with biopsies and small-bowel barium x-rays are
temic disease such as dermatitis herpetiformis (celiac
disease), erythema nodosum (ulcerative colitis), flushing
helpful to rule out structural or occult inflammatory disease.
(carcinoid), or oral ulcers for IBD or celiac disease? When suggested by history or other findings, screens for
peptide hormones should be pursued (e.g., serum gastrin,
VIP, calcitonin, and thyroid hormone/thyroid-stimulating hor-
mone, or urinary 5-hydroxyindolacetic acid, and histamine).
Further evaluation of osmotic diarrhea should include
A therapeutic trial is often appropriate, definitive, and
tests for lactose intolerance and magnesium ingestion,
highly cost effective when a specific diagnosis is sug-
the two most common causes. Low fecal pH suggests
gested on the initial physician encounter. For example,
carbohydrate malabsorption; lactose malabsorption can
chronic watery diarrhea, which ceases with fasting in an
be confirmed by lactose breath testing or by a therapeu-
otherwise healthy young adult, may justify a trial of a
tic trial with lactose exclusion and observation of the
lactose-restricted diet; bloating and diarrhea persisting
effect of lactose challenge (e.g., a liter of milk). Lactase
since a mountain backpacking trip may warrant a trial
determination on small-bowel biopsy is not generally
of metronidazole for likely giardiasis; and postprandial
available. If fecal magnesium or laxative levels are ele-
diarrhea persisting following resection of terminal ileum
vated, inadvertent or surreptitious ingestion should be
might be due to bile acid malabsorption and be treated
considered and psychiatric help should be sought.
with cholestyramine or colesevelam before further evalua-
For those with proven fatty diarrhea, endoscopy with
tion. Persistent symptoms require additional investigation.
small-bowel biopsy (including aspiration for Giardia
Certain diagnoses may be suggested on the ini-
and quantitative cultures) should be performed; if this
tial encounter (e.g., idiopathic IBD); however, additional
procedure is unrevealing, a small-bowel radiograph is
focused evaluations may be necessary to confirm the diag-
often an appropriate next step. If small-bowel studies
nosis and characterize the severity or extent of disease so
are negative or if pancreatic disease is suspected, pan-
that treatment can be best guided. Patients suspected of
creatic exocrine insufficiency should be excluded with
having IBS should be initially evaluated with flexible sig-
direct tests, such as the secretin-cholecystokinin stimu-
moidoscopy with colorectal biopsies; those with normal
lation test or a variation that could be performed endo-
findings might be reassured and, as indicated, treated
scopically. In general, indirect tests such as assay of fecal
empirically with antispasmodics, antidiarrheals, bulk agents,
elastase or chymotrypsin activity or a bentiromide test
anxiolytics, or antidepressants. Any patient who presents
have fallen out of favor because of low sensitivity and
with chronic diarrhea and hematochezia should be evalu-
specificity.
ated with stool microbiologic studies and colonoscopy.
Chronic inflammatory-type diarrheas should be sus-
In an estimated two-thirds of cases, the cause
pected by the presence of blood or leukocytes in the
for chronic diarrhea remains unclear after the initial
stool. Such findings warrant stool cultures; inspection
encounter, and further testing is required. Quantitative
for ova and parasites; C. difficile toxin assay; colonoscopy
stool collection and analyses can yield important objec-
with biopsies; and, if indicated, small-bowel contrast
tive data that may establish a diagnosis or characterize
studies.
the type of diarrhea as a triage for focused additional
studies (Fig. 6-3B). If stool weight is >200 g/d, additional
stool analyses should be performed that might include
electrolyte concentration, pH, occult blood testing, Treatment Chronic Diarrhea
leukocyte inspection (or leukocyte protein assay), fat
quantitation, and laxative screens. Treatment of chronic diarrhea depends on the specific
For secretory diarrheas (watery, normal osmotic gap), etiology and may be curative, suppressive, or empirical. If
possible medication-related side effects or surreptitious the cause can be eradicated, treatment is curative as with
The perception of hard stools or excessive strain- 53
resection of a colorectal cancer, antibiotic administration ing is more difficult to assess objectively, and the need
for Whipple’s disease or tropical sprue, or discontinuation for enemas or digital disimpaction is a clinically useful
of a drug. For many chronic conditions, diarrhea can be
CHAPTER 6
way to corroborate the patient’s perceptions of difficult
controlled by suppression of the underlying mechanism. defecation.
Examples include elimination of dietary lactose for lac- Psychosocial or cultural factors may also be impor-
tase deficiency or gluten for celiac sprue, use of glucocor- tant. A person whose parents attached great importance
ticoids or other anti-inflammatory agents for idiopathic to daily defecation will become greatly concerned
IBDs, adsorptive agents such as cholestyramine for ileal when he or she misses a daily bowel movement; some
bile acid malabsorption, proton pump inhibitors such children withhold stool to gain attention or because
APPROACH TO THE
PATIENT Constipation Known No known underlying disorder
disorder
A careful history should explore the patient’s symptoms
Anorectal manometry and balloon expulsion
and confirm whether he or she is indeed constipated
based on frequency (e.g., fewer than three bowel move-
ments per week), consistency (lumpy/hard), excessive Normal Rectoanal angle measurement,
defecation proctography?
straining, prolonged defecation time, or need to sup-
port the perineum or digitate the anorectum. In the vast Rx
majority of cases (probably >90%), there is no underly- Appropriate Rx: Rehabilitation
program, surgery, or other
ing cause (e.g., cancer, depression, or hypothyroidism),
and constipation responds to ample hydration, exer-
cise, and supplementation of dietary fiber (15–25 g/d). Figure 6-4
A good diet and medication history and attention to Algorithm for the management of constipation.
psychosocial issues are key. Physical examination and,
particularly, a rectal examination should exclude fecal
impaction and most of the important diseases that
present with constipation and possibly indicate fea-
with enema or glycerine suppository as needed.
tures suggesting an evacuation disorder (e.g., high anal
After breakfast, a distraction-free 15–20 min on the
sphincter tone).
toilet without straining is encouraged. Excessive strain-
The presence of weight loss, rectal bleeding, or
ing may lead to development of hemorrhoids, and, if
anemia with constipation mandates either flexible sig-
there is weakness of the pelvic floor or injury to the
moidoscopy plus barium enema or colonoscopy alone,
pudendal nerve, may result in obstructed defecation
particularly in patients >40 years, to exclude structural
from descending perineum syndrome several years
diseases such as cancer or strictures. Colonoscopy alone
later. Those few who do not benefit from the simple
is most cost-effective in this setting because it provides
measures delineated above or require long-term treat-
an opportunity to biopsy mucosal lesions, perform pol-
ment with potent laxatives, with the attendant risk of
ypectomy, or dilate strictures. Barium enema has advan-
developing laxative abuse syndrome, are assumed to
tages over colonoscopy in the patient with isolated
have severe or intractable constipation and should have
constipation because it is less costly and identifies
further investigation (Fig. 6-4). Novel agents that induce
colonic dilation and all significant mucosal lesions or
secretion (e.g., lubiprostone, a chloride channel activa-
strictures that are likely to present with constipation.
tor) are also available.
Melanosis coli, or pigmentation of the colon mucosa,
indicates the use of anthraquinone laxatives such as
cascara or senna; however, this is usually apparent
from a careful history. An unexpected disorder such as Investigation of Severe Constipation
megacolon or cathartic colon may also be detected by
colonic radiographs. Measurement of serum calcium, A small minority (probably <5%) of patients have severe
potassium, and thyroid-stimulating hormone levels will or “intractable” constipation. These are the patients
identify rare patients with metabolic disorders. most likely to be seen by gastroenterologists or in refer-
Patients with more troublesome constipation may ral centers. Further observation of the patient may occa-
not respond to fiber alone and may be helped by a sionally reveal a previously unrecognized cause, such as
bowel-training regimen: taking an osmotic laxative an evacuation disorder, laxative abuse, malingering, or
(lactulose, sorbitol, polyethylene glycol) and evacuating psychological disorder. In these patients, evaluations of
the physiologic function of the colon and pelvic floor
and of psychological status aid in the rational choice of to bony landmarks (>4 cm, suggesting excessive peri- 55
treatment. Even among these highly selected patients neal descent).
with severe constipation, a cause can be identified in A useful overall test of evacuation is the balloon expul-
CHAPTER 6
only about two-thirds of tertiary referral patients (dis- sion test. A balloon-tipped urinary catheter is placed and
cussed later). inflated with 50 mL of water. Normally, a patient can
expel it while seated on a toilet or in the left lateral decu-
Measurement of colonic transit bitus position. In the lateral position, the weight needed
to facilitate expulsion of the balloon is determined; nor-
Radiopaque marker transit tests are easy, repeatable, gen- mally, expulsion occurs with <200 g added.
erally safe, inexpensive, reliable, and highly applicable in Anorectal manometry, when used in the evaluation
GASTROINTESTINAL BLEEDING
Loren Laine
Bleeding from the gastrointestinal (GI) tract may pres- due to decompensation from other underlying illnesses.
ent in five ways. Hematemesis is vomitus of red blood or The mortality rate for patients <60 years in the absence
“coffee-grounds” material. Melena is black, tarry, foul- of major concurrent illness is <1%. Independent
smelling stool. Hematochezia is the passage of bright red predictors of rebleeding and death in patients
or maroon blood from the rectum. Occult GI bleeding hospitalized with UGIB include increasing age, comor-
(GIB) may be identified in the absence of overt bleed- bidities, and hemodynamic compromise (tachycardia or
ing by a fecal occult blood test or the presence of iron hypotension).
deficiency. Finally, patients may present only with Peptic ulcers are the most common cause of UGIB,
symptoms of blood loss or anemia such as lightheadedness, accounting for up to ∼50% of cases; an increasing
syncope, angina, or dyspnea. proportion is due to nonsteroidal anti-inflammatory
drugs (NSAIDs), with the prevalence of Helicobacter
pylori decreasing. Mallory-Weiss tears account for
SOURCES OF GASTROINTESTINAL ∼5–10% of cases. The proportion of patients bleeding
BLEEDING from varices varies widely from ∼5 to 40%, depend-
Upper gastrointestinal sources of bleeding ing on the population. Hemorrhagic or erosive gas-
tropathy (e.g., due to NSAIDs or alcohol) and erosive
(Table 7-1) The annual incidence of hospital admis- esophagitis often cause mild UGIB, but major bleed-
sions for upper GIB (UGIB) in the United States and ing is rare.
Europe is ∼0.1%, with a mortality rate of ∼5–10%.
Patients rarely die from exsanguination; rather, they die Peptic ulcers
In addition to clinical features, characteristics of an ulcer
at endoscopy provide important prognostic informa-
TABLe 7-1 tion. One-third of patients with active bleeding or a
SOURCES OF BLEEDING IN PATIENTS HOSPITALIZED nonbleeding visible vessel have further bleeding that
FOR UPPER GI BLEEDING requires urgent surgery if they are treated conserva-
SOURCES OF BLEEDING PROPORTION OF PATIENTS, % tively. These patients clearly benefit from endoscopic
therapy with bipolar electrocoagulation; heater probe;
Ulcers 31–67
injection therapy (e.g., absolute alcohol, 1:10,000 epi-
Varices 6–39
Mallory-Weiss tears 2–8
nephrine); and/or clips with reductions in bleed-
Gastroduodenal erosions 2–18 ing, hospital stay, mortality rate, and costs. In contrast,
Erosive esophagitis 1–13 patients with clean-based ulcers have rates of recurrent
Neoplasm 2–8 bleeding approaching zero. If there is no other reason
Vascular ectasias 0–6 for hospitalization, such patients may be discharged on
No source identified 5–14 the first hospital day, following stabilization. Patients
without clean-based ulcers should usually remain in the
Source: Data on hospitalizations from year 2000 onward from Am J hospital for 3 days because most episodes of recurrent
Gastroenterol 98:1494, 2003; Gastrointest Endosc 57:AB147, 2003;
60:875, 2004; Eur J Gastroenterol Hepatol 16:177, 2004; 17:641,
bleeding occur within 3 days.
2005; J Clin Gastroenterol 42:128, 2008; World J Gastroenterol Randomized controlled trials document that a high-
14:5046, 2008; Dig Dis Sci 54:333, 2009. dose, constant-infusion IV proton pump inhibitor (PPI)
57
58 (e.g., omeprazole 80-mg bolus and 8-mg/h infusion), Endoscopic therapy for acute bleeding and repeated
designed to sustain intragastric pH >6 and enhance sessions of endoscopic therapy to eradicate esophageal
clot stability, decreases further bleeding and mortality varices significantly reduce rebleeding and mortality.
in patients with high-risk ulcers (active bleeding, non- Ligation is the endoscopic therapy of choice for esopha-
SECTION I
bleeding visible vessel, adherent clot) when given after geal varices because it has less rebleeding, a lower mor-
endoscopic therapy. Institution of PPI therapy at pre- tality rate, fewer local complications, and it requires
sentation in all patients with UGIB decreases high-risk fewer treatment sessions to achieve variceal eradication
ulcer characteristics (e.g., active bleeding) but does not than sclerotherapy.
significantly improve outcomes such as further bleed- Octreotide (50-μg bolus and 50-μg/h IV infusion for
ing, transfusions, or mortality as compared to initiating 2–5 days) further helps in the control of acute bleed-
Cardinal Manifestations of Gastrointestinal Disease
therapy only when high-risk ulcers are identified at the ing when used in combination with endoscopic ther-
time of endoscopy. apy. Other vasoactive agents such as somatostatin and
Approximately one-third of patients with bleeding terlipressin, available outside the United States, are also
ulcers will rebleed within the next 1–2 years if no pre- effective. Antibiotic therapy (e.g., ceftriaxone) is also
ventive strategies are employed. Prevention of recur- recommended for patients with cirrhosis present-
rent bleeding focuses on the three main factors in ulcer ing with UGIB because antibiotics decrease bacterial
pathogenesis, H. pylori, NSAIDs, and acid. Eradication infections and mortality in this population. Over the
of H. pylori in patients with bleeding ulcers decreases long term, treatment with nonselective beta blockers
rates of rebleeding to <5%. If a bleeding ulcer devel- decreases recurrent bleeding from esophageal varices.
ops in a patient taking NSAIDs, the NSAIDs should Chronic therapy with beta blockers plus endoscopic
be discontinued, if possible. If NSAIDs must be con- ligation is recommended for prevention of recurrent
tinued or reinstituted, a cyclooxygenase 2 (COX-2) esophageal variceal bleeding.
selective inhibitor (coxib) plus a PPI should be used. In patients who have persistent or recurrent bleed-
PPI co-therapy alone or a coxib alone is associated ing despite endoscopic and medical therapy, more inva-
with an annual rebleeding rate of ∼10% in patients sive therapy with transjugular intrahepatic portosystemic
with a recent bleeding ulcer, while combination of a shunt (TIPS) is recommended. Older studies indicate
coxib and PPI provides a further significant decrease in that most patients with TIPS developed shunt stenosis
recurrent ulcer bleeding. Patients with cardiovascular within 1–2 years and required reintervention to main-
disease who develop bleeding ulcers while taking low- tain shunt patency. The use of coated stents appears to
dose aspirin should restart aspirin as soon as possible decrease shunt dysfunction by ∼50% in the first 2 years.
after their bleeding episode (e.g., ≤7 days). A random- A randomized comparison of TIPS (with uncoated
ized trial showed that failure to restart aspirin was asso- stents) and distal splenorenal shunt in Child-Pugh class
ciated with a nonsignificant difference in rebleeding A or B cirrhotic patients with refractory variceal bleed-
(5% vs. 10% at 30 days), but a significant increase in ing revealed no significant difference in rebleeding,
mortality at 30 days (9% vs. 1%) and 8 weeks (13% vs. encephalopathy, or survival, but had a much higher rate
1%) as compared to immediate reinstitution of aspirin. of reintervention with TIPS (82% vs. 11%). Therefore,
Patients with bleeding ulcers unrelated to H. pylori decompressive surgery may be an option in patients
or NSAIDs should remain on full-dose antisecretory with milder, well-compensated cirrhosis.
therapy indefinitely. Peptic ulcers are discussed in Portal hypertension is also responsible for bleed-
Chap. 14. ing from gastric varices, varices in the small and large
intestine, and portal hypertensive gastropathy and
Mallory-Weiss tears enterocolopathy.
The classic history is vomiting, retching, or cough-
ing preceding hematemesis, especially in an alcoholic
patient. Bleeding from these tears, which are usually on emorrhagic and erosive gastropathy
H
(“gastritis”)
the gastric side of the gastroesophageal junction, stops
spontaneously in 80–90% of patients and recurs in only Hemorrhagic and erosive gastropathy, often labeled gas-
0–7%. Endoscopic therapy is indicated for actively tritis, refers to endoscopically visualized subepithelial
bleeding Mallory-Weiss tears. Angiographic therapy hemorrhages and erosions. These are mucosal lesions
with embolization and operative therapy with oversew- and, thus, do not cause major bleeding. They develop
ing of the tear are rarely required. Mallory-Weiss tears in various clinical settings, the most important of
are discussed in Chap. 13. which are NSAID use, alcohol intake, and stress. Half
of patients who chronically ingest NSAIDs have ero-
Esophageal varices sions (15–30% have ulcers), while up to 20% of actively
Patients with variceal hemorrhage have poorer out- drinking alcoholic patients with symptoms of UGIB
comes than patients with other sources of UGIB. have evidence of subepithelial hemorrhages or erosions.
Stress-related gastric mucosal injury occurs only in vascular ectasias isolated to a segment of the small intes- 59
extremely sick patients: those who have experienced tine when endoscopic therapy is unsuccessful. Although
serious trauma, major surgery, burns covering more estrogen/progesterone compounds have been used for
CHAPTER 7
than one-third of the body surface area, major intra- vascular ectasias, a double-blind trial found no benefit
cranial disease, or severe medical illness (i.e., ventilator in prevention of recurrent bleeding. Isolated lesions,
dependence, coagulopathy). Significant bleeding prob- such as tumors, diverticula, or duplications, are gener-
ably does not develop unless ulceration occurs. The ally treated with surgical resection.
mortality rate in these patients is quite high because of
their serious underlying illnesses. Colonic sources of bleeding
The incidence of bleeding from stress-related gastric
Gastrointestinal Bleeding
The incidence of hospitalizations for LGIB is ≥20%
mucosal injury or ulceration has decreased dramatically that for UGIB. Hemorrhoids are probably the most
in recent years, most likely due to better care of criti- common cause of LGIB; anal fissures also cause minor
cally ill patients. Pharmacologic prophylaxis for bleeding bleeding and pain. If these local anal processes, which
may be considered in the high-risk patients mentioned rarely require hospitalization, are excluded, the most
earlier. Multiple trials document the efficacy of intra- common causes of LGIB in adults are diverticula, vas-
venous H2-receptor antagonist therapy, which is more cular ectasias (especially in the proximal colon of
effective than sucralfate but not superior to a PPI patients >70 years), neoplasms (primarily adenocar-
immediate-release suspension given via nasogastric tube. cinoma), and colitis—most commonly infectious or
Prophylactic therapy decreases bleeding but does not idiopathic inflammatory bowel disease, but occasion-
lower the mortality rate. ally ischemic or radiation-induced. Uncommon causes
include post-polypectomy bleeding, solitary rectal ulcer
Other causes syndrome, NSAID-induced ulcers or colitis, trauma,
Other less frequent causes of UGIB include erosive varices (most commonly rectal), lymphoid nodular
duodenitis, neoplasms, aortoenteric fistulas, vascular hyperplasia, vasculitis, and aortocolic fistulas. In children
lesions [including hereditary hemorrhagic telangiectasias and adolescents, the most common colonic causes of
(Osler-Weber-Rendu) and gastric antral vascular ectasia significant GIB are inflammatory bowel disease and
(“watermelon stomach”)], Dieulafoy’s lesion (in which juvenile polyps.
an aberrant vessel in the mucosa bleeds from a pinpoint Diverticular bleeding is abrupt in onset, usually pain-
mucosal defect), prolapse gastropathy (prolapse of proxi- less, sometimes massive, and often from the right colon;
mal stomach into esophagus with retching, especially in minor and occult bleeding is not characteristic. Clini-
alcoholics), and hemobilia or hemosuccus pancreaticus cal reports suggest that bleeding colonic diverticula stop
(bleeding from the bile duct or pancreatic duct). bleeding spontaneously in ∼80% of patients and rebleed
in about 20–25% of patients. Intraarterial vasopressin or
Small-intestinal sources of bleeding embolization by superselective technique should stop
bleeding in a majority of patients. If bleeding persists or
Small-intestinal sources of bleeding (bleeding from sites
recurs, segmental surgical resection is indicated.
beyond the reach of the standard upper endoscope) are
Bleeding from right colonic vascular ectasias in the
difficult to diagnose and are responsible for the major-
elderly may be overt or occult; it tends to be chronic
ity of cases of obscure GIB. Fortunately, small-intestinal
and only occasionally is hemodynamically signifi-
bleeding is uncommon. The most common causes in
cant. Endoscopic hemostatic therapy may be useful
adults are vascular ectasias, tumors (e.g., adenocarci-
in the treatment of vascular ectasias, as well as dis-
noma, leiomyoma, lymphoma, benign polyps, carci-
crete bleeding ulcers and post-polypectomy bleeding,
noid, metastases, and lipoma), and NSAID-induced
while endoscopic polypectomy, if possible, is used for
erosions and ulcers. Other less common causes in adults
bleeding colonic polyps. Surgical therapy is gener-
include Crohn’s disease, infection, ischemia, vasculitis,
ally required for major, persistent, or recurrent bleed-
small-bowel varices, diverticula, Meckel’s diverticulum,
ing from the wide variety of colonic sources of GIB
duplication cysts, and intussusception.
that cannot be treated medically, angiographically, or
Meckel’s diverticulum is the most common cause of
endoscopically.
significant lower GIB (LGIB) in children, decreasing
in frequency as a cause of bleeding with age. In adults
<40–50 years, small-bowel tumors often account for APPROACH TO THE
obscure GIB; in patients >50–60 years, vascular ecta- PATIENT Gastrointestinal Bleeding
sias and NSAID-induced lesions are more commonly
Measurement of the heart rate and blood pressure
responsible.
is the best way to initially assess a patient with GIB.
Vascular ectasias should be treated with endoscopic
Clinically significant bleeding leads to postural changes
therapy if possible. Surgical therapy can be used for
60
in heart rate or blood pressure, tachycardia, and, finally, A nonbloody nasogastric aspirate may be seen in
recumbent hypotension. In contrast, the hemoglobin up to 18% of patients with UGIB—usually from a duo-
does not fall immediately with acute GIB, due to pro- denal source. Even a bile-stained appearance does not
SECTION I
portionate reductions in plasma and red cell volumes exclude a bleeding postpyloric lesion because reports of
(i.e., “people bleed whole blood”). Thus, hemoglobin bile in the aspirate are incorrect in ∼50% of cases. Test-
may be normal or only minimally decreased at the ini- ing of aspirates that are not grossly bloody for occult
tial presentation of a severe bleeding episode. As extra- blood is not useful.
vascular fluid enters the vascular space to restore vol-
Diagnostic Evaluation of the Patient
ume, the hemoglobin falls, but this process may take
Cardinal Manifestations of Gastrointestinal Disease
with GIB
up to 72 h. Patients with slow, chronic GIB may have
Upper GIB (Fig. 7-1) History and physical exami-
very low hemoglobin values despite normal blood
nation are not usually diagnostic of the source of GIB.
pressure and heart rate. With the development of
Upper endoscopy is the test of choice in patients with
iron-deficiency anemia, the mean corpuscular volume
UGIB and should be performed urgently in patients who
will be low and red blood cell distribution width will
present with hemodynamic instability (hypotension,
increase.
tachycardia, or postural changes in heart rate or blood
Differentiation of Upper from Lower pressure). Early endoscopy is also beneficial in cases of
GIB Hematemesis indicates an upper GI source of milder bleeding for management decisions. Patients
bleeding (above the ligament of Treitz). Melena indi- with major bleeding and high-risk endoscopic findings
cates that blood has been present in the GI tract for at (e.g., varices, ulcers with active bleeding or a visible
least 14 h (and as long as 3–5 days). The more proximal vessel) benefit from endoscopic hemostatic therapy,
the bleeding site, the more likely melena will occur. while patients with low-risk lesions (e.g., clean-based
Hematochezia usually represents a lower GI source of ulcers, nonbleeding Mallory-Weiss tears, erosive or
bleeding, although an upper GI lesion may bleed so hemorrhagic gastropathy) who have stable vital signs
briskly that blood does not remain in the bowel long and hemoglobin, and no other medical problems, can
enough for melena to develop. When hematochezia is be discharged home.
the presenting symptom of UGIB, it is associated with Lower GIB (Fig. 7-2) Patients with hematochezia
hemodynamic instability and dropping hemoglobin. and hemodynamic instability should have upper endos-
Bleeding lesions of the small bowel may present as copy to rule out an upper GI source before evaluation
melena or hematochezia. Other clues to UGIB include of the lower GI tract. Patients with presumed LGIB may
hyperactive bowel sounds and an elevated blood urea undergo early sigmoidoscopy for the detection of obvi-
nitrogen level (due to volume depletion and blood pro- ous, low-lying lesions. However, the procedure is dif-
teins absorbed in the small intestine). ficult with brisk bleeding, and it is usually not possible
IV PPI therapy IV PPI therapy No IV PPI No IV PPI ICU for 1-2 days; Endoscopic No
+ endoscopic +/– endoscopic or endoscopic or endoscopic ward for 2-3 days therapy endoscopic
therapy therapy therapy therapy therapy
Figure 7-1
Suggested algorithm for patients with acute upper gas- further bleeding or other concomitant medical problems.
trointestinal bleeding. Recommendations on level of care ICU, intensive care unit; PPI, proton pump inhibitor.
and time of discharge assume patient is stabilized without
Acute lower has been identified by routine endoscopic and contrast 61
GI bleeding
x-ray studies; it may be overt (melena, hematochezia) or
occult (iron-deficiency anemia). Current guidelines sug-
CHAPTER 7
gest angiography as the initial test for massive obscure
No hemodynamic Hemodynamic
instability instability bleeding, and video capsule endoscopy, which allows
examination of the entire small intestine, for all others.
Push enteroscopy, with a specially designed entero-
Age < 40 yrs Age ≥ 40 yrs Upper endoscopy scope or a pediatric colonoscope to inspect the entire
duodenum and part of the jejunum, also may be con-
Gastrointestinal Bleeding
Flexible
sigmoidoscopy sidered as an initial evaluation. A systematic review
(colonoscopy if
iron-deficiency
of 14 trials comparing push enteroscopy to capsule
anemia, familial revealed “clinically significant findings” in 26% and
colon cancer, or
copious bleeding)* Colonoscopy Colonoscopy† 56% of patients, respectively. However, in contrast to
enteroscopy, lack of control of the capsule prevents its
manipulation and full visualization of the intestine; in
Site identified; Site identified; Site not identified;
bleeding stops bleeding persists bleeding persists
addition, tissue cannot be sampled and therapy cannot
be applied.
Obscure bleeding
If capsule endoscopy is positive, management (e.g.,
Angiography enteroscopy, laparoscopy) is dictated by the finding.
work-up
Bleeding persists If capsule is negative, current recommendations sug-
gest patients may be either observed, or if their clini-
Surgery
cal course mandates (e.g., recurrent bleeding, need
for transfusions or hospitalization), undergo further
Figure 7-2
testing. Newer endoscopic techniques (e.g., double-
Suggested algorithm for patients with acute lower gas-
balloon, single-balloon, and spiral enteroscopy) allow
trointestinal bleeding. *Some suggest colonoscopy for any
the endoscopist to examine, obtain specimens from,
degree of rectal bleeding in patients <40 years as well. †If
and provide therapy to much or all of the small intes-
massive bleeding does not allow time for colonic lavage,
tine. Newer imaging techniques (CT and MR enterog-
proceed to angiography.
raphy) are now frequently being used in place of older
specialized small-bowel radiographic exams (e.g.,
to identify the area of bleeding. Sigmoidoscopy is useful enteroclysis). Other tests include 99mTc-labeled red
primarily in patients <40 years with minor bleeding. blood cell scintigraphy; angiography, which may be
Colonoscopy after an oral lavage solution is the pro- useful even if bleeding has subsided because it may
cedure of choice in patients admitted with LGIB unless disclose vascular anomalies or tumor vessels; and 99mTc-
bleeding is too massive or unless sigmoidoscopy has pertechnetate scintigraphy for diagnosis of Meckel’s
disclosed an obvious actively bleeding lesion. 99mTc- diverticulum (especially in young patients). When all
labeled red cell scan allows repeated imaging for up to tests are unrevealing, intraoperative endoscopy is indi-
24 h and may identify the general location of bleeding. cated in patients with severe recurrent or persistent
However, radionuclide scans should be interpreted with bleeding requiring repeated transfusions.
caution because results, especially from later images, Positive Fecal Occult Blood Test Fecal
are highly variable. In active LGIB, angiography can occult blood testing is recommended only for colorec-
detect the site of bleeding (extravasation of contrast tal cancer screening and may be used in average-risk
into the gut) and permits treatment with emboliza- adults (beginning at age 50) and in adults with a first-
tion or intraarterial infusion of vasopressin. Even after degree relative with colorectal neoplasm at ≥60 years
bleeding has stopped, angiography may identify lesions or two second-degree relatives with colorectal cancer
with abnormal vasculature, such as vascular ectasias or (beginning at age 40). A positive test necessitates colo-
tumors. noscopy. If evaluation of the colon is negative, further
GIB of Obscure Origin Obscure GIB is defined workup is not recommended unless iron-deficiency
as persistent or recurrent bleeding for which no source anemia or GI symptoms are present.
CHaPTEr 8
JAUNDICE
Jaundice, or icterus, is a yellowish discoloration of tis- an elevation of the direct serum bilirubin fraction and,
sue resulting from the deposition of bilirubin. Tissue therefore, the presence of liver disease.
deposition of bilirubin occurs only in the presence of Increased serum bilirubin levels occur when an
serum hyperbilirubinemia and is a sign of either liver imbalance exists between bilirubin production and
disease or, less often, a hemolytic disorder. The degree clearance. A logical evaluation of the patient who is
of serum bilirubin elevation can be estimated by physi- jaundiced requires an understanding of bilirubin pro-
cal examination. Slight increases in serum bilirubin are duction and metabolism.
best detected by examining the sclerae, which have a
particular affinity for bilirubin due to their high elastin
content. The presence of scleral icterus indicates a serum
produCtion and MetaBolisM
bilirubin of at least 51 μmol/L (3 mg/dL). The ability to
of BiliruBin
detect scleral icterus is made more difficult if the exam-
ining room has fluorescent lighting. If the examiner (See also Chap. 37) Bilirubin, a tetrapyrrole pigment, is a
suspects scleral icterus, a second place to examine is under- breakdown product of heme (ferroprotoporphyrin IX).
neath the tongue. As serum bilirubin levels rise, the skin About 70–80% of the 250–300 mg of bilirubin produced
will eventually become yellow in light-skinned patients each day is derived from the breakdown of hemoglo-
and even green if the process is long-standing; the green bin in senescent red blood cells. The remainder comes
color is produced by oxidation of bilirubin to biliverdin. from prematurely destroyed erythroid cells in bone mar-
The differential diagnosis for yellowing of the skin row and from the turnover of hemoproteins such as
is limited. In addition to jaundice, it includes carote- myoglobin and cytochromes found in tissues throughout
noderma, the use of the drug quinacrine, and exces- the body.
sive exposure to phenols. Carotenoderma is the yellow The formation of bilirubin occurs in reticuloendo-
color imparted to the skin by the presence of carotene; thelial cells, primarily in the spleen and liver. The first
it occurs in healthy individuals who ingest excessive reaction, catalyzed by the microsomal enzyme heme
amounts of vegetables and fruits that contain carotene, oxygenase, oxidatively cleaves the α bridge of the por-
such as carrots, leafy vegetables, squash, peaches, and phyrin group and opens the heme ring. The end prod-
oranges. Unlike jaundice, where the yellow coloration ucts of this reaction are biliverdin, carbon monoxide,
of the skin is uniformly distributed over the body, in and iron. The second reaction, catalyzed by the cyto-
carotenoderma, the pigment is concentrated on the solic enzyme biliverdin reductase, reduces the cen-
palms, soles, forehead, and nasolabial folds. Caroteno- tral methylene bridge of biliverdin and converts it to
derma can be distinguished from jaundice by the spar- bilirubin. Bilirubin formed in the reticuloendothelial
ing of the sclerae. Quinacrine causes a yellow discolor- cells is virtually insoluble in water. This is due to tight
ation of the skin in 4–37% of patients treated with it. internal hydrogen bonding between the water-soluble
Unlike carotene, quinacrine can cause discoloration of moieties of bilirubin, proprionic acid carboxyl groups
the sclerae. of one dipyrrolic half of the molecule with the imino
Another sensitive indicator of increased serum biliru- and lactam groups of the opposite half. This configu-
bin is darkening of the urine, which is due to the renal ration blocks solvent access to the polar residues of
excretion of conjugated bilirubin. Patients often describe bilirubin and places the hydrophobic residues on the
their urine as tea- or cola-colored. Bilirubinuria indicates outside. To be transported in blood, bilirubin must be
62
solubilized. This is accomplished by its reversible, non- alcohol. The indirect fraction is the difference between 63
covalent binding to albumin. Unconjugated bilirubin the total and the direct bilirubin and provides an esti-
bound to albumin is transported to the liver, where mate of the unconjugated bilirubin in serum.
CHAPTER 8
it, but not the albumin, is taken up by hepatocytes via With the van den Bergh method, the normal serum
a process that at least partly involves carrier-mediated bilirubin concentration usually is 17 μmol/L (<1 mg/
membrane transport. No specific bilirubin transporter dL). Up to 30%, or 5.1 μmol/L (0.3 mg/dL), of the
has yet been identified (Chap. 37, Fig. 37-1). total may be direct-reacting (conjugated) bilirubin.
After entering the hepatocyte, unconjugated bilirubin Total serum bilirubin concentrations are between 3.4
is bound in the cytosol to a number of proteins including and 15.4 μmol/L (0.2 and 0.9 mg/dL) in 95% of a nor-
proteins in the glutathione-S-transferase superfamily. These mal population.
Jaundice
proteins serve both to reduce efflux of bilirubin back into Several new techniques, although less convenient to
the serum and to present the bilirubin for conjugation. In perform, have added considerably to our understanding
the endoplasmic reticulum, bilirubin is solubilized by con- of bilirubin metabolism. First, they demonstrate that in
jugation to glucuronic acid, a process that disrupts the inter- normal persons or those with Gilbert’s syndrome, almost
nal hydrogen bonds and yields bilirubin monoglucuronide 100% of the serum bilirubin is unconjugated; <3% is
and diglucuronide. The conjugation of glucuronic acid monoconjugated bilirubin. Second, in jaundiced patients
to bilirubin is catalyzed by bilirubin uridine diphosphate- with hepatobiliary disease, the total serum bilirubin con-
glucuronosyl transferase (UDPGT). The now hydrophilic centration measured by these new, more accurate meth-
bilirubin conjugates diffuse from the endoplasmic reticu- ods is lower than the values found with diazo methods.
lum to the canalicular membrane, where bilirubin mono- This suggests that there are diazo-positive compounds
glucuronide and diglucuronide are actively transported into distinct from bilirubin in the serum of patients with
canalicular bile by an energy-dependent mechanism involv- hepatobiliary disease. Third, these studies indicate that,
ing the multiple drug resistance protein 2. in jaundiced patients with hepatobiliary disease, mono-
The conjugated bilirubin excreted into bile drains glucuronides of bilirubin predominate over the digluc-
into the duodenum and passes unchanged through uronides. Fourth, part of the direct-reacting bilirubin
the proximal small bowel. Conjugated bilirubin is not fraction includes conjugated bilirubin that is covalently
taken up by the intestinal mucosa. When the conju- linked to albumin. This albumin-linked bilirubin frac-
gated bilirubin reaches the distal ileum and colon, it tion (delta fraction, or biliprotein) represents an important
is hydrolyzed to unconjugated bilirubin by bacterial fraction of total serum bilirubin in patients with cho-
β-glucuronidases. The unconjugated bilirubin is reduced lestasis and hepatobiliary disorders. Albumin-bound
by normal gut bacteria to form a group of colorless conjugated bilirubin is formed in serum when hepatic
tetrapyrroles called urobilinogens. About 80–90% of excretion of bilirubin glucuronides is impaired and the
these products are excreted in feces, either unchanged glucuronides are present in serum in increasing amounts.
or oxidized to orange derivatives called urobilins. The By virtue of its tight binding to albumin, the clearance
remaining 10–20% of the urobilinogens are passively rate of albumin-bound bilirubin from serum approxi-
absorbed, enter the portal venous blood, and are reex- mates the half-life of albumin, 12–14 days, rather than
creted by the liver. A small fraction (usually <3 mg/dL) the short half-life of bilirubin, about 4 h.
escapes hepatic uptake, filters across the renal glomeru- The prolonged half-life of albumin-bound conju-
lus, and is excreted in urine. gated bilirubin explains two previously unexplained
enigmas in jaundiced patients with liver disease: (1) that
Measurement of Serum Bilirubin some patients with conjugated hyperbilirubinemia do not
exhibit bilirubinuria during the recovery phase of their
The terms direct and indirect bilirubin, conjugated and disease because the bilirubin is covalently bound to albu-
unconjugated bilirubin, respectively, are based on the min and therefore not filtered by the renal glomeruli, and
original van den Bergh reaction. This assay, or a varia- (2) that the elevated serum bilirubin level declines more
tion of it, is still used in most clinical chemistry labo- slowly than expected in some patients who otherwise
ratories to determine the serum bilirubin level. In this appear to be recovering satisfactorily. Late in the recov-
assay, bilirubin is exposed to diazotized sulfanilic acid, ery phase of hepatobiliary disorders, all the conjugated
splitting into two relatively stable dipyrrylmethene bilirubin may be in the albumin-linked form. Its value in
azopigments that absorb maximally at 540 nm, allow- serum falls slowly because of the long half-life of albumin.
ing for photometric analysis. The direct fraction is
that which reacts with diazotized sulfanilic acid in the
absence of an accelerator substance such as alcohol. The Measurement of Urine Bilirubin
direct fraction provides an approximate determination Unconjugated bilirubin is always bound to albumin
of the conjugated bilirubin in serum. The total serum in the serum, is not filtered by the kidney, and is not
bilirubin is the amount that reacts after the addition of found in the urine. Conjugated bilirubin is filtered at the
64 glomerulus and the majority is reabsorbed by the proximal
tubules; a small fraction is excreted in the urine. Any bili- from damaged hepatocytes or bile ducts. An increase
rubin found in the urine is conjugated bilirubin. The pres- in unconjugated bilirubin in serum results from either
ence of bilirubinuria implies the presence of liver disease. overproduction, impairment of uptake, or conjugation
SECTION I
A urine dipstick test (Ictotest) gives the same information of bilirubin. An increase in conjugated bilirubin is due to
as fractionation of the serum bilirubin. This test is very decreased excretion into the bile ductules or backward
accurate. A false-negative test is possible in patients with leakage of the pigment. The initial steps in evaluating
prolonged cholestasis due to the predominance of conju- the patient with jaundice are to determine (1) whether
gated bilirubin covalently bound to albumin. the hyperbilirubinemia is predominantly conjugated or
unconjugated in nature, and (2) whether other biochemi-
Cardinal Manifestations of Gastrointestinal Disease
CHAPTER 8
A. Hemolytic disorders
1. Inherited probenecid, may cause unconjugated hyperbilirubine-
a. Spherocytosis, elliptocytosis mia by diminishing hepatic uptake of bilirubin. Impaired
Glucose-6-phosphate dehydrogenase and bilirubin conjugation occurs in three genetic conditions:
pyruvate kinase deficiencies Crigler-Najjar syndrome, types I and II, and Gilbert’s
b. Sickle cell anemia syndrome. Crigler-Najjar type I is an exceptionally rare
2. Acquired condition found in neonates and characterized by severe
Jaundice
a. Microangiopathic hemolytic anemias
jaundice [bilirubin >342 μmol/L (>20 mg/dL)] and neuro-
b. Paroxysmal nocturnal hemoglobinuria
c. Spur cell anemia
logic impairment due to kernicterus, frequently leading
d. Immune hemolysis to death in infancy or childhood. These patients have a
e. Parasitic infections complete absence of bilirubin UDPGT activity, usually
1. Malaria due to mutations in the critical 3′ domain of the UDPGT
2. Babesiosis gene, and are totally unable to conjugate, and hence
B. Ineffective erythropoiesis cannot excrete, bilirubin. The only effective treatment
1. Cobalamin, folate, thalassemia, and severe iron is orthotopic liver transplantation. Use of gene therapy
deficiencies
and allogeneic hepatocyte infusion are experimental
C. Drugs
1. Rifampicin, probenecid, ribavirin approaches of future promise for this devastating disease.
D. Inherited conditions Crigler-Najjar type II is somewhat more common than
1. Crigler-Najjar types I and II type I. Patients live into adulthood with serum bilirubin
2. Gilbert’s syndrome levels that range from 103–428 μmol/L (6–25 mg/dL). In
II. Direct hyperbilirubinemia these patients, mutations in the bilirubin UDPGT gene
A. Inherited conditions cause reduced but not completely absent activity of
1. Dubin-Johnson syndrome
the enzyme. Bilirubin UDPGT activity can be induced by
2. Rotor’s syndrome
the administration of phenobarbital, which can reduce
serum bilirubin levels in these patients. Despite marked
jaundice, these patients usually survive into adulthood,
is whether the patient is suffering from a hemolytic pro- although they may be susceptible to kernicterus under
cess resulting in an overproduction of bilirubin (hemo- the stress of intercurrent illness or surgery.
lytic disorders and ineffective erythropoiesis) or from Gilbert’s syndrome is also marked by the impaired
impaired hepatic uptake/conjugation of bilirubin (drug conjugation of bilirubin due to reduced bilirubin
effect or genetic disorders). UDPGT activity to approximately one-third of normal.
Hemolytic disorders that cause excessive heme pro- Gilbert’s syndrome is very common, with a reported
duction may be either inherited or acquired. Inherited incidence of 3–12%. Patients with Gilbert’s syndrome
disorders include spherocytosis, sickle cell anemia, have a mild unconjugated hyperbilirubinemia with
thalassemia, and deficiency of red cell enzymes such serum levels almost always <103 μmol/L (6 mg/dL).
as pyruvate kinase and glucose-6-phosphate dehy- The serum levels may fluctuate, and jaundice is often
drogenase. In these conditions, the serum bilirubin identified only during periods of fasting. One molecu-
rarely exceeds 86 μmol/L (5 mg/dL). Higher levels may lar defect that has been identified in patients with
occur when there is coexistent renal or hepatocellular Gilbert’s syndrome is in the TATAA element in the 5′
dysfunction or in acute hemolysis such as a sickle cell promoter region of the bilirubin UDPGT gene upstream
crisis. In evaluating jaundice in patients with chronic of exon 1. This defect alone is not necessarily sufficient
hemolysis, it is important to remember the high inci- for producing the clinical syndrome of Gilbert’s as
dence of pigmented (calcium bilirubinate) gallstones there are patients who are homozygous for this defect
found in these patients, which increases the likelihood yet do not have the levels of hyperbilirubinemia typi-
of choledocholithiasis as an alternative explanation for cally seen in Gilbert’s syndrome. An enhancer polymor-
hyperbilirubinemia. phism that lowers transcriptional activity has been
Acquired hemolytic disorders include microangio- identified. The decrease in transcription caused by
pathic hemolytic anemia (e.g., hemolytic-uremic syn- both mutations together may be critical for producing
drome), paroxysmal nocturnal hemoglobinuria, spur cell the syndrome. Unlike both Crigler-Najjar syndromes,
anemia, and immune hemolysis and parasitic infections Gilbert’s syndrome is very common. The reported inci-
including malaria and babesiosis. Ineffective erythropoi- dence is 3–7% of the population with males predomi-
esis occurs in cobalamin, folate, and iron deficiencies. nating over females by a ratio of 2–7:1.
66 Conjugated Hyperbilirubinemia Elevated con- c irrhosis. Stigmata of chronic liver disease, including spi-
jugated hyperbilirubinemia is found in two rare inherited der nevi, palmar erythema, gynecomastia, caput medu-
conditions: Dubin-Johnson syndrome and Rotor’s syndrome sae, Dupuytren’s contractures, parotid gland enlarge-
SECTION I
(Table 8-1). Patients with both conditions present with ment, and testicular atrophy are commonly seen in
asymptomatic jaundice, typically in the second generation advanced alcoholic (Laennec’s) cirrhosis and occasion-
of life. The defect in Dubin-Johnson syndrome is mutations ally in other types of cirrhosis. An enlarged left supracla-
in the gene for multiple drug resistance protein 2. These vicular node (Virchow’s node) or periumbilical nodule
patients have altered excretion of bilirubin into the bile (Sister Mary Joseph’s nodule) suggests an abdominal
ducts. Rotor’s syndrome seems to be a problem with the malignancy. Jugular venous distention, a sign of right-
Cardinal Manifestations of Gastrointestinal Disease
hepatic storage of bilirubin. Differentiating between these sided heart failure, suggests hepatic congestion. Right
syndromes is possible, but clinically unnecessary, due to pleural effusion, in the absence of clinically apparent
their benign nature. ascites, may be seen in advanced cirrhosis.
The abdominal examination should focus on the size
Elevation of Serum Bilirubin with
and consistency of the liver, whether the spleen is pal-
Other Liver Test Abnormalities The
pable and hence enlarged, and whether there is ascites
remainder of this chapter will focus on the evaluation of
present. Patients with cirrhosis may have an enlarged
the patient with a conjugated hyperbilirubinemia in the
left lobe of the liver, which is felt below the xiphoid, and
setting of other liver test abnormalities. This group of
an enlarged spleen. A grossly enlarged nodular liver or
patients can be divided into those with a primary hepa-
an obvious abdominal mass suggests malignancy. An
tocellular process and those with intra- or extrahepatic
enlarged tender liver could be viral or alcoholic hepati-
cholestasis. Being able to make this differentiation will
tis; an infiltrative process such as amyloid; or, less often,
guide the physician’s evaluation (Fig. 8-1). This differen-
an acutely congested liver secondary to right-sided
tiation is made on the basis of the history and physical
heart failure. Severe right upper quadrant tenderness
examination as well as the pattern of liver test abnor-
with respiratory arrest on inspiration (Murphy’s sign)
malities.
suggests cholecystitis or, occasionally, ascending chol-
History A complete medical history is perhaps the angitis. Ascites in the presence of jaundice suggests
single most important part of the evaluation of the either cirrhosis or malignancy with peritoneal spread.
patient with unexplained jaundice. Important consid-
Laboratory Tests When the physician encounters
erations include the use of or exposure to any chemical
a patient with unexplained jaundice, there is a battery
or medication, either physician-prescribed, over-the-
of tests that are helpful in the initial evaluation. These
counter, complementary or alternative medicines such
include total and direct serum bilirubin with fraction-
as herbal and vitamin preparations, or other drugs such
ation, aminotransferases, alkaline phosphatase, albu-
as anabolic steroids. The patient should be carefully
min, and prothrombin time tests. Enzyme tests [alanine
questioned about possible parenteral exposures, includ-
aminotransferase (ALT), aspartate aminotransferase (AST),
ing transfusions, intravenous and intranasal drug use,
and alkaline phosphatase (ALP)] are helpful in differen-
tattoos, and sexual activity. Other important questions
tiating between a hepatocellular process and a choles-
include recent travel history; exposure to people with
tatic process (Table 36-1; Fig. 8-1), a critical step in deter-
jaundice; exposure to possibly contaminated foods;
mining what additional workup is indicated. Patients
occupational exposure to hepatotoxins; alcohol con-
with a hepatocellular process generally have a dispro-
sumption; the duration of jaundice; and the presence of
portionate rise in the aminotransferases compared to
any accompanying symptoms such as arthralgias, myal-
the ALP. Patients with a cholestatic process have a dis-
gias, rash, anorexia, weight loss, abdominal pain, fever,
proportionate rise in the ALP compared to the amino-
pruritus, and changes in the urine and stool. While none
transferases. The bilirubin can be prominently elevated
of these latter symptoms are specific for any one condi-
in both hepatocellular and cholestatic conditions and,
tion, they can suggest a particular diagnosis. A history
therefore, is not necessarily helpful in differentiating
of arthralgias and myalgias predating jaundice suggests
between the two.
hepatitis, either viral or drug-related. Jaundice asso-
In addition to the enzyme tests, all jaundiced
ciated with the sudden onset of severe right upper
patients should have additional blood tests, specifically
quadrant pain and shaking chills suggests choledocholi-
an albumin level and a prothrombin time, to assess liver
thiasis and ascending cholangitis.
function. A low albumin level suggests a chronic pro-
Physical Examination The general assessment cess such as cirrhosis or cancer. A normal albumin level
should include assessment of the patient’s nutritional is suggestive of a more acute process such as viral hepa-
status. Temporal and proximal muscle wasting suggests titis or choledocholithiasis. An elevated prothrombin
long-standing diseases such as pancreatic cancer or time indicates either vitamin K deficiency due to
rolonged jaundice and malabsorption of vitamin K or
p from cirrhosis can have normal or only slight elevations 67
significant hepatocellular dysfunction. The failure of the of the aminotransferases.
prothrombin time to correct with parenteral administra- When the physician determines that the patient has
CHAPTER 8
tion of vitamin K indicates severe hepatocellular injury. a hepatocellular disease, appropriate testing for acute
The results of the bilirubin, enzyme tests, albu- viral hepatitis includes a hepatitis A IgM antibody, a
min, and prothrombin time tests will usually indicate hepatitis B surface antigen and core IgM antibody, and a
whether a jaundiced patient has a hepatocellular or hepatitis C viral RNA test. It can take many weeks for the
a cholestatic disease, as well as some indication of the hepatitis C antibody to become detectable, making it an
duration and severity of the disease. The causes and unreliable test if acute hepatitis C is suspected. Depend-
Jaundice
evaluation of hepatocellular and cholestatic diseases are ing on circumstances, studies for hepatitis D and E,
quite different. Epstein-Barr virus (EBV), and cytomegalovirus (CMV)
may be indicated. Ceruloplasmin is the initial screening
Hepatocellular Conditions Hepatocellular dis-
test for Wilson’s disease. Testing for autoimmune hepa-
eases that can cause jaundice include viral hepatitis,
titis usually includes an antinuclear antibody and mea-
drug or environmental toxicity, alcohol, and end-stage
surement of specific immunoglobulins.
cirrhosis from any cause (Table 8-2). Wilson’s disease,
Drug-induced hepatocellular injury can be classi-
once believed to occur primarily in young adults,
fied either as predictable or unpredictable. Predict-
should be considered in all adults if no other cause of
able drug reactions are dose-dependent and affect all
jaundice is found. Autoimmune hepatitis is typically
patients who ingest a toxic dose of the drug in question.
seen in young to middle-aged women but may affect
The classic example is acetaminophen hepatotoxicity.
men and women of any age. Alcoholic hepatitis can
Unpredictable or idiosyncratic drug reactions are not
be differentiated from viral and toxin-related hepatitis
dose-dependent and occur in a minority of patients. A
by the pattern of the aminotransferases. Patients with
great number of drugs can cause idiosyncratic hepatic
alcoholic hepatitis typically have an AST:ALT ratio of at
injury. Environmental toxins are also an important cause
least 2:1. The AST rarely exceeds 300 U/L. Patients with
of hepatocellular injury. Examples include industrial
acute viral hepatitis and toxin-related injury severe
chemicals such as vinyl chloride, herbal preparations
enough to produce jaundice typically have amino-
containing pyrrolizidine alkaloids (Jamaica bush tea)
transferases >500 U/L, with the ALT greater than or
and Kava Kava, and the mushrooms Amanita phalloides
equal to the AST. The degree of aminotransferase ele-
or A. verna that contain highly hepatotoxic amatoxins.
vation can occasionally help in differentiating between
hepatocellular and cholestatic processes. While ALT Cholestatic Conditions When the pattern of
and AST values less than 8 times normal may be seen the liver tests suggests a cholestatic disorder, the next
in either hepatocellular or cholestatic liver disease, step is to determine whether it is intra- or extrahepatic
values 25 times normal or higher are seen primarily in cholestasis (Fig. 8-1). Distinguishing intrahepatic from
acute hepatocellular diseases. Patients with jaundice extrahepatic cholestasis may be difficult. History, physi-
cal examination, and laboratory tests are often not help-
ful. The next appropriate test is an ultrasound. The ultra-
sound is inexpensive, does not expose the patient to
Table 8-2
ionizing radiation, and can detect dilation of the intra-
Hepatocellular Conditions That May and extrahepatic biliary tree with a high degree of sen-
Produce Jaundice
sitivity and specificity. The absence of biliary dilatation
Viral hepatitis suggests intrahepatic cholestasis, while the presence
Hepatitis A, B, C, D, and E
of biliary dilatation indicates extrahepatic cholesta-
Epstein-Barr virus
Cytomegalovirus sis. False-negative results occur in patients with partial
Herpes simplex obstruction of the common bile duct or in patients with
Alcohol cirrhosis or primary sclerosing cholangitis (PSC) where
Drug toxicity scarring prevents the intrahepatic ducts from dilating.
Predictable, dose-dependent (e.g., acetaminophen) Although ultrasonography may indicate extrahepatic
Unpredictable, idiosyncratic (e.g., isoniazid) cholestasis, it rarely identifies the site or cause of obstruc-
Environmental toxins
tion. The distal common bile duct is a particularly diffi-
Vinyl chloride
Jamaica bush tea—pyrrolizidine alkaloids
cult area to visualize by ultrasound because of overlying
Kava Kava bowel gas. Appropriate next tests include CT, magnetic
Wild mushrooms—Amanita phalloides or A. verna resonance cholangiography (MRCP), and endoscopic ret-
Wilson’s disease rograde cholangiopancreatography (ERCP). CT scanning
Autoimmune hepatitis and MRCP are better than ultrasonography for assessing
68 Table 8-3
the head of the pancreas and for identifying choledocho- Cholestatic Conditions That May Produce
lithiasis in the distal common bile duct, particularly when Jaundice
the ducts are not dilated. ERCP is the “gold standard” for
SECTION I
I. Intrahepatic
identifying choledocholithiasis. It is performed by intro- A. Viral hepatitis
ducing a side-viewing endoscope perorally into the 1. Fibrosing cholestatic hepatitis—hepatitis B and C
duodenum. The ampulla of Vater is visualized, and a cath- 2. Hepatitis A, Epstein-Barr virus, cytomegalovirus
eter is advanced through the ampulla. Injection of dye B. Alcoholic hepatitis
allows for the visualization of the common bile duct and C. Drug toxicity
the pancreatic duct. Beyond its diagnostic capabilities, 1. Pure cholestasis—anabolic and contraceptive
Cardinal Manifestations of Gastrointestinal Disease
steroids
ERCP allows for therapeutic interventions, including the
2. Cholestatic hepatitis—chlorpromazine,
removal of common bile duct stones and the placement erythromycin estolate
of stents. In patients in whom ERCP is unsuccessful and 3. Chronic cholestasis—chlorpromazine and
there is a high likelihood of the need for a therapeutic prochlorperazine
intervention, transhepatic cholangiography can provide D. Primary biliary cirrhosis
the same information and allow for intervention. MRCP E. Primary sclerosing cholangitis
has replaced ERCP as the initial diagnostic test in cases F. Vanishing bile duct syndrome
1. Chronic rejection of liver transplants
where the need for intervention is felt to be small.
2. Sarcoidosis
In patients with apparent intrahepatic cholesta- 3. Drugs
sis, the diagnosis is often made by serologic testing in G. Inherited
combination with percutaneous liver biopsy. The list of 1. Progressive familial intrahepatic cholestasis
possible causes of intrahepatic cholestasis is long and 2. Benign recurrent cholestasis
varied (Table 8-3). A number of conditions that typically H. Cholestasis of pregnancy
cause a hepatocellular pattern of injury can also present I. Total parenteral nutrition
J. Nonhepatobiliary sepsis
as a cholestatic variant. Both hepatitis B and C can cause
K. Benign postoperative cholestasis
a cholestatic hepatitis (fibrosing cholestatic hepatitis). L. Paraneoplastic syndrome
This disease variant has been reported in patients who M. Venoocclusive disease
have undergone solid organ transplantation. Hepatitis N. Graft-versus-host disease
A, alcoholic hepatitis, EBV, and CMV may also present as O. Infiltrative disease
cholestatic liver disease. 1. TB
Drugs may cause intrahepatic cholestasis, a vari- 2. Lymphoma
3. Amyloid
ant of drug-induced hepatitis. Drug-induced cholesta-
P. Infections
sis is usually reversible after eliminating the offending 1. Malaria
drug, although it may take many months for cholesta- 2. Leptospirosis
sis to resolve. Drugs most commonly associated with II. Extrahepatic
cholestasis are the anabolic and contraceptive ste- A. Malignant
roids. Cholestatic hepatitis has been reported with 1. Cholangiocarcinoma
chlorpromazine, imipramine, tolbutamide, sulindac, 2. Pancreatic cancer
cimetidine, and erythromycin estolate. It also occurs in 3. Gallbladder cancer
4. Ampullary cancer
patients taking trimethoprim; sulfamethoxazole; and
5. Malignant involvement of the porta hepatis lymph
penicillin-based antibiotics such as ampicillin, dicloxa- nodes
cillin, and clavulinic acid. Rarely, cholestasis may be B. Benign
chronic and associated with progressive fibrosis despite 1. Choledocholithiasis
early discontinuation of the drug. Chronic cholestasis 2. Postoperative biliary structures
has been associated with chlorpromazine and prochlor- 3. Primary sclerosing cholangitis
perazine. 4. Chronic pancreatitis
5. AIDS cholangiopathy
Primary biliary cirrhosis is an autoimmune disease
6. Mirizzi’s syndrome
predominantly of middle-aged women in which there is 7. Parasitic disease (ascariasis)
a progressive destruction of interlobular bile ducts. The
diagnosis is made by the presence of the antimitochon-
drial antibody that is found in 95% of patients. Primary
sclerosing cholangitis is characterized by the destruc- PSC, both intra- and extrahepatic ducts are involved.
tion and fibrosis of larger bile ducts. The disease may The diagnosis of PSC is made by imaging the biliary tree.
involve only the intrahepatic ducts and present as intra- The pathognomonic findings are multiple strictures of
hepatic cholestasis. However, in 95% of patients with bile ducts with dilatations proximal to the strictures.
pproximately 75% of patients with PSC have inflamma-
A by encephalopathy and renal failure. Weil’s disease, a 69
tory bowel disease. severe presentation of leptospirosis, is marked by jaun-
The vanishing bile duct syndrome and adult bile ducto- dice with renal failure, fever, headache, and muscle pain.
CHAPTER 8
penia are rare conditions in which there are a decreased Causes of extrahepatic cholestasis can be split into
number of bile ducts seen in liver biopsy specimens. malignant and benign (Table 8-3). Malignant causes
The histologic picture is similar to that found in pri- include pancreatic, gallbladder, ampullary, and cholangio-
mary biliary cirrhosis. This picture is seen in patients carcinoma. The latter is most commonly associated with
who develop chronic rejection after liver transplanta- PSC and is exceptionally difficult to diagnose because its
tion and in those who develop graft-versus-host disease appearance is often identical to that of PSC. Pancreatic
Jaundice
after bone marrow transplantation. Vanishing bile duct and gallbladder tumors, as well as cholangiocarcinoma,
syndrome also occurs in rare cases of sarcoidosis, in are rarely resectable and have poor prognoses. Ampul-
patients taking certain drugs including chlorpromazine, lary carcinoma has the highest surgical cure rate of all the
and idiopathically. tumors that present as painless jaundice. Hilar lymphade-
There are also familial forms of intrahepatic cho- nopathy due to metastases from other cancers may cause
lestasis. The familial intrahepatic cholestatic syndromes obstruction of the extrahepatic biliary tree.
include progressive familial intrahepatic cholestasis (PFIC) Choledocholithiasis is the most common cause of
types 1–3, and benign recurrent cholestasis (BRC). PFIC1 extrahepatic cholestasis. The clinical presentation can
and BRC are autosomal recessive diseases that result range from mild right upper quadrant discomfort with
from mutations in the ATP8B1 gene that encodes a pro- only minimal elevations of the enzyme tests to ascend-
tein belonging to the subfamily of P-type ATPases; the ing cholangitis with jaundice, sepsis, and circulatory col-
exact function of this protein remains poorly defined. lapse. PSC may occur with clinically important strictures
While PFIC1 is a progressive condition that manifests in limited to the extrahepatic biliary tree. In cases where
childhood, BRC presents later than PFIC1 and is marked there is a dominant stricture, patients can be effectively
by recurrent episodes of jaundice and pruritus; the managed with serial endoscopic dilatations. Chronic
episodes are self-limited but can be debilitating. pancreatitis rarely causes strictures of the distal com-
PFIC2 is caused by mutations in the ABCB11 gene, which mon bile duct, where it passes through the head of the
encodes the bile salt export pump, and PFIC3 is caused pancreas. AIDS cholangiopathy is a condition, usually
by mutations in the multidrug-resistant P-glycoprotein 3. due to infection of the bile duct epithelium with CMV or
Cholestasis of pregnancy occurs in the second and cryptosporidia, which has a cholangiographic appear-
third trimesters and resolves after delivery. Its cause is ance similar to that of PSC. These patients usually pres-
unknown, but the condition is probably inherited and ent with greatly elevated serum alkaline phosphatase
cholestasis can be triggered by estrogen administration. levels (mean, 800 IU/L), but the bilirubin is often near
Other causes of intrahepatic cholestasis include normal. These patients do not typically present with
total parenteral nutrition (TPN); nonhepatobiliary sep- jaundice.
sis; benign postoperative cholestasis; and a paraneo-
plastic syndrome associated with a number of different
malignancies, including Hodgkin’s disease, medullary
Summary
thyroid cancer, renal cell cancer, renal sarcoma, T cell
lymphoma, prostate cancer, and several gastrointesti- The goal of this chapter is not to provide an encyclo-
nal malignancies. The term Stauffer’s syndrome has been pedic review of all of the conditions that can cause
used for intrahepatic cholestasis specifically associated jaundice. Rather, it is intended to provide a frame-
with renal cell cancer. In patients developing cholesta- work that helps a physician to evaluate the patient with
sis in the intensive care unit, the major considerations jaundice in a logical way (Fig. 8-1).
should be sepsis, shock liver, and TPN jaundice. Jaundice Simply stated, the initial step is to obtain appropri-
occurring after bone marrow transplantation is most ate blood tests to determine if the patient has an isolated
likely due to venoocclusive disease or graft-versus-host elevation of serum bilirubin. If so, is the bilirubin eleva-
disease. tion due to an increased unconjugated or conjugated
Jaundice with associated liver dysfunction can be fraction? If the hyperbilirubinemia is accompanied by
seen in severe cases of Plasmodium falciparum. The other liver test abnormalities, is the disorder hepatocel-
jaundice in these cases is a combination of indirect lular or cholestatic? If cholestatic, is it intra- or extra-
hyperbilirubinemia from hemolysis and both choles- hepatic? All of these questions can be answered with a
tatic and hepatocellular jaundice. Poor outcomes are thoughtful history, physical examination, and interpre-
seen in these cases when the jaundice is accompanied tation of laboratory and radiologic tests and procedures.
cHAPteR 9
CHAPTER 9
sion. The absence of abdominal dullness, however, does
not exclude ascites, because a minimum of 1500 mL of
Fatal Growth ascites is required for detection on physical examina-
tion. Finally, the abdomen should be palpated to assess
An abdominal mass can result in abdominal swelling. for tenderness, a mass, enlargement of the spleen or
Enlargement of the intraabdominal organs, specifically liver, or presence of a nodular liver suggesting cirrhosis
the liver (hepatomegaly) or spleen (splenomegaly), or or tumor. Light palpation of the liver may detect pulsa-
Ascites
Pathogenesis in Cirrhosis Figure 9-2
CT of a patient with peritoneal carcinomatosis (white
Ascites in patients with cirrhosis is the result of portal arrow) and ascites (yellow arrow).
hypertension and renal salt and water retention. Portal
hypertension signifies elevation of the pressure within
the portal vein. According to Ohm’s law, pressure is pancreatic disease. Peritoneal carcinomatosis can result
the product of resistance and flow. Increased hepatic from primary peritoneal malignancies such as mesotheli-
resistance occurs by several mechanisms. First, the oma or sarcoma, abdominal malignancies such as gastric
development of hepatic fibrosis, which defines cirrhosis, or colonic adenocarcinoma, or metastatic disease from
disrupts the normal architecture of the hepatic sinusoids breast or lung carcinoma or melanoma (Fig. 9-2). The
and impedes normal blood flow through the liver. Sec- tumor cells lining the peritoneum produce a protein-
ond, activation of hepatic stellate cells, which mediate rich fluid that contributes to the development of ascites.
fibrogenesis, leads to smooth muscle contraction and Fluid from the extracellular space is drawn into the
fibrosis. Finally, cirrhosis is associated with a decrease in peritoneum, further contributing to the development
endothelial nitric oxide synthetase (eNOS) production, of ascites. Tuberculous peritonitis causes ascites via a
which results in decreased nitric oxide production and similar mechanism; tubercles deposited on the peri-
increased intrahepatic vasoconstriction. toneum exude a proteinaceous fluid. Pancreatic asci-
The development of cirrhosis is also associated with tes results from leakage of pancreatic enzymes into the
increased systemic circulating levels of nitric oxide peritoneum.
(contrary to the decrease seen intrahepatically) as well
as increased levels of vascular endothelial growth fac-
tor and tumor necrosis factor that result in splanchnic
Causes
arterial vasodilatation. Vasodilatation of the splanchnic Cirrhosis accounts for 84% of cases of ascites. Cardiac
circulation results in pooling of blood and a decrease ascites, peritoneal carcinomatosis, and “mixed” ascites
in the effective circulating volume, which is perceived resulting from cirrhosis and a second disease account
by the kidneys as hypovolemia. Compensatory vaso- for 10 to 15% of cases. Less common causes of ascites
constriction via release of antidiuretic hormone ensues, include massive hepatic metastasis, infection (tuberculo-
thereby leading to free water retention and activation of sis, Chlamydia), pancreatitis, and renal disease (nephrotic
the sympathetic nervous system and renin angiotensin syndrome). Rare causes of ascites include hypothyroid-
aldosterone system, leading in turn to renal sodium and ism and familial Mediterranean fever.
water retention.
Evaluation
Pathogenesis in the Absence
Once the presence of ascites has been confirmed, the
of Cirrhosis
etiology of the ascites is best determined by paracentesis.
Ascites in the absence of cirrhosis generally results Paracentesis is a bedside procedure in which a needle
from peritoneal carcinomatosis, peritoneal infection, or or small catheter is passed transcutaneously to extract
ascitic fluid from the peritoneum. The lower quadrants counterbalances the portal pressure. Possible causes 73
are the most frequent sites for paracentesis. Occasionally, include cirrhosis, cardiac ascites, sinusoidal obstruction
an infraumbilical approach is used. The left lower quad- syndrome (venoocclusive disease), massive liver metasta-
CHAPTER 9
rant is preferred because of the greater depth of ascites sis, or hepatic vein thrombosis (Budd-Chiari syndrome).
and thinner abdominal wall. Paracentesis is a safe proce- A SAAG <1.1 g/dL indicates that the ascites is not
dure even in patients with coagulopathy; complications, related to portal hypertension as in tuberculous perito-
including abdominal wall hematomas, hypotension, hep- nitis, peritoneal carcinomatosis, or pancreatic ascites.
atorenal syndrome, and infection, are infrequent. For high-SAAG (≥1.1) ascites, the ascitic protein level
Once ascitic fluid has been extracted, its gross can provide further clues to the etiology (see Fig. 9-3). An
appearance should be examined. Turbid fluid can result ascitic protein level of ≥2.5 g/dL indicates that the hepatic
SAAG
omy or laparoscopy with peritoneal biopsies for histol- SBP also can occasionally complicate ascites caused
ogy and culture remains the gold standard. by nephrotic syndrome, heart failure, acute hepatitis,
and acute liver failure but is rare in malignant ascites.
Patients with SBP generally note an increase in abdomi-
nal girth; however, abdominal tenderness is found in
Treatment Ascites only 40% of patients, and rebound tenderness is rare.
Cardinal Manifestations of Gastrointestinal Disease
Involuntary weight loss (IWL) is frequently insidi- both fat and skeletal muscle occurs. Age-dependent
ous and can have important implications, often changes also occur at the cellular level. Telomeres
serving as a harbinger of serious underlying disease. shorten, and body cell mass—the fat-free portion of
Clinically important weight loss is defined as the loss cells—declines steadily with aging.
of 10 pounds (4.5 kg) or >5% of one’s body weight Between ages 20 and 80, mean energy intake is
over a period of 6–12 months. IWL is encountered in reduced by up to 1200 kcal/d in men and 800 kcal/d
up to 8% of all adult outpatients and 27% of frail per- in women. Decreased hunger is a reflection of reduced
sons age 65 years and older. There is no identifiable physical activity and loss of lean body mass, produc-
cause in up to one-quarter of patients despite extensive ing lower demand for calories and food intake. Several
investigation. Conversely, up to half of people who important age-associated physiologic changes also pre-
claim to have lost weight have no documented evi- dispose elderly persons to weight loss, such as declining
dence of weight loss. People with no known cause of chemosensory function (smell and taste), reduced effi-
weight loss generally have a better prognosis than do ciency of chewing, slowed gastric emptying, and altera-
those with known causes, particularly when the source tions in the neuroendocrine axis, including changes in
is neoplastic. Weight loss in older persons is associ- levels of leptin, cholecystokinin, neuropeptide Y, and
ated with a variety of deleterious effects, including hip other hormones and peptides. These changes are associ-
fracture, pressure ulcers, impaired immune function, ated with early satiety and a decline in both appetite and
decreased functional status, and death. Not surpris- the hedonistic appreciation of food. Collectively, they
ingly, significant weight loss is associated with increased contribute to the “anorexia of aging.”
mortality, which can range from 9% to as high as 38%
within 1 to 2.5 years in the absence of clinical aware-
ness and attention. CAuses of InvoluntAry WeIght loss
Most causes of IWL belong to one of four categories:
(1) malignant neoplasms, (2) chronic inflammatory or
PhysIology of WeIght regulAtIon infectious diseases, (3) metabolic disorders (e.g., hyper-
WIth AgIng thyroidism and diabetes), or (4) psychiatric disorders
(See also Chap. 57) Among healthy aging people, total (Table 10-1). Not infrequently, more than one of
body weight peaks in the sixth decade of life and gener- these causes can be responsible for IWL. In most series,
ally remains stable until the ninth decade, after which IWL is caused by malignant disease in a quarter of
it gradually falls. In contrast, lean body mass (fat-free patients and by organic disease in one-third, with the
mass) begins to decline at a rate of 0.3 kg per year in the remainder due to psychiatric disease, medications, or
third decade, and the rate of decline increases further uncertain causes.
beginning at age 60 in men and age 65 in women. The most common malignant causes of IWL are gas-
These changes in lean body mass largely reflect the age- trointestinal, hepatobiliary, hematologic, lung, breast,
dependent decline in growth hormone secretion and, genitourinary, ovarian, and prostate. Half of all patients
consequently, circulating levels of insulin-like growth with cancer lose some body weight; one-third lose
factor type I (IGF-I) that occur with normal aging. In more than 5% of their original body weight, and up to
the healthy elderly, an increase in fat tissue balances the 20% of all cancer deaths are caused directly by cachexia
loss in lean body mass until very old age, when loss of (through immobility and/or cardiac/respiratory failure).
75
76 Table 10-1 Tuberculosis, fungal diseases, parasites, subacute
Causes of Involuntary Weight Loss bacterial endocarditis, and HIV are well-documented
Cancer Medications causes of IWL. Cardiovascular and pulmonary diseases
cause unintentional weight loss through increased meta-
SECTION I
Colon Sedatives
Hepatobiliary Antibiotics bolic demand and decreased appetite and caloric intake.
Hematologic Nonsteroidal anti- Uremia produces nausea, anorexia, and vomiting. Con-
Lung inflammatory drugs nective tissue diseases may increase metabolic demand
Breast Serotonin reuptake and disrupt nutritional balance. As the incidence of
Genitourinary inhibitors
diabetes mellitus increases with aging, the associated
Ovarian Metformin
glucosuria can contribute to weight loss. Hyperthy-
Cardinal Manifestations of Gastrointestinal Disease
Prostate Levodopa
Angiotensin-converting roidism in the elderly may have less prominent sym-
Gastrointestinal
disorders enzyme inhibitors pathomimetic features and may present as “apathetic
Malabsorption Other drugs hyperthyroidism” or T3 toxicosis.
Peptic ulcer Disorders of the mouth Neurologic injuries such as stroke, quadriplegia, and
Inflammatory bowel and teeth multiple sclerosis may lead to visceral and autonomic
disease Caries dysfunction that can impair caloric intake. Dysphagia
Pancreatitis Dygeusia from these neurologic insults is a common mechanism.
Obstruction/constipation Age-related factors Functional disability that compromises activities of daily
Pernicious anemia Physiologic changes living (ADLs) is a common cause of undernutrition in
Endocrine and metabolic Visual impairment
the elderly. Visual impairment from ophthalmic or cen-
Hyperthyroidism Decreased taste and smell
Diabetes mellitus Functional disabilities
tral nervous system disorders such as a tremor can limit
Pheochromocytoma the ability of people to prepare and eat meals. IWL
Neurologic
Adrenal insufficiency Stroke
may be one of the earliest manifestations of Alzheimer’s
Cardiac disorders Parkinson’s disease dementia.
Chronic ischemia Neuromuscular disorders Isolation and depression are significant causes of
Chronic congestive Dementia IWL that may manifest as an inability to care for one-
heart Social self, including nutritional needs. A cytokine-mediated
failure Isolation inflammatory metabolic cascade can be both a cause of
Respiratory disorders Economic hardship and a manifestation of depression. Bereavement can be
Emphysema Psychiatric and behavioral a cause of IWL and, when present, is more pronounced
Chronic obstructive Depression in men. More intense forms of mental illness such as
pulmonary disease Anxiety paranoid disorders may lead to delusions about food
Renal insufficiency Paranoia and cause weight loss. Alcoholism can be a significant
Rheumatologic disease Bereavement
Infections Alcoholism
source of weight loss and malnutrition.
HIV Eating disorders Elderly persons living in poverty may have to choose
Tuberculosis Increased activity or between purchasing food and purchasing medications.
Parasitic infection exercise Institutionalization is an independent risk factor, as up
Subacute bacterial Idiopathic to 30–50% of nursing home patients have inadequate
endocarditis food intake.
Medications can cause anorexia, nausea, vomit-
ing, gastrointestinal distress, diarrhea, dry mouth, and
The greatest incidence of weight loss is seen among changes in taste. This is particularly an issue in the
patients with solid tumors. Malignancy that reveals itself elderly, many of whom take five or more medications.
through significant weight loss usually has a very poor
prognosis.
In addition to malignancies, gastrointestinal causes
Assessment
are among the most prominent causes of IWL. Peptic
ulcer disease, inflammatory bowel disease, dysmotil- The four major manifestations of IWL are (1) anorexia
ity syndromes, chronic pancreatitis, celiac disease, con- (loss of appetite), (2) sarcopenia (loss of muscle mass),
stipation, and atrophic gastritis are some of the more (3) cachexia (a syndrome that combines weight loss, loss
common entities. Oral and dental problems are easily of muscle and adipose tissue, anorexia, and weakness),
overlooked and may manifest with halitosis, poor oral and (4) dehydration. The current obesity epidemic
hygiene, xerostomia, inability to chew, reduced masti- adds complexity, as excess adipose tissue can mask the
catory force, nonocclusion, temporomandibular joint development of sarcopenia and delay awareness of the
syndrome, edentulousness, and pain due to caries or development of cachexia. If it is not possible to measure
abscesses. weight directly, a change in clothing size, corroboration
of weight loss by a relative or friend, and a numeric screening tests, such as mammography and colonos- 77
estimate of weight loss provided by the patient are sug- copy, should be performed. Patients at risk should have
gestive of true weight loss. HIV testing. All elderly patients with weight loss should
CHAPTER 10
Initial assessment includes a comprehensive history undergo screening for dementia and depression by using
and physical, a complete blood count, tests of liver instruments such as the Mini-Mental State Examina-
enzyme levels, a C-reactive protein, erythrocyte sedi- tion and the Geriatric Depression Scale, respectively.
mentation rate, renal function studies, thyroid function The Mini-Nutritional Assessment (www.mna-elderly.com)
tests, chest radiography, and an abdominal ultrasound and the Nutrition Screening Initiative (www.aafp.org/
(Table 10-2). Age, sex, and risk factor–specific cancer afp/980301ap/edits.html) are also available for the nutri-
tional assessment of elderly patients. Almost all patients
Evaluation of the
Patient with
Alimentary Tract
Syndromes
chaPtEr 11
CHAPTER 11
hours, propagation through the colon takes more than one common intestinal maldigestion syndrome, lactase defi-
day in most individuals. Colonic motor patterns exhibit a ciency, produces gas and diarrhea after dairy products
to-and-fro character that facilitates slow fecal desiccation. and has no adverse outcomes. Other intestinal enzyme
The proximal colon serves to mix and absorb fluid, while deficiencies produce similar symptoms after ingestion of
the distal colon exhibits peristaltic contractions and mass other simple sugars. Conversely, celiac disease, bacte-
actions that function to expel the stool. The colon termi- rial overgrowth, infectious enteritis, Crohn’s ileitis, and
nates in the anus, a structure with volitional and involun-
tion causes marked delays in small-bowel transit due to cancers arise after prior anal infection or inflammation.
enteric nerve or intestinal smooth-muscle injury. Slow- Pancreatic and biliary cancers elicit severe pain, weight
transit constipation is produced by diffusely impaired loss, and jaundice and have poor prognoses. Hepatocellu-
colonic propulsion. Constipation also is produced by lar carcinoma usually arises in the setting of chronic viral
outlet abnormalities such as rectal prolapse, intussuscep- hepatitis or cirrhosis secondary to other causes. Most GI
tion, or dyssynergia—a failure of anal or puborectalis cancers exhibit carcinomatous histology; however, lym-
Evaluation of the Patient with Alimentary Tract Syndromes
relaxation upon attempted defecation. phomas and other cell types also are observed.
Disorders of rapid propulsion are less common than
those with delayed transit. Rapid gastric emptying Disorders without obvious
occurs in postvagotomy dumping syndrome, with gastric organic abnormalities
hypersecretion, and in some cases of functional dyspepsia The most common GI disorders show no abnormalities on
and cyclic vomiting syndrome. Exaggerated intestinal or biochemical or structural testing and include irritable bowel
colonic motor patterns may be responsible for diarrhea syndrome, functional dyspepsia, functional chest pain, and
in irritable bowel syndrome. Accelerated transit with functional heartburn. These disorders exhibit altered gut
hyperdefecation is noted in hyperthyroidism. motor function; however, the pathogenic relevance of
these abnormalities is uncertain. Exaggerated visceral sen-
Immune dysregulation sory responses to noxious stimulation may cause discomfort
in these disorders. Symptoms in other patients result from
Many inflammatory GI conditions are consequences
altered processing of visceral pain sensations in the cen-
of altered gut immune function. The mucosal inflam-
tral nervous system. Functional bowel patients with severe
mation of celiac disease results from dietary inges-
symptoms may exhibit significant emotional disturbances
tion of gluten-containing grains. Some patients with
on psychometric testing. Subtle immunologic defects may
food allergy also exhibit altered immune populations.
contribute to functional symptoms as well.
Eosinophilic esophagitis and eosinophilic gastroenteri-
tis are inflammatory disorders with prominent mucosal
eosinophils. Ulcerative colitis and Crohn’s disease are Genetic influences
disorders of uncertain etiology that produce muco- Although many GI diseases result from environmental
sal injury primarily in the lower gut. The microscopic factors, others exhibit hereditary components. Family
colitides, lymphocytic and collagenous colitis, exhibit members of inflammatory bowel disease patients show
colonic subepithelial infiltrates without visible mucosal a genetic predisposition to disease development them-
damage. Bacterial, viral, and protozoal organisms may selves. Colonic and esophageal malignancies arise in
produce ileitis or colitis in selected patient populations. certain inherited disorders. Rare genetic dysmotil-
ity syndromes are described. Familial clustering is even
Impaired gut blood flow observed in the functional bowel disorders, although
this may be secondary learned familial illness behavior
Different GI regions are at variable risk for ischemic rather than a true hereditary factor.
damage from impaired blood flow. Rare cases of gas-
troparesis result from blockage of the celiac and supe-
rior mesenteric arteries. More commonly encountered
are intestinal and colonic ischemia that are conse- Symptoms of Gastrointestinal
quences of arterial embolus, arterial thrombosis, venous Disease
thrombosis, or hypoperfusion from dehydration, sep- The most common GI symptoms are abdominal pain,
sis, hemorrhage, or reduced cardiac output. These may heartburn, nausea and vomiting, altered bowel habits,
produce mucosal injury, hemorrhage, or even perfo- GI bleeding, and jaundice (Table 11-1). Others are
ration. Some cases of radiation enterocolitis exhibit dysphagia, anorexia, weight loss, fatigue, and extraintes-
reduced mucosal blood flow. tinal symptoms.
Table 11-1 83
Common Causes of Common GI Symptoms
Obstructive
Abdominal Pain Nausea and Vomiting Diarrhea GI Bleeding Jaundice
CHAPTER 11
Esophagitis Pregnancy Celiac disease Diverticula Ampullary carcinoma
GI obstruction Endocrine disease Pancreatic insufficiency Hemorrhoids Pancreatitis
Inflammatory bowel Motion sickness Hyperthyroidism Fissures Pancreatic tumor
disease Central nervous system Ischemia Inflammatory
Functional bowel dis- disease Endocrine tumor bowel disease
order Infectious colitis
Vascular disease
chronic pancreatitis, stricture, and malignancy. ease and irritable bowel syndrome. Defecation relieves
discomfort in inflammatory bowel disease and irritable
Other symptoms bowel syndrome. Functional bowel disorders are exac-
erbated by stress. Sudden awakening from sound sleep
Other symptoms are manifestations of GI disease. suggests organic rather than functional disease. Diarrhea
Dysphagia, odynophagia, and unexplained chest pain from malabsorption usually improves with fasting, while
Evaluation of the Patient with Alimentary Tract Syndromes
suggest esophageal disease. A globus sensation is reported secretory diarrhea persists without oral intake.
with esophagopharyngeal conditions, but also occurs Symptom relation to other factors narrows the list
with functional GI disorders. Weight loss, anorexia, of diagnostic possibilities. Obstructive symptoms with
and fatigue are nonspecific symptoms of neoplastic, prior abdominal surgery raise concern for adhesions,
inflammatory, gut motility, pancreatic, small-bowel whereas loose stools after gastrectomy or gallbladder
mucosal, and psychiatric conditions. Fever is reported excision suggest dumping syndrome or postcholecys-
with inflammatory illness, but malignancies also evoke tectomy diarrhea. Symptom onset after travel prompts
febrile responses. GI disorders also produce extraintesti- a search for enteric infection. Medications may pro-
nal symptoms. Inflammatory bowel disease is associated duce pain, altered bowel habits, or GI bleeding. Lower
with hepatobiliary dysfunction, skin and eye lesions, GI bleeding likely results from neoplasms, diverticula,
and arthritis. Celiac disease may present with dermatitis or vascular lesions in an older person and from ano-
herpetiformis. Jaundice can produce pruritus. Con- rectal abnormalities or inflammatory bowel disease in a
versely, systemic diseases can have GI consequences. younger individual. Celiac disease is prevalent in peo-
Systemic lupus may cause gut ischemia, presenting with ple of northern European descent, while inflammatory
pain or bleeding. Overwhelming stress or severe burns bowel disease is more common in certain Jewish popu-
may lead to gastric ulcer formation. lations. A sexual history may raise concern for sexually
transmitted diseases or immunodeficiency.
For more than two decades, working groups have
Evaluation of the Patient with been convened to devise symptom criteria to improve
Gastrointestinal Disease the confident diagnosis of functional bowel disorders
and to minimize the numbers of unnecessary diagnostic
Evaluation of the patient with GI disease begins with a tests performed. The most widely accepted symptom-
careful history and examination. Subsequent investiga- based criteria are the Rome criteria. When tested against
tion with a variety of tools designed to test gut struc- findings of structural investigations, the Rome criteria
ture or function are indicated in selected cases. Some exhibit diagnostic specificities exceeding 90% for many
patients exhibit normal findings on diagnostic testing. of the functional bowel disorders.
In these individuals, validated symptom profiles are
employed to confidently diagnose a functional bowel
disorder. Physical Examination
The physical exam complements information from
the history. Abnormal vital signs provide diagnostic
History clues and determine the need for acute intervention.
The history of the patient with suspected GI disease has Fever suggests inflammation or neoplasm. Orthostasis
several components. Symptom timing suggests specific is found with significant blood loss, dehydration, sep-
etiologies. Symptoms of short duration commonly result sis, or autonomic neuropathy. Skin, eye, or joint find-
from acute infection, toxin exposure, or abrupt inflam- ings may point to specific diagnoses. Neck exam with
mation or ischemia. Long-standing symptoms point to swallowing assessment evaluates dysphagia. Cardiopul-
underlying chronic inflammatory or neoplastic condi- monary disease may present with abdominal pain or
tions or functional bowel disorders. Symptoms from nausea; thus lung and cardiac exams are important. Pelvic
examination tests for a gynecologic source of abdomi- therapy in some diseases, as with thiopurine metabo- 85
nal pain. Rectal exam may detect blood, indicating gut lite levels in inflammatory bowel disease. Other body
mucosal injury or neoplasm or a palpable inflammatory fluids are sampled under certain circumstances. Ascitic
mass in appendicitis. Metabolic conditions and gut motor fluid is analyzed for infection, malignancy, or findings
disorders have associated peripheral neuropathy. of portal hypertension. Cerebrospinal fluid is obtained
Inspection of the abdomen may reveal distention for suspected central nervous system causes of vomit-
from obstruction, tumor, or ascites or vascular abnor- ing. Urine samples screen for carcinoid, porphyria, and
malities with liver disease. Ecchymoses develop with heavy metal intoxication.
severe pancreatitis. Auscultation can detect bruits or
CHAPTER 11
friction rubs from vascular disease or hepatic tumors. Luminal contents
Loss of bowel sounds signifies ileus, while high-pitched,
hyperactive sounds characterize intestinal obstruction. Luminal contents can be examined for diagnostic clues.
Percussion assesses liver size and can detect shifting Stool samples are cultured for bacterial pathogens,
dullness from ascites. Palpation assesses for hepato- examined for leukocytes and parasites, or tested for
splenomegaly as well as neoplastic or inflammatory Giardia antigen. Duodenal aspirates can be examined
masses. Abdominal exam is helpful in evaluating unex- for parasites or cultured for bacterial overgrowth. Fecal
CHAPTER 11
disease or amyloid. Liver biopsy is indicated in cases nostomy is considered for gastric dysmotility syndromes
with abnormal liver chemistries, unexplained jaundice, that preclude feeding into the stomach. Intravenous
following liver transplant to exclude rejection, and to hyperalimentation is employed for individuals with gen-
characterize the degree of inflammation in patients with eralized gut malfunction who cannot tolerate or who
chronic viral hepatitis prior to initiating antiviral ther- cannot be sustained with enteral nutrition.
apy. Biopsies obtained during CT or ultrasound can Pharmacotherapy Several medications are
Crohn’s disease. Some cases of irritable bowel syndrome Radiologic measures also are useful in GI disease. Angio-
(especially those with diarrhea) respond to nonabsorb- graphic embolization or vasoconstriction decreases bleed-
able antibiotic therapy. Anti-inflammatory and immuno- ing from sites not amenable to endoscopic intervention.
suppressive drugs are used in ulcerative colitis, Crohn’s Dilatation or stenting with fluoroscopic guidance relieves
disease, microscopic colitis, refractory celiac disease, and luminal strictures. Contrast enemas can reduce volvulus
gut vasculitis. Chemotherapy with or without radiother- and evacuate air in acute colonic pseudoobstruction. CT
Evaluation of the Patient with Alimentary Tract Syndromes
apy is offered for GI malignancies. Most GI carcinomas and ultrasound help drain abdominal fluid collections, in
respond poorly to such therapy, whereas lymphomas many cases obviating the need for surgery. Percutaneous
may be cured with such intervention. transhepatic cholangiography relieves biliary obstruction
when ERCP is contraindicated. Lithotripsy can fragment
Alternative Therapies Alternative treatments
gallstones in patients who are not candidates for surgery.
are marketed to treat selected GI symptoms. Ginger,
In some instances, radiologic approaches offer advantages
acupressure, and acustimulation have been advocated
over endoscopy for gastroenterostomy placement. Finally,
for nausea, while pyridoxine has been investigated for
central venous catheters for parenteral nutrition may be
nausea of first-trimester pregnancy. Probiotics con-
placed using radiographic techniques.
taining active bacterial cultures are used as adjuncts in
some cases of infectious diarrhea and irritable bowel Surgery Surgery is performed to cure disease, con-
syndrome. Probiotics that selectively nourish benign trol symptoms without cure, maintain nutrition, or pal-
luminal bacteria may ultimately show benefit in func- liate unresectable neoplasm. Medication-unresponsive
tional disorders as well. Low-potency pancreatic enzyme ulcerative colitis, diverticulitis, cholecystitis, appendicitis,
preparations are sold as general digestive aids but have and intraabdominal abscess are curable with surgery,
little evidence to support their efficacy. while only symptom control without cure is possible
with Crohn’s disease. Surgery is mandated for ulcer com-
Enteric Therapies/Interventional
plications such as bleeding, obstruction, or perforation
Endoscopy and Radiology Simple luminal
and intestinal obstructions that persist after conservative
interventions are commonly performed for GI diseases.
care. Fundoplication of the gastroesophageal junction
Nasogastric tube suction decompresses the upper gut
is performed for severe ulcerative esophagitis and drug-
in ileus or mechanical obstruction. Nasogastric lavage of
refractory symptomatic acid reflux. Achalasia responds to
saline or water in the patient with upper GI hemorrhage
operations to relieve lower esophageal sphincter pressure.
determines the rate of bleeding and helps evacuate
Operations for motor disorders have been introduced
blood prior to endoscopy. Enteral feedings can be initi-
including implanted electrical stimulators for gastropare-
ated through a nasogastric or nasoenteric tube. Enemas
sis and electrical devices and artificial sphincters for fecal
relieve fecal impaction or assist in gas evacuation in acute
incontinence. Surgery may be needed to place a jejunos-
colonic pseudoobstruction. A rectal tube can be left in
tomy for long-term enteral feedings. The threshold for
place to vent the distal colon in colonic pseudoobstruc-
performing surgery depends on the clinical setting. In all
tion and other colonic distention disorders.
cases, the benefits of operation must be weighed against
In addition to its diagnostic role, endoscopy has thera-
the potential for postoperative complications.
peutic capabilities in certain settings. Cautery techniques
can stop hemorrhage from ulcers, vascular malforma- Therapy Directed to External
tions, and tumors. Injection with vasoconstrictor sub- Influences In some conditions, GI symptoms
stances or sclerosants is used for bleeding ulcers, vascu- respond to treatments directed outside the gut. Psy-
lar malformations, varices, and hemorrhoids. Endoscopic chological therapies including psychotherapy, behavior
encirclement of varices and hemorrhoids with constrict- modification, hypnosis, and biofeedback have shown
ing bands stops hemorrhage from these sites, while efficacy in functional bowel disorders. Patients with sig-
endoscopically placed clips can occlude arterial bleeding nificant psychological dysfunction and those with little
sites. Endoscopy can remove polyps or debulk lumen- response to treatments targeting the gut are likely to
narrowing malignancies. Endoscopic mucosal resection benefit from this form of therapy.
cHAptER 12
GASTROINTESTINAL ENDOSCOPY
89
90
SECTION II
A B
Evaluation of the Patient with Alimentary Tract Syndromes
C D
Figure 12-3
Barrett’s esophagus. A. Pink tongues of Barrett’s mucosa of intramucosal adenocarcinoma in the endoscopically
extending proximally from the gastroesophageal junction. resected nodule. Tumor extends into the esophageal submu
B. Barrett’s esophagus with a suspicious nodule (arrow) iden cosa (arrow). D. Barrett’s esophagus with locally advanced
tified during endoscopic surveillance. C. Histologic finding adenocarcinoma.
Colonoscopy
Colonoscopy is performed by passing a flexible colono-
scope through the anal canal into the rectum and colon.
The cecum is reached in >95% of cases, and the termi-
nal ileum can often be examined. Colonoscopy is the
gold standard for diagnosis of colonic mucosal disease.
Colonoscopy has greater sensitivity than barium enema
for colitis (Fig. 12-4), polyps (Fig. 12-5), and cancer A B
(Fig. 12-6). CT colonography is an emerging technol-
ogy that rivals colonoscopy’s accuracy for detection of
polyps and cancer. Conscious sedation is usually given
before colonoscopy in the United States, although a
willing patient and a skilled examiner can complete the
procedure without sedation in many cases.
Flexible Sigmoidoscopy
Flexible sigmoidoscopy is similar to colonoscopy but C D
visualizes only the rectum and a variable portion of the Figure 12-4
left colon, typically to 60 cm from the anal verge. This Causes of colitis. A. Chronic ulcerative colitis with diffuse
procedure causes abdominal cramping, but it is brief and ulcerations and exudates. B. Severe Crohn’s colitis with
is usually performed without sedation. Flexible sigmoid- deep ulcers. C. Pseudomembranous colitis with yellow,
oscopy is primarily used for evaluation of diarrhea and adherent pseudomembranes. D. Ischemic colitis with patchy
rectal outlet bleeding. mucosal edema, subepithelial hemorrhage, and cyanosis.
91
CHAPTER 12
A B
Figure 12-5
Colonic polyps. A. Pedunculated colon polyp on a thick
stalk covered with normal mucosa (arrow). B. Sessile rectal
polyp.
Gastrointestinal Endoscopy
Figure 12-7
Capsule endoscopy image of jejunal vascular ectasia.
Small-Bowel Endoscopy
Three techniques are currently used to evaluate the
small intestine, most often in patients presenting with
presumed small-bowel bleeding. For capsule endoscopy
the patient swallows a disposable capsule that contains
a complementary metal oxide silicon (CMOS) chip
camera. Color still images (Fig. 12-7) are transmit-
ted wirelessly to an external receiver at several frames
per second until the capsule’s battery is exhausted or it
is passed into the toilet. Although capsule endoscopy
enables visualization of the jejunal and ileal mucosa
beyond the reach of a conventional endoscope, it
remains solely a diagnostic procedure at present.
Push enteroscopy is performed with a long endoscope
similar in design to an upper endoscope. The entero-
scope is pushed down the small bowel, sometimes with
the help of a stiffening overtube that extends from the
mouth to the small intestine. The proximal to mid-jeju- Figure 12-8
num is usually reached, and the endoscope’s instrument Radiograph of a double-balloon enteroscope in the small
channel allows for biopsies or endoscopic therapy. intestine.
92
A B C
SECTION II
Figure 12-9
Nonsteroidal anti-inflammatory drug (NSAID)-induced B. Balloon dilatation of the ileal stricture. C. Appearance of
proximal ileal stricture diagnosed by double-balloon stricture after dilatation.
endoscopy. A. Ileal stricture causing obstructive symptoms.
Evaluation of the Patient with Alimentary Tract Syndromes
endoscopic therapy can be performed throughout the for therapy but remains important in diagnosis, especially
visualized small bowel (Fig. 12-9). for ductal strictures and bile duct stones.
A B
A B
Figure 12-10
C D
Endoscopic retrograde cholangiopancreatography (ERCP)
for bile duct stones with cholangitis. A. Faceted bile Figure 12-11
duct stones are demonstrated in the common bile duct. Endoscopic sphincterotomy. A. A normal-appearing ampulla
B. After endoscopic sphincterotomy, the stones are extrac of Vater. B. Sphincterotomy is performed with electrocautery.
ted with a Dormia basket. A small abscess communicates C. Bile duct stones are extracted with a balloon catheter.
with the left hepatic duct. D. Final appearance of the sphincterotomy.
high-resolution images are obtained. EUS provides 93
the most accurate preoperative local staging of esopha-
geal, pancreatic, and rectal malignancies (Fig. 12-14),
although it does not detect most distant metastases. EUS
is also useful for diagnosis of bile duct stones, gallbladder
disease, submucosal gastrointestinal lesions, and chronic
pancreatitis. Fine-needle aspirates and core biopsies of
masses and lymph nodes in the posterior mediastinum,
abdomen, pancreas, retroperitoneum, and pelvis can be
CHAPTER 12
obtained under EUS guidance (Fig. 12-15).
A B
Gastrointestinal Endoscopy
that entail passage of an endoscope or its accessories
through the wall of the gastrointestinal tract (e.g., stom-
ach) to perform diagnostic or therapeutic interventions.
Some NOTES procedures, such as percutaneous endo-
scopic gastrostomy (PEG) or endoscopic necrosectomy
C D of pancreatic necrosis, are established clinical procedures;
others, such as endoscopic appendectomy, cholecystec-
Figure 12-12
Endoscopic diagnosis, staging, and palliation of hilar
tomy, and tubal ligation, are in development, and their
cholangiocarcinoma. A. Endoscopic retrograde cholan
ultimate clinical application is presently unclear. NOTES
giopancreatography (ERCP) in a patient with obstructive is currently an area of intense innovation and endoscopic
jaundice demonstrates a malignant-appearing stricture of research.
the biliary confluence extending into the left and right intra
hepatic ducts. B. Intraductal ultrasound of the biliary stric
ture demonstrates marked bile duct wall thickening due
Risks of Endoscopy
to tumor (T) with partial encasement of the hepatic artery
(arrow). C. Intraductal biopsy obtained during ERCP demon Medications used during conscious sedation may cause
strates malignant cells infiltrating the submucosa of the bile respiratory depression or allergic reactions. All endo-
duct wall (arrow). D. Endoscopic placement of bilateral self- scopic procedures carry some risk of bleeding and gas-
expanding metal stents (arrow) relieves the biliary obstruc trointestinal perforation. These risks are quite low with
tion. GB, gallbladder. ( Image C courtesy of Dr. Thomas
diagnostic upper endoscopy and colonoscopy (<1:1000
Smyrk; with permission.)
procedures), although the risk is as high as 2:100 when
therapeutic procedures such as polypectomy, control of
hemorrhage, or stricture dilatation are performed. Bleed-
ing and perforation are rare with flexible sigmoidoscopy.
The risks for diagnostic EUS (without needle aspiration)
are similar to the risks for diagnostic upper endoscopy.
Infectious complications are unusual with most
endoscopic procedures. Some procedures carry a higher
incidence of postprocedure bacteremia, and prophylac-
tic antibiotics may be indicated (Table 12-1).
ERCP carries additional risks. Pancreatitis occurs
in about 5% of patients undergoing ERCP and in up
to 25% of patients with sphincter of Oddi dysfunc-
tion. Young anicteric patients with normal ducts are at
increased risk. Post-ERCP pancreatitis is usually mild
Figure 12-13
and self-limited but may rarely result in prolonged hos-
Bile leak (arrow) from a duct of Luschka after laparoscopic pitalization, surgery, diabetes, or death. Bleeding occurs
cholecystectomy. Contrast leaks from a small right intrahe in 1% of endoscopic sphincterotomies. Ascending chol-
patic duct into the gallbladder fossa, then flows into the pig angitis, pseudocyst infection, retroperitoneal perfora-
tail of a percutaneous drainage catheter. tion, and abscess may occur as a result of ERCP.
94
SECTION II
A B C
Figure 12-14
Local staging of gastrointestinal cancers with endo- cancer. The tumor does not invade the mp. B. T2 esophageal
scopic ultrasound. In each example the white arrowhead cancer. The tumor invades the mp. C. T3 esophageal can
Evaluation of the Patient with Alimentary Tract Syndromes
marks the primary tumor and the black arrow indicates the cer. The tumor extends through the mp into the surrounding
muscularis propria (mp) of the intestinal wall. A. T1 gastric tissue, and focally abuts the aorta. AO, aorta.
Initial evaluation
The initial evaluation of the bleeding patient focuses
on the magnitude of hemorrhage as reflected by the
postural vital signs, the frequency of hematemesis or
melena, and (in some cases) findings on nasogastric
lavage. Decreases in hematocrit and hemoglobin lag
behind the clinical course and are not reliable gauges
A B
of the magnitude of acute bleeding. This initial eval-
Figure 12-15 uation, completed well before the bleeding source is
Endoscopic ultrasound (EUS)-guided fine-needle aspira- confidently identified, guides immediate supportive
tion (FNA). A. Ultrasound image of a 22-gauge needle passed care of the patient and helps determine the timing of
through the duodenal wall and positioned in a hypoechoic pan endoscopy. The severity of the initial hemorrhage is
creatic head mass. B. Micrograph of aspirated malignant cells. the most important indication for urgent endoscopy,
( Image B courtesy of Dr. Michael R. Henry; with permission.) since a large initial bleed increases the likelihood of
ongoing or recurrent bleeding. Patients with rest-
ing hypotension, repeated hematemesis, bloody naso-
Percutaneous gastrostomy tube placement during gastric aspirate that does not clear with large volume
EGD is associated with a 10–15% incidence of compli- lavage, or orthostatic change in vital signs, or those
cations, most often wound infections. Fasciitis, pneu- requiring blood transfusions, should be considered for
monia, bleeding, buried bumper syndrome, and colonic urgent endoscopy. In addition, patients with cirrhosis,
injury may result from gastrostomy tube placement. coagulopathy, or respiratory or renal failure, and those
over 70 years of age are more likely to have significant
rebleeding.
Bedside evaluation also suggests an upper or lower
Urgent Endoscopy gastrointestinal source of bleeding in most patients.
Over 90% of patients with melena are bleeding proxi-
Acute Gastrointestinal Hemorrhage mal to the ligament of Treitz, and about 90% of patients
Endoscopy is an important diagnostic and therapeutic with hematochezia are bleeding from the colon. Melena
technique for patients with acute gastrointestinal hem- can result from bleeding in the small bowel or right
orrhage. Although gastrointestinal bleeding stops sponta- colon, especially in older patients with slow colonic
neously in most cases, some patients will have persistent transit. Conversely, some patients with massive hema-
or recurrent hemorrhage that may be life-threatening. tochezia may be bleeding from an upper gastrointestinal
Table 12-1 95
Antibiotic Prophylaxis for Endoscopic Procedures
Periprocedural
Patient Condition Procedure Contemplated Goal of Prophylaxis Antibiotic Prophylaxis
All cardiac conditions Any endoscopic procedure Prevention of infective Not indicated
endocarditis
Bile-duct obstruction in the ERCP with complete Prevention of cholangitis Not recommended
absence of cholangitis drainage
CHAPTER 12
Bile-duct obstruction in absence ERCP with anticipated Prevention of cholangitis Recommended; continue
of cholangitis incomplete drainage (e.g., antibiotics after the
PSC, hilar strictures) procedure
Sterile pancreatic fluid collection ERCP Prevention of cyst infection Recommended
(e.g., pseudocyst, necrosis),
which communicates with
pancreatic duct
Gastrointestinal Endoscopy
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 Insufficient data to make
firm recommendationb
Cystic lesions along GI tract EUS-FNA Prevention of cyst infection Recommended
(including mediastinum)
All patients Percutaneous endoscopic Prevention of peristomal Recommended
feeding tube placement infection
Cirrhosis with acute GI bleeding Required for all patients, Prevention of infectious com Upon admissionc
regardless of endoscopic plications and reduction of
procedures mortality
Synthetic vascular graft and Any endoscopic procedure Prevention of graft and Not recommendedd
other nonvalvular cardiovascular device infection
devices
Prosthetic joints Any endoscopic procedure Prevention of septic arthritis Not recommendede
a
Low rates of bacteremia and local infection.
b
Endoscopists may choose on a case-by-case basis.
c
Risk for bacterial infection associated with cirrhosis and GI bleeding is well established.
d
No reported cases of infection associated with endoscopy.
e
Very low risk of infection.
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; EUS-FNA, endoscopic ultrasound–fine-needle aspiration; PSC, primary
sclerosing cholangitis.
Source: Adapted from S Banerjee et al: Gastrointest Endosc 67:719, 2008; with permission from Elsevier.
source, such as a gastric Dieulafoy’s lesion or duodenal Most patients with impressive hematochezia can
ulcer, with rapid intestinal transit. Early upper endos- undergo colonoscopy after a rapid colonic purge with
copy should be considered in such patients. a polyethylene glycol solution; the preparation fluid
Endoscopy should be performed after the patient has may be administered via a nasogastric tube. Colonos-
been resuscitated with intravenous fluids and transfu- copy has a higher diagnostic yield than radionuclide
sions as necessary. Marked coagulopathy or thrombocy- bleeding scans or angiography in lower gastrointesti-
topenia is usually treated before endoscopy, since cor- nal bleeding, and endoscopic therapy can be applied in
rection of these abnormalities may lead to resolution of some cases. In a minority of cases, endoscopic assess-
bleeding, and techniques for endoscopic hemostasis are ment is hindered by poor visualization due to persis-
limited in such patients. Metabolic derangements should tent vigorous bleeding with recurrent hemodynamic
also be addressed. Tracheal intubation for airway pro- instability, and other techniques (such as angiography
tection should be considered before upper endoscopy or emergent subtotal colectomy) must be employed.
in patients with repeated recent hematemesis and sus- In such patients, massive bleeding originating from an
pected variceal hemorrhage. upper gastrointestinal source should also be considered
96 and excluded by upper endoscopy. The anal and rectal Endoscopic therapy of ulcers with high-risk stigmata
mucosa should be visualized endoscopically early in the typically lowers the rebleeding rate to 5–10%. Several
course of massive rectal bleeding, as bleeding lesions hemostatic techniques are available, including injection
in or close to the anal canal may be identified that are of epinephrine or a sclerosant into and around the ves-
amenable to endoscopic or surgical transanal hemostatic sel, “coaptive coagulation” of the vessel in the base of
techniques. the ulcer using a thermal probe that is pressed against
the site of bleeding, placement of hemoclips, or a com-
bination of these modalities. In conjunction with endo-
Peptic ulcer scopic therapy, the administration of a proton pump
inhibitor decreases the risk of rebleeding and improves
SECTION II
A B C
D E
Figure 12-16
Stigmata of hemorrhage in peptic ulcers. A. Gastric clot. D. Gastric ulcer with a pigmented protuberance/visible
antral ulcer with a clean base. B. Duodenal ulcer with flat vessel. E. Duodenal ulcer with active spurting (arrow).
pigmented spots. C. Duodenal ulcer with a dense adherent
97
CHAPTER 12
A B
Figure 12-19
Dieulafoy’s lesion. A. Actively spurting jejunal Dieulafoy’s
lesion. There is no underlying mucosal lesion. B. Histology
Figure 12-17 of a gastric Dieulafoy’s lesion. A persistent caliber artery
Esophageal varices. (arrows) is present in the gastric submucosa, immediately
beneath the mucosa.
Gastrointestinal Endoscopy
varices (Fig. 12-17), particularly in patients in whom
beta blockers are contraindicated or not tolerated
(primary prophylaxis). EVL is also the preferred endo- these varices is associated with a high rebleeding rate.
scopic therapy for control of active esophageal variceal Complications of cyanoacrylate injection include infec-
bleeding and for subsequent eradication of esophageal tion and glue embolization to other organs, such as the
varices (secondary prophylaxis). During EVL, a varix is lungs, brain, and spleen.
suctioned into a cap fitted on the end of the endoscope, After treatment of the acute hemorrhage, an elective
and a rubber band is released from the cap, ligating the course of endoscopic therapy can be undertaken with
varix. EVL controls acute hemorrhage in up to 90% of the goal of eradicating esophageal varices and prevent-
patients. Complications of EVL, such as postbanding ing rebleeding months to years later. However, this
ulcer bleeding and esophageal stenosis, are uncommon. chronic therapy is less successful, preventing long-term
Endoscopic variceal sclerotherapy (EVS) involves the rebleeding in ∼50% of patients. Pharmacologic therapies
injection of a sclerosing, thrombogenic solution into or that decrease portal pressure have similar efficacy, and
next to the esophageal varices. EVS also controls acute the two modalities may be combined.
hemorrhage in most patients but has a higher compli-
cation rate than EVL. These techniques are used when Dieulafoy’s lesion
varices are actively bleeding during endoscopy or (more
commonly) when varices are the only identifiable cause This lesion, also called persistent caliber artery, is a large-
of acute hemorrhage. Bleeding from large gastric fun- caliber arteriole that runs immediately beneath the gas-
dic varices (Fig. 12-18) is best treated with endoscopic trointestinal mucosa and bleeds through a pinpoint
cyanoacrylate (“glue”) injection, since EVL or EVS of mucosal erosion (Fig. 12-19). Dieulafoy’s lesion is seen
most commonly on the lesser curvature of the proxi-
mal stomach, causes impressive arterial hemorrhage, and
may be difficult to diagnose; it is often recognized only
after repeated endoscopy for recurrent bleeding. Endo-
scopic therapy, such as thermal coagulation, is typically
effective for control of bleeding and ablation of the
underlying vessel once the lesion has been identified.
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 asso-
ciated with retching or vomiting (Fig. 12-20). When
the tear disrupts a submucosal arteriole, brisk hemor-
Figure 12-18 rhage may result. Endoscopy is the best method of
Gastric fundic varices. diagnosis, and an actively bleeding tear can be treated
98 enteroscopy with endoscopic therapy, pharmacologic
treatment with octreotide or estrogen/progesterone ther-
apy, or intraoperative enteroscopy.
Colonic diverticula
Diverticula form where nutrient arteries penetrate the
muscular wall of the colon en route to the colonic
mucosa (Fig. 12-22). The artery found in the base of
SECTION II
Vascular ectasias
Vascular ectasias are flat mucosal vascular anomalies that
are best diagnosed by endoscopy. They usually cause
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 (GAVE) or “watermelon
stomach”] (Fig. 12-21). Cecal vascular ectasias (senile
lesions), GAVE, and radiation-induced rectal ectasias
are often responsive to local endoscopic ablative ther-
apy, such as argon plasma coagulation. Patients with
diffuse small-bowel vascular ectasias (associated with
chronic renal failure and with hereditary hemorrhagic
telangiectasia) may continue to bleed despite endo-
scopic treatment of easily accessible lesions by conven- Figure 12-22
tional endoscopy. These patients may benefit from deep Colonic diverticula.
A B C
Figure 12-21
Gastrointestinal vascular ectasias. A. Gastric antral vas vascular ectasias. C. Radiation-induced vascular ectasias of
cular ectasia (“watermelon stomach”) characterized by the rectum in a patient previously treated for prostate cancer.
stripes of prominent flat or raised vascular ectasias. B. Cecal
Gastrointestinal Obstruction 99
and Pseudoobstruction
Endoscopy is useful for evaluation and treatment of
some forms of gastrointestinal obstruction. An impor-
tant exception is small bowel obstruction due to surgical
adhesions, which is generally not diagnosed or treated
endoscopically. Esophageal, gastroduodenal, and colonic
obstruction or pseudoobstruction can all be diagnosed
and often managed endoscopically.
CHAPTER 12
A C
Gastrointestinal Endoscopy
untreated, the patient may develop esophageal ulceration,
ischemia, and perforation. Patients with persistent esopha-
geal obstruction often have hypersalivation and are usually
unable to swallow water; endoscopy is generally the best
B D
initial test in such patients, since endoscopic removal of the
obstructing material is usually possible, and the presence Figure 12-24
of an underlying esophageal pathology can often be deter- Biliary and duodenal self-expanding metal stents (SEMS)
mined. Radiographs of the chest and neck should be con- for obstruction caused by pancreatic cancer. A. Endo
sidered before endoscopy in patients with fever, obstruction scopic retrograde cholangiopancreatography (ERCP) dem
for ≥24 h, or ingestion of a sharp object such as a fishbone. onstrates a distal bile duct stricture (arrow). B. A biliary
Radiographic contrast studies interfere with subsequent SEMS is placed. C. Contrast injection demonstrates a duo
endoscopy and are not advisable in most patients with a denal stricture (arrow). D. Biliary and duodenal SEMS in
clinical picture of esophageal obstruction. Occasionally, sub- place.
lingual nifedipine or nitrates, or intravenous glucagon, may
resolve an esophageal food impaction, but in most patients peptic ulceration with stenosis of the pylorus. Patients
an underlying web, ring, or stricture is present and endo- vomit partially digested food many hours after eating.
scopic removal of the obstructing food bolus is necessary. Gastric decompression with a nasogastric tube and sub-
sequent lavage for removal of retained material is the
Gastric outlet obstruction first step in treatment. The diagnosis can then be con-
Obstruction of the gastric outlet is commonly caused by firmed with a saline load test, if desired. Endoscopy is
gastric, duodenal, or pancreatic malignancy, or chronic useful for diagnosis and treatment. Patients with benign
pyloric stenosis may be treated with endoscopic balloon
dilatation of the pylorus, and a course of endoscopic
dilatation results in long-term relief of symptoms in
about 50% of patients. Malignant gastric outlet obstruc-
tion can be relieved with endoscopically placed expand-
able stents (Fig. 12-24) in patients with inoperable
malignancy.
A B
Figure 12-26
Acute colonic pseudoobstruction. A. Acute colonic dilatation placement of decompression tube with marked improvement in
occurring in a patient soon after knee surgery. B. Colonoscopic colonic dilatation.
101
CHAPTER 12
Gastrointestinal Endoscopy
B C
Figure 12-27
Obstructing colonic carcinoma. A. Colonic adenocarci stent. C. Radiograph of expanded stent across the obstruct
noma causing marked luminal narrowing of the descending ing tumor with a residual waist (arrow). (Image A courtesy of
colon. B. Endoscopic placement of a self-expanding metal Dr. Glenn Alexander; with permission.)
persistent bile duct stone is unlikely (as in a patient with Abdominal ultrasound is often performed to assess for
gallstone pancreatitis), ERCP may be supplanted by less gallbladder stones and bile duct dilation. However,
invasive imaging techniques, such as EUS or MRCP. the bile duct may not be dilated early in the course of
acute biliary obstruction. Medical management usu-
Ascending cholangitis ally improves the patient’s clinical status, providing a
window of approximately 24 h during which bili-
Charcot’s triad of jaundice, abdominal pain, and fever is ary drainage should be established, typically by ERCP.
present in about 70% of patients with ascending cholan- Undue delay can result in recrudescence of overt sepsis
gitis and biliary sepsis. These patients are managed ini- and increased morbidity and mortality rates. In addition
tially with fluid resuscitation and intravenous antibiotics. to Charcot’s triad, the additional presence of shock and
A B C
Figure 12-28
Methods of bile duct imaging. Arrows mark bile duct (EUS). B. Magnetic resonance cholangiopancreatography
stones. Arrowheads indicate the common bile duct, and the (MRCP). C. Helical computed tomography (CT).
asterisk marks the portal vein. A. Endoscopic ultrasound
102 confusion (Reynolds’s pentad) is associated with high
Elective Endoscopy
mortality rate and should prompt an urgent intervention
to restore biliary drainage. Dyspepsia
Gallstone pancreatitis Dyspepsia is a chronic or recurrent burning discomfort
or pain in the upper abdomen that may be caused by
Gallstones may cause acute pancreatitis as they pass diverse processes such as gastroesophageal reflux, peptic
through the ampulla of Vater. The occurrence of gallstone ulcer disease, and “nonulcer dyspepsia,” a heterogeneous
pancreatitis usually implies passage of a stone into the duo- category that includes disorders of motility, sensation,
denum, and only about 20% of patients harbor a persistent and somatization. Gastric and esophageal malignan-
SECTION II
stone in the ampulla or the common bile duct. Retained cies are less common causes of dyspepsia. Careful
stones are more common in patients with jaundice, rising history-taking allows accurate differential diagnosis of
serum liver tests following hospitalization, severe pancre- dyspepsia in only about half of patients. In the remain-
atitis, or superimposed ascending cholangitis. der, endoscopy can be a useful diagnostic tool, espe-
Urgent ERCP decreases the morbidity rate of gall- cially in patients whose symptoms are not resolved by
stone pancreatitis in a subset of patients with retained an empirical trial of symptomatic treatment. Endoscopy
Evaluation of the Patient with Alimentary Tract Syndromes
bile duct stones. It is unclear whether the benefit of should be performed at the outset in patients with dys-
ERCP is mainly attributable to treatment and preven- pepsia and alarm features, such as weight loss or iron-
tion of ascending cholangitis or to relief of pancreatic deficiency anemia.
duct obstruction. ERCP is warranted early in the course
of gallstone pancreatitis if ascending cholangitis is sus-
pected, especially in a jaundiced patient. Urgent ERCP
also appears to benefit patients predicted to have severe
Gastroesophageal Reflux
pancreatitis using a clinical index of severity such as the
Disease (GERD)
Glasgow or Ranson score. Since the benefit of ERCP When classic symptoms of gastroesophageal reflux are
is limited to patients with a retained bile duct stone, a present, such as water brash and substernal heartburn,
strategy of initial MRCP or EUS for diagnosis decreases presumptive diagnosis and empirical treatment are
the utilization of ERCP in gallstone pancreatitis and often sufficient. Endoscopy is a sensitive test for diag-
improves clinical outcomes by limiting the occurrence nosis of esophagitis (Fig. 12-29), but will miss noner-
of ERCP-related complications. osive reflux disease (NERD) since some patients have
A B
C D
Figure 12-29
Causes of esophagitis. A. Severe reflux esophagitis with shallow ulcerations. D. Candida esophagitis with white
mucosal ulceration and friability. B. Cytomegalovirus esoph plaques adherent to the esophageal mucosa.
agitis. C. Herpes simplex virus esophagitis with target-type
symptomatic reflux without esophagitis. The most sen- 103
sitive test for diagnosis of GERD is 24-h ambulatory
pH monitoring. Endoscopy is indicated in patients with
reflux symptoms refractory to antisecretory therapy; in
those with alarm symptoms such as dysphagia, weight
loss, or gastrointestinal bleeding; and in those with
recurrent dyspepsia after treatment that is not clearly
due to reflux on clinical grounds alone. Endoscopy
may be considered in patients with long-standing (≥10
CHAPTER 12
years) GERD with frequent symptoms, as they have a
sixfold increased risk of harboring Barrett’s esophagus
compared to a patient with <1 year of reflux symp-
toms. Patients with Barrett’s esophagus (Fig. 12-3)
generally undergo a surveillance program of periodic
endoscopy with biopsies to detect dysplasia or early
carcinoma.
Gastrointestinal Endoscopy
Barrett’s esophagus
Barrett’s esophagus is specialized columnar metaplasia Figure 12-30
that replaces the normal squamous mucosa of the dis- Peptic esophageal stricture associated with ulceration
tal esophagus in some persons with GERD. Barrett’s and scarring of the distal esophagus.
epithelium is a major risk factor for adenocarcinoma of
the esophagus and is readily detected endoscopically,
due to proximal displacement of the squamocolum- Nonulcer Dyspepsia
nar junction (Fig. 12-3). A screening EGD for Bar-
rett’s esophagus may be considered in patients with a Nonulcer dyspepsia may be associated with bloating
chronic history (>10 year) of GERD symptoms. Endo- and, unlike peptic ulcer, tends not to remit and recur.
scopic biopsy is the gold standard for confirmation of Most patients describe marginal relief on acid-reducing,
Barrett’s esophagus, and for dysplasia or cancer aris- prokinetic, or anti-Helicobacter therapy, and are referred
ing in Barrett’s mucosa. Endoscopic therapies such as for endoscopy to exclude a refractory ulcer and assess
endoscopic mucosal resection (EMR), endoscopic sub- for other causes. Although endoscopy is useful for
mucosal dissection (ESD), photodynamic therapy (PDT), excluding other diagnoses, its impact on the treatment
and radiofrequency ablation (RFA) are effective modal- of patients with nonulcer dyspepsia is limited.
ities for treatment of high-grade dysplasia and intramu-
cosal cancer in Barrett’s esophagus. Dysphagia
About 50% of patients presenting with difficulty swal-
lowing have a mechanical obstruction; the remain-
Peptic Ulcer
der has a motility disorder, such as achalasia or diffuse
Peptic ulcer classically causes epigastric gnawing or esophageal spasm. Careful history-taking often points
burning, often occurring nocturnally and promptly to a presumptive diagnosis and leads to the appro-
relieved by food or antacids. Although endoscopy is the priate use of diagnostic tests. Esophageal strictures
most sensitive diagnostic test for peptic ulcer, it is not (Fig. 12-30) typically cause progressive dysphagia,
a cost-effective strategy in young patients with ulcer- first for solids, then for liquids; motility disorders often
like dyspeptic symptoms unless endoscopy is available at cause intermittent dysphagia for both solids and liquids.
low cost. Patients with suspected peptic ulcer should be Some underlying disorders have characteristic historic
evaluated for Helicobacter pylori infection. Serology (past features: Schatzki’s ring (Fig. 12-31) causes episodic
or present infection), urea breath testing (current infec- dysphagia for solids, typically at the beginning of a
tion), and stool tests are noninvasive and less costly than meal; oropharyngeal motor disorders typically present
endoscopy with biopsy. Patients with alarm symptoms with difficulty initiating deglutition (transfer dysphagia)
and those with persistent symptoms despite treatment and nasal reflux or coughing with swallowing; and
should undergo endoscopy to exclude gastric malig- achalasia may cause nocturnal regurgitation of undi-
nancy and other etiologies. gested food.
104 perforation in a patient with stenosis of the cervical
esophagus or a Zenker’s diverticulum, but gentle pas-
sage of an endoscope 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 esophageal
motility disorder is suspected, esophageal radiography
and/or a video-swallow study are the best initial diag-
nostic tests. The oropharyngeal swallowing mechanism,
esophageal peristalsis, and the lower esophageal sphincter
SECTION II
in the Stool
Iron-deficiency anemia may be attributed to poor
Figure 12-31 iron absorption (as in celiac sprue) or, more com-
Schatzki’s ring at the gastroesophageal junction. monly, chronic blood loss. Intestinal bleeding should
be strongly suspected in men and postmenopausal
women with iron-deficiency anemia, and colonos-
When mechanical obstruction is suspected, endos- copy is indicated in such patients, even in the absence
copy is a useful initial diagnostic test, since it permits of detectable occult blood in the stool. Approxi-
immediate biopsy and/or dilatation of strictures, masses, mately 30% will have large colonic polyps, 10% will
or rings. The presence of linear furrows and mul- have colorectal cancer, and a few additional patients
tiple corrugated rings throughout a narrowed esopha- will have colonic vascular lesions. When a convincing
gus (feline esophagus) should raise suspicion for eosino- source of blood loss is not found in the colon, upper
philic esophagitis, an increasingly recognized cause for gastrointestinal endoscopy should be considered; if no
recurrent dysphagia and food impaction (Fig. 12-32). lesion is found, duodenal biopsies should be obtained
Blind or forceful passage of an endoscope may lead to to exclude sprue (Fig. 12-33). Small bowel evalua-
tion with capsule endoscopy or deep enteroscopy
may be appropriate if both EGD and colonoscopy are
unrevealing (Fig. 12-34).
Tests for occult blood in the stool detect hemo-
globin or the heme moiety and are most sensitive for
Figure 12-32
Eosinophilic esophagitis with multiple circular rings of
the esophagus creating a corrugated appearance, and
an impacted grape at the narrowed esophagogastric
junction. The diagnosis requires biopsy with histologic find Figure 12-33
ing of >15–20 eosinophils/high-power field. Scalloped duodenal folds in a patient with celiac sprue.
Colorectal Cancer Screening 105
The majority of colon cancers develop from pre
existing colonic adenomas, and colorectal cancer can
be largely prevented by the detection and removal of
adenomatous polyps. 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, fam-
ily members with adenomatous polyps or cancer, or
CHAPTER 12
certain familial cancer syndromes (Fig. 12-36) are
Figure 12-34 at increased risk for colorectal cancer. An individual
Capsule endoscopy images of a mildly scalloped jeju- without these factors is generally considered at average
nal fold (left) and an ileal tumor (right) in a patient with risk.
celiac sprue. ( Images courtesy of Dr. Elizabeth Rajan; with Screening strategies are summarized in Table 12-2.
permission.) While stool tests for occult blood have been shown to
Gastrointestinal Endoscopy
decrease mortality rate from colorectal cancer, they do
not detect some cancers and many polyps, and direct
colonic blood loss, although they will also detect larger visualization of the colon is a more effective screening
amounts of upper gastrointestinal bleeding. Patients
over age 50 with occult blood in normal-appear-
ing stool should undergo colonoscopy to diagnose or
exclude colorectal neoplasia. The diagnostic yield is
lower than in iron-deficiency anemia. Whether upper
endoscopy is also indicated depends on the patient’s
symptoms.
The small intestine may be the source of chronic
intestinal bleeding, especially if colonoscopy and
upper endoscopy are not diagnostic. The utility of
small bowel evaluation varies with the clinical setting
and is most important in patients in whom bleeding
causes chronic or recurrent anemia. In contrast to the
low diagnostic yield of small bowel radiography, posi-
tive findings on capsule endoscopy are seen in 50–70%
of patients with suspected small-intestinal bleeding.
The most common finding is mucosal vascular ecta-
sias. Deep enteroscopy may follow capsule endoscopy
for biopsy of lesions or to provide specific therapy, Figure 12-36
such as argon plasma coagulation of vascular ectasias Innumerable colon polyps of various sizes in a patient
(Fig. 12-35). with familial adenomatous polyposis syndrome.
A B
Figure 12-35
A. Mid-jejunal vascular ectasia identified by double-balloon endoscopy. B. Ablation of vascular ectasia with argon plasma
coagulation.
106 Table 12-2
Colorectal Cancer Screening Strategies
Choices/Recommendations Comments
Average-Risk Patients
Asymptomatic individuals ≥50 years of Colonoscopy every 10 yearsa Preferred cancer prevention strategy
age (≥45 years of age for Annual fecal immunochemical test (FIT) Cancer detection strategy;
African Americans) for occult bleeding, fecal DNA testing fails to detect many polyps
every 3 years and some cancers
CT colonography every 5 years Evolving technology (see text)
SECTION II
1 or 2 small (<1 cm) adenomas with Repeat colonoscopy in 5 years Assuming complete polyp resection
low-grade dysplasia
3 to 9 adenomas, or any adenoma ≥1 cm Repeat colonoscopy in 3 years; Assuming complete polyp resection
or containing high-grade dysplasia or subsequent colonoscopy based on
villus features findings
≥10 adenomas Colonoscopy in <3 years based on Consider evaluation for FAP or HNPCC;
clinical judgment see recommendations below
Piecemeal removal of a sessile polyp Exam in 2 to 6 months to verify
complete removal
Small (<1 cm) hyperplastic polyps of Colonoscopy in 10 years
sigmoid and rectum
>2 serrated polyps, or any serrated or Repeat colonoscopy in 3 years
hyperplastic polyp ≥1 cm
Incompletely removed serrated Exam in 2 to 6 months to verify
polyp ≥1 cm complete removal
Colon cancer Evaluate entire colon around the time of
resection, then repeat colonoscopy in
3 years
Inflammatory Bowel Disease
Long-standing (>8 years) ulcerative Colonoscopy with biopsies every 1 to 3
colitis or Crohn’s colitis, or left-sided years
ulcerative colitis of >15 years’ duration
Family History of Polyps or Colorectal Cancer
First-degree relatives with only small Same as average risk
tubular adenomas
Single first-degree relative with CRC or Same as average risk
advanced adenoma at age ≥60 years
Single first-degree relative with CRC or Colonoscopy every 5 years beginning
advanced adenoma at age <60 years, at age 40 years or 10 years younger
OR two first-degree relatives with than age at diagnosis of the youngest
CRC or advanced adenomas at any age affected relative
FAP Sigmoidoscopy or colonoscopy annually, Consider genetic counseling and
beginning at age 10–12 years testing
HNPCC Colonoscopy every 2 years beginning Consider histologic evaluation for
at age 20–25 years until age 40, then microsatellite instability in tumor
annually thereafter specimens of patients who meet
Bethesda criteria; consider genetic
counseling and testing
a
Assumes good colonic preparation and complete exam to cecum.
Abbreviations: CRC, colorectal cancer; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer.
Source: Adapted from SJ Winawer et al: Gastroenterology 130:1872, 2006 and B Levin et al: CA Cancer J Clin 58:130, 2008.
strategy. Either sigmoidoscopy or colonoscopy may be Diarrhea 107
used for cancer screening in asymptomatic average-risk
individuals. The use of sigmoidoscopy was based on the Most cases of diarrhea are acute, self-limited, and due
historical finding that the majority of colorectal cancers to infections or medication. Chronic diarrhea (lasting
occurred in the rectum and left colon, and that patients >6 weeks) is more often due to a primary inflamma-
with right-sided colon cancers had left-sided polyps. tory, malabsorptive, or motility disorder; is less likely
Over the past several decades, however, the distribution to resolve spontaneously; and generally requires diag-
of colon cancers has changed, with proportionally fewer nostic evaluation. Patients with chronic diarrhea or
rectal and left-sided cancers than in the past. Large severe, unexplained acute diarrhea often undergo
endoscopy if stool tests for pathogens are unrevealing.
CHAPTER 12
studies of colonoscopy for screening of average-risk
individuals show that cancers are roughly equally dis- The choice of endoscopic testing depends on the clini-
tributed between left and right colon and half of cal setting.
patients with right-sided lesions have no polyps in the Patients with colonic symptoms and findings such
left colon. Visualization of the entire colon thus appears as bloody diarrhea, tenesmus, fever, or leukocytes in
to be the optimal strategy for colorectal cancer screen- stool generally undergo sigmoidoscopy or colonos-
ing and prevention. copy to assess for colitis (Fig. 12-4). Sigmoidoscopy is
Gastrointestinal Endoscopy
Virtual colonoscopy (VC) is a radiologic technique an appropriate initial test in most patients. Conversely,
that images the colon with CT following rectal insuf- patients with symptoms and findings suggesting small-
flation of the colonic lumen. Computer render- bowel disease, such as large-volume watery stools,
ing of CT images generates an electronic display of substantial weight loss, and malabsorption of iron, cal-
a virtual “flight” along the colonic lumen, simulating cium, or fat may undergo upper endoscopy with duo-
colonoscopy (Fig. 12-37). Comparative studies of denal aspirates for assessment of bacterial overgrowth
virtual and routine colonoscopy have shown conflict- and biopsies for assessment of mucosal diseases, such as
ing results, but technical refinements have improved celiac sprue.
the performance characteristics of VC. The use of Many patients with chronic diarrhea do not fit either
VC for colorectal cancer screening may become more of these patterns. In the setting of a long-standing his-
widespread in the future, particularly at institutions tory of alternating constipation and diarrhea dating to
with demonstrated skill with this technique. Find- early adulthood, without findings such as blood in the
ings detected during virtual colonoscopy often require stool or anemia, a diagnosis of irritable bowel syndrome
subsequent conventional colonoscopy for confirma- may be made without direct visualization of the bowel.
tion and treatment. Steatorrhea and upper abdominal pain may prompt
evaluation of the pancreas rather than the gut. Patients
whose chronic diarrhea is not easily categorized often
undergo initial colonoscopy to examine the entire colon
and terminal ileum for inflammatory or neoplastic
disease (Fig. 12-38).
Figure 12-37
Virtual colonoscopy image of a colon polyp (arrow). Figure 12-38
(Image courtesy of Dr. Jeff Fidler; with permission.) Ulcerated ileal carcinoid tumor.
108 causing contraction of the gallbladder. Bile is suctioned
from the duodenum as it drains from the papilla, and
the darkest fraction is examined for cholesterol crystals
or bilirubinate granules. The combination of EUS of
the gallbladder and bile microscopy is probably the most
sensitive means of diagnosing microlithiasis.
Previously undetected chronic pancreatitis, pan-
creatic malignancy, or pancreas divisum may be diag-
nosed by either ERCP or EUS. Sphincter of Oddi
dysfunction or stenosis is a potential cause for pancre-
SECTION II
Cancer Staging
Minor Hematochezia Local staging of esophageal, gastric, pancreatic, bile
duct, and rectal cancers can be obtained with EUS
Bright red blood passed with or on formed brown (Fig. 12-14). EUS with fine-needle aspiration (Fig. 12-15)
stool usually has a rectal, anal, or distal sigmoid source currently provides the most accurate preoperative assess-
(Fig. 12-39). Patients with even trivial amounts of ment of local tumor and nodal staging, but it does not
hematochezia should be investigated with flexible sig- detect most distant metastases. Details of the local tumor
moidoscopy and anoscopy to exclude polyps or cancers stage can guide treatment decisions including resectabil-
in the distal colon. Patients reporting red blood on the ity and need for neoadjuvant therapy. EUS with trans-
toilet tissue only, without blood in the toilet or on the esophageal needle biopsy may also be used to assess the
stool, are generally bleeding from a lesion in the anal presence of non-small cell lung cancer in mediastinal
canal. Careful external inspection, digital examination, nodes.
and proctoscopy with anoscopy are sufficient for diag-
nosis in most cases.
Open-Access Endoscopy
Pancreatitis Direct scheduling of endoscopic procedures by primary
About 20% of patients with pancreatitis have no identi- care physicians without preceding gastroenterology
fied cause after routine clinical investigation (including a consultation, or open-access endoscopy, is common. When
review of medication and alcohol use, measurement of the indications for endoscopy are clear-cut and appro-
serum triglyceride and calcium levels, abdominal ultra- priate, the procedural risks are low, and the patient
sonography, and CT). Endoscopic assessment leads to a understands what to expect, open-access endoscopy
specific diagnosis in the majority of such patients, often streamlines patient care and decreases costs.
altering clinical management. Endoscopic investigation Patients referred for open-access endoscopy should
is particularly appropriate if the patient has had more have a recent history, physical examination, and medi-
than one episode of pancreatitis. cation review. A copy of such an evaluation should
Microlithiasis, or the presence of microscopic crys- be available when the patient comes to the endoscopy
tals in bile, is a leading cause of previously unexplained suite. Patients with unstable cardiovascular or respi-
acute pancreatitis and is sometimes seen during abdomi- ratory conditions should not be referred directly for
nal ultrasonography as layering sludge or flecks of float- open-access endoscopy. Patients with particular con-
ing, echogenic material in the gallbladder. Gallbladder ditions and undergoing certain procedures should be
bile can be obtained for microscopic analysis by admin- prescribed prophylactic antibiotics prior to endoscopy
istering a cholecystokinin analogue during endoscopy, (Table 12-1). In addition, patients taking anticoagulants
and/or antiplatelet drugs may require adjustment of satiety. Open-access colonoscopy is often requested in 109
these agents before endoscopy based on the procedure men or postmenopausal women with iron-deficiency
risk for bleeding and condition risk for a thrombo anemia, in patients over age 50 with occult blood in
embolic event (Figs. 12-40 and 12-41). Common the stool, in patients with a previous history of colorec-
indications for open-access EGD include dyspepsia tal adenomatous polyps or cancer, and for colorectal
resistant to a trial of appropriate therapy; dysphagia; gas- cancer screening. Flexible sigmoidoscopy is commonly
trointestinal bleeding; and persistent anorexia or early performed as an open-access procedure.
CHAPTER 12
MANAGEMENT OF ANTITHROMBOTIC AGENTS FOR ELECTIVE ENDOSCOPIC PROCEDURES
Gastrointestinal Endoscopy
Low High Low High Low High
bleeding risk bleeding risk bleeding risk bleeding risk bleeding risk bleeding risk
Consider
Discontinue
discontinuing
7–10 days prior
7–10 days prior
Figure 12-40
Management of antithrombotic agents for elective endo- active congestive heart failure, left ventricular ejection fraction
scopic procedures. Higher-risk procedures for bleeding: <35%, a history of a thromboembolic event, hypertension,
Polypectomy, biliary or pancreatic sphincterotomy, thera diabetes mellitus, or age >75 years; mechanical valve in the
peutic balloon-assisted enteroscopy, PEG placement, pneu mitral position; mechanical valve in any position and previous
matic or bougie dilatation, treatment of varices, endoscopic thromboembolic event; recently (<1 year) placed coronary
hemostasis, tumor ablation by any technique, cystogastros stent; acute coronary syndrome; non-stented percutane
tomy, EUS with FNA. Low-risk procedures for bleeding: Diag ous coronary intervention after myocardial infarction. Low-
nostic (EGD, colonoscopy, flexible sigmoidoscopy) including risk conditions for thromboembolic event: Uncomplicated or
biopsy, ERCP without sphincterotomy, EUS without FNA, paroxysmal nonvalvular atrial fibrillation; bioprosthetic valve;
enteroscopy and diagnostic balloon-assisted enteroscopy, cap mechanical valve in the aortic position; deep vein thrombo
sule endoscopy, enteral stent deployment (without dilatation). sis. (Adapted from MA Anderson et al: Gastrointest Endosc
Higher-risk conditions for thromboembolic event: Atrial fibrilla 70:1060, 2009; with permission from Elsevier.)
tion associated with valvular heart disease, prosthetic valves,
110 MANAGEMENT OF ANTITHROMBOTIC AGENTS FOR URGENT ENDOSCOPIC PROCEDURES
risk, consider
Low High Low High bridge therapy
thromboembolic thromboembolic thromboembolic thromboembolic
risk risk risk risk
Consider Consider
Continue Discontinue
continuing discontinuing
Evaluation of the Patient with Alimentary Tract Syndromes
If unable to delay procedure for 7–10 days, hold as many as possible up to 7–10 days
In patients on dual antiplatelet therapy or monotherapy with a thienopyridine, consider
continuing aspirin (dual therapy patients) or starting aspirin (thienopyridine monotherapy
patients) in the periendoscopic period
Figure 12-41
Management of antithrombotic agents for urgent endo- isease, prosthetic valves, active congestive heart failure,
d
scopic procedures. Higher-risk procedures for bleeding: left ventricular ejection fraction <35%, a history of a throm
Polypectomy, biliary or pancreatic sphincterotomy, thera boembolic event, hypertension, diabetes mellitus, or age
peutic balloon-assisted entero-scopy, PEG placement, >75 years; mechanical valve in the mitral position; mechani
pneumatic or bougie dilatation, treatment of varices, endo cal valve in any position and previous thromboembolic event;
scopic hemostasis, tumor ablation by any technique, cys recently (>1 year) placed coronary stent; acute coronary
togastrostomy, EUS with FNA. Low-risk procedures for syndrome; non-stented percutaneous coronary intervention
bleeding: Diagnostic (EGD, colonoscopy, flexible sigmoidos after myocardial infarction. Low-risk conditions for thrombo
copy) including biopsy, ERCP without sphincterotomy, EUS embolic event: Uncomplicated or paroxysmal nonvalvular
without FNA, enteroscopy and diagnostic balloon-assisted atrial fibrillation; bioprosthetic valve; mechanical valve in the
enteroscopy, capsule endoscopy, enteral stent deployment aortic position, deep vein thrombosis. (Adapted from MA
(without dilatation). Higher-risk conditions for thromboem Anderson et al: Gastrointest Endosc 70:1060, 2009; with per-
bolic event: Atrail fibrillation associated with valvular heart mission from Elsevier.)
When patients are referred for open-access colonos- the quality of colonic preparation. Sodium phosphate
copy, the primary care provider may need to choose a purgatives may cause fluid and electrolyte abnormalities
colonic preparation. Commonly used oral preparations and renal toxicity, especially in patients with renal fail-
include polyethylene glycol lavage solution, with or ure or congestive heart failure and those over 70 years
without citric acid. A “split-dose” regimen improves of age.
SECTION III
Disorders of the
Alimentary Tract
chapter 13
CHAPTER 13
Globus sensation, alternatively labeled “globus hystericus,” of esophageal function and morphology that may be
is the perception of a lump or fullness in the throat that is undetected on endoscopy. Hypopharyngeal pathology
felt irrespective of swallowing. Although such patients are and disorders of the cricopharyngeal muscle are better
frequently referred for an evaluation of dysphagia, glo- appreciated on radiographic examination, particularly
bus sensation is often relieved by the act of swallowing. As with videofluoroscopic recording. The major short-
implied by its alternative name (globus hystericus), globus coming of barium radiography is that it rarely obviates
Figure 13-1
High-resolution esophageal pressure topography (right) LES, lower esophageal sphincter; E, esophageal body;
SECTION III
and conventional manometry (left) of a normal swallow. UES, upper esophageal sphincter.
Eso tibule
mon causes of intermittent food impaction, also known
ves
pha
as “steakhouse syndrome” as meat is a typical instigator.
gea
Phrenic Symptomatic rings are easily treated by dilatation.
l
ampulla
Slid ernia
A ring Web-like constrictions higher in the esophagus can
ing
h
be of congenital or inflammatory origin. Asymptomatic
hiat
cervical esophageal webs are demonstrated in about 10%
al
of people and typically originate along the anterior aspect
of the esophagus. When circumferential, they can cause
B ring intermittent dysphagia to solids similar to Schatzki’s rings
squamo-columnar
and are similarly treated with dilatation. The combi-
junction
nation of symptomatic proximal esophageal webs and
iron-deficiency anemia in middle-aged women consti-
Rugal folds tutes Plummer-Vinson syndrome.
Diaphragmatic
traversing hiatus
impression
CHAPTER 13
Diverticula
Esophageal diverticula are categorized by location with
the most common being epiphrenic, hypopharyngeal
(Zenker’s), and mid esophageal. Epiphrenic and Zenker’s
Figure 13-2 diverticula are false diverticula involving herniation of
Radiographic anatomy of the gastroesophageal junction. the mucosa and submucosa through the muscular layer
A B C
Figure 13-3
Examples of small (left) and large (middle, right) Zenker’s hypopharynx. Smaller diverticula are evident only during the
diverticulum arising from Killian’s triangle in the distal swallow, whereas larger ones retain food and fluid.
116 marsupialization procedure in which an endoscopic sta- Tumors
pling device is used to divide the cricopharyngeus.
Epiphrenic diverticula are usually associated with Esophageal cancer occurs in about 4.5:100,000 people
achalasia or a distal esophageal stricture. Mid-esophageal in the United States with the associated mortality being
diverticula may be caused by traction from adjacent only slightly less at 4.4:100,000. It is about 10 times less
inflammation (classically tuberculosis) in which case common than colorectal cancer but kills about one-
they are true diverticula involving all layers of the quarter as many patients. These statistics emphasize both
esophageal wall, or by pulsion associated with esopha- the rarity and lethality of esophageal cancer. One nota-
geal motor disorders. Mid-esophageal and epiphrenic ble trend is the shift of dominant esophageal cancer type
diverticula are usually asymptomatic until they enlarge from squamous cell to adenocarcinoma, strongly linked
sufficiently to retain food and cause dysphagia and to reflux disease and Barrett’s metaplasia. Other distinc-
regurgitation. Symptoms attributable to the diverticula tions between cell types are the predilection for adeno-
tend to correlate more with the underlying esophageal carcinoma to affect white males in the distal esophagus
disorder than the size of the diverticula. Large diver- and squamous cell to affect black males in the more
ticula can be removed surgically, usually in conjunc- proximal esophagus with the added risk factors of smok-
tion with a myotomy if the underlying cause is achala- ing, alcohol consumption, caustic injury, and human
sia. Diffuse intramural esophageal diverticulosis is a rare papilloma virus infection (Chap. 49).
The typical presentation of esophageal cancer is of
SECTION III
Congenital Anomalies
The most common congenital esophageal anomaly is
esophageal atresia, occurring in about 1 in 5000 live
births. Atresia can occur in several permutations, the
common denominator being developmental failure
of fusion between the proximal and distal esophagus
associated with a tracheoesophageal fistula, most com-
monly with the distal segment excluded. Alternatively,
there can be an H-type configuration in which esoph-
ageal fusion has occurred, but with a tracheoesopha-
geal fistula. Esophageal atresia is usually recognized and
corrected surgically within the first few days of life.
Later life complications include dysphagia from anasto-
Figure 13-4 motic strictures or absent peristalsis and reflux, which
Intramural esophageal pseudodiverticulosis associated can be severe. Less common developmental anoma-
with chronic obstruction. Invaginations of contrast into the lies include congenital esophageal stenosis, webs, and
esophageal wall outline deep esophageal glands. duplications.
Dysphagia can also result from congenital abnor- with advanced achalasia are at risk for bronchitis, pneu- 117
malities that cause extrinsic compression of the esopha- monia, or lung abscess from chronic regurgitation and
gus. In dysphagia lusoria, the esophagus is compressed aspiration. Chest pain is frequent early in the course
by an aberrant right subclavian artery arising from the of achalasia, thought to result from esophageal spasm.
descending aorta and passing behind the esophagus. Patients describe a squeezing, pressure-like retrosternal
Alternatively vascular rings may surround and constrict pain, sometimes radiating to the neck, arms, jaw, and
the esophagus. back. Paradoxically, some patients complain of heart-
Heterotopic gastric mucosa, also known as an esoph- burn that may be a chest pain equivalent. Treatment of
ageal inlet patch, is a focus of gastric type epithelium in achalasia is less effective in relieving chest pain than it is
the proximal cervical esophagus; the estimated preva- in relieving dysphagia or regurgitation.
lence is 4.5%. The inlet patch is thought to result from The differential diagnosis of achalasia includes DES,
incomplete replacement of embryonic columnar epi- Chagas’ disease, and pseudoachalasia. Chagas’ disease
thelium with squamous epithelium. The majority of is endemic in areas of central Brazil, Venezuela, and
patches are asymptomatic, but acid production can northern Argentina, spread by the bite of the reduvid
occur as most contain fundic type gastric epithelium (kissing) bug that transmits the protozoan, Trypanosoma
with parietal cells. cruzi. The chronic phase of the disease develops years
after infection and results from destruction of auto-
CHAPTER 13
nomic ganglion cells throughout the body, includ-
ing the heart, gut, urinary tract, and respiratory tract.
Esophageal MOTILITY Disorders Tumor infiltration, most commonly seen with car-
Esophageal motility disorders are diseases attributable to cinoma in the gastric fundus or distal esophagus can
esophageal neuromuscular dysfunction commonly associ- mimic idiopathic achalasia. The resultant “pseudoacha-
ated with dysphagia, chest pain, or heartburn. The major lasia” accounts for up to 5% of suspected cases and is
100 10
75
15
50 Cm
25 20
0 25
–10
30
mmHg
35 Stomach
0 1 2 3 4 5 6 7 8 9 10
Seconds
mmHg 0 5 10 15 20 25
tion because of their effects on blood pressure. Botu- Seconds
linum toxin, injected into the LES under endoscopic mmHg C. Spastic achalasia
100 0 Pharynx
guidance, inhibits acetylcholine release from nerve end- 90
ings and improves dysphagia in about 66% of cases for 80
5
at least 6 months. Sildenafil, or alternative phosphodies- 70 10
terase inhibitors, effectively decrease LES pressure, but 60
practicalities limit their clinical use in achalasia. 50
15
Cm
The only durable therapies for achalasia are pneu- 40 20
matic dilatation and Heller myotomy. Pneumatic dila- 30
25
tation, with a reported efficacy ranging from 32–98%, 20
15
is an endoscopic technique using a noncompliant, 10
5
30
0
cylindrical balloon dilator positioned across the LES 35 Stomach
–10
and inflated to a diameter of 3–4 cm. The major com- 0 10 20 30 40 50
plication is perforation with a reported incidence of Seconds
1–5%. The most common surgical procedure for acha- Figure 13-6
lasia is laparoscopic Heller myotomy, usually performed Three subtypes of achalasia: classic (A), with esophageal
in conjunction with an antireflux procedure (partial compression (B), and spastic achalasia (C) imaged with
fundoplication); good to excellent results are reported in pressure topography. All are characterized by impaired
62–100% of cases. Occasionally, patients with advanced lower esophageal sphincter (LES) relaxation and absent peri-
disease fail to respond to pneumatic dilatation or Heller stalsis. However, classic achalasia has minimal pressurization
myotomy. In such refractory cases, esophageal resec- of the esophageal body while substantial fluid pressurization
tion with gastric pull-up or interposition of a segment is observed in achalasia with esophageal compression and
of transverse colon may be the only option other than spastic esophageal contractions are observed with spastic
gastrostomy feeding. achalasia.
In untreated or inadequately treated achalasia, esoph-
ageal dilatation predisposes to stasis esophagitis. Pro-
Diffuse Esophageal Spasm (DES)
longed stasis esophagitis is the likely explanation for the
association between achalasia and esophageal squamous DES is manifested by episodes of dysphagia and chest
cell cancer. Tumors develop after years of achalasia, pain attributable to abnormal esophageal contractions
usually in the setting of a greatly dilated esophagus with with normal deglutitive LES relaxation. Beyond that,
the overall squamous cell cancer risk increased 17-fold there is little consensus. The pathophysiology and nat-
compared to controls. ural history of DES are ill defined. Radiographically,
of disorders being diagnosed as DES. In fact, high- 119
resolution manometry suggests that DES, when defined
in a restrictive fashion (Fig. 13-8), is actually much less
common than achalasia and suspected cases are often
incorrectly categorized achalasia.
Esophageal chest pain closely mimics angina pecto-
ris. Features suggesting esophageal pain include pain
that is nonexertional, prolonged, interrupts sleep, is
meal-related, is relieved with antacids, and is accompa-
nied by heartburn, dysphagia, or regurgitation. How-
ever, all of these features exhibit overlap with cardiac
pain, which still must be the primary consideration.
Furthermore, even within the spectrum of esophageal
diseases, both chest pain and dysphagia are also char-
acteristic of peptic or infectious esophagitis. Only after
these more common entities have been excluded by
evaluation and/or treatment should a diagnosis of DES
CHAPTER 13
Figure 13-7 be pursued.
Diffuse esophageal spasm. The characteristic “corkscrew” Although the defining criteria are currently disputed,
esophagus results from spastic contraction of the circular DES is diagnosed by manometry. Endoscopy is useful to
muscle in the esophageal wall; more precisely, this is actually identify alternative structural and inflammatory lesions
a helical array of muscle. These findings are also seen with that may cause chest pain. Radiographically, a “cork-
spastic achalasia. screw esophagus,” “rosary bead esophagus,” pseudodi-
mmHg
150
Spastic nutcracker Diffuse esophageal spasm
100
50
0 5 10 15 20
Time (sec) Non-propagated contraction
0
Propagated contraction
Figure 13-8
Esophageal pressure topography of the two major variants extraordinarily vigorous and repetitive contractions with normal
of esophageal spasm: spastic nutcracker (left) and diffuse peristaltic onset. Diffuse esophageal spasm is similar but primarily
esophageal spasm (right). Spastic nutcracker is defined by the defined by a rapid propagation at the onset of the contraction.
120 Nonspecific Manometric Findings troublesome symptoms or an array of potential esopha-
geal and extraesophageal manifestations. It is estimated
Manometric studies done to evaluate chest pain and/or that 15% of adults in the United States are affected by
dysphagia often report minor abnormalities (hyperten- GERD, although such estimates are based only on self-
sive or hypotensive peristalsis, hypertensive LES, etc.) reported chronic heartburn. With respect to the esopha-
that are insufficient to diagnose either achalasia or DES. gus, the spectrum of injury includes esophagitis, stricture,
These findings are of unclear significance. Reflux and Barrett’s esophagus, and adenocarcinoma (Fig. 13-9).
psychiatric diagnoses, particularly anxiety and depres- Of particular concern is the rising incidence of esopha-
sion, are common among such individuals. A lower geal adenocarcinoma, an epidemiologic trend that par-
visceral pain threshold and symptoms of irritable bowel allels the increasing incidence of GERD. There were
syndrome are noted in more than half of such patients. about 8000 incident cases of esophageal adenocarci-
Consequently, therapy for these individuals should noma in the United States in 2010 (half of all esopha-
either target the most common esophageal disorder, geal cancers); it is estimated that this disease burden has
GERD, or more global conditions such as depression or increased two- to sixfold in the last 20 years.
somatization neurosis that are found to be coexistent.
Pathophysiology
SECTION III
Figure 13-9
Endoscopic appearance of (A) peptic esophagitis, (D) adenocarcinoma developing within an area of Bar-
(B) a peptic stricture, (C) Barrett’s metaplasia, and rett’s esophagus.
mechanism of belching (transient LES relaxation), but Symptoms 121
esophagitis results from excessive reflux, often accom-
panied by impaired clearance of the refluxed gastric Heartburn and regurgitation are the typical symptoms
juice. Restricting reflux to that which is physiologi- of GERD. Somewhat less common are dysphagia and
cally intended depends on the anatomic and physiologic chest pain. In each case, multiple potential mecha-
integrity of the esophagogastric junction, a complex nisms for symptom genesis operate that extend beyond
sphincter comprised of both the LES and the surround- the basic concepts of mucosal erosion and activation of
ing crural diaphragm. Three dominant mechanisms afferent sensory nerves. Specifically, hypersensitivity and
of esophagogastric junction incompetence are recog- functional pain are increasingly recognized as confound-
nized: (1) transient LES relaxations (a vagovagal reflex ing factors. Nonetheless the dominant clinical strategy
in which LES relaxation is elicited by gastric distention), is of empirical treatment with acid inhibitors, reserving
(2) LES hypotension, or (3) anatomic distortion of the further evaluation for those who fail to respond. Impor-
esophagogastric junction inclusive of hiatus hernia. tant exceptions to this are patients with chest pain or
Of note, the third factor, esophagogastric junction persistent dysphagia, each of which may be indicative
anatomic disruption, is both significant unto itself and of more morbid conditions. With chest pain, cardiac
also because it interacts with the first two mechanisms. disease must be carefully considered. In the case of per-
Transient LES relaxations account for at least 90% of sistent dysphagia, chronic reflux can lead to the devel-
CHAPTER 13
reflux in normal subjects or GERD patients without opment of a peptic stricture or adenocarcinoma, each
hiatus hernia, but patients with hiatus hernia have a of which benefits from early detection and/or specific
more heterogeneous mechanistic profile. Factors tend- therapy.
ing to exacerbate reflux regardless of mechanism are Extraesophageal syndromes with an established asso-
abdominal obesity, pregnancy, gastric hypersecretory ciation to GERD include chronic cough, laryngitis,
states, delayed gastric emptying, disruption of esopha- asthma, and dental erosions. A multitude of other con-
ditions including pharyngitis, chronic bronchitis, pul-
tologic consequence of GERD is Barrett’s metaplasia mortality ranging from 3–10%, along with substantial
with the associated risk of esophageal adenocarcinoma, morbidity. That, along with increasing evidence of the
and the incidence of these lesions has increased, not effectiveness of endoscopic therapy with purpose-built
decreased, in the era of potent acid suppression. Bar- radio frequency ablation devices, has led many to favor
rett’s metaplasia, endoscopically recognized by tongues this therapy as a preferable alternative.
of reddish mucosa extending proximally from the gas-
Disorders of the Alimentary Tract
Figure 13-10
Histopathology of Barrett’s metaplasia and Barrett’s with high-grade dysplasia. H&E, hematoxylin and eosin.
Eosinophilic Esophagitis 123
with sleep disturbance from nighttime heartburn is
likely to benefit from elevation of the head of the bed
Eosinophilic esophagitis (EoE) is increasingly recognized
and avoidance of eating before retiring, but those rec-
in adults and children around the world. Population-
ommendations are superfluous for a patient without
based studies suggest the prevalence to be in excess of
nighttime symptoms. The most broadly applicable rec-
1:1000 with a predilection for white males. The increas-
ommendation is for weight reduction. Even though the
ing prevalence of EoE is attributable to a combination
benefit with respect to reflux cannot be assured, the
of an increasing incidence and a growing awareness of
strong epidemiologic association between obesity and
the condition. There is also an incompletely understood,
GERD and the secondary health gains of weight reduc-
but important, overlap between EoE and GERD that
tion are beyond dispute.
delays or confuses diagnosis of the disease in many cases.
The dominant pharmacologic approach to GERD
EoE is diagnosed based on the combination of typical
management is with inhibitors of gastric acid secretion
esophageal symptoms and esophageal mucosal biopsies
and abundant data support the effectiveness of this
demonstrating esophageal squamous epithelial infiltra-
approach. Pharmacologically reducing the acidity of
tion with eosinophils. Secondary etiologies of esophageal
gastric juice does not prevent reflux, but it ameliorates
eosinophilia including GERD, drug hypersensitivity,
reflux symptoms and allows esophagitis to heal. The
connective tissue disorders, hypereosinophilic syndrome
CHAPTER 13
hierarchy of effectiveness among pharmaceuticals par-
and infection are excluded. Current evidence indicates
allels their antisecretory potency. Proton pump inhibi-
that EoE is an allergic disorder induced by antigen sen-
tors (PPIs), are more efficacious than histamine2 receptor
sitization in susceptible individuals. Studies have dem-
antagonists (H2RAs), and both are superior to placebo.
onstrated an important role for dietary allergens in both
No major differences exist among PPIs, and only modest
the pathogenesis and treatment of EoE. Aeroallergens
gain is achieved by increased dosage.
may also contribute but there is much less evidence in
Paradoxically, the perceived frequency and sever-
Infectious Esophagitis
With the increased use of immunosuppression for organ
transplantation as well as chronic inflammatory diseases
and chemotherapy along with the AIDS epidemic,
infections with Candida species, herpesvirus, and cyto-
SECTION III
with HIV, and (D) a Schatzki’s ring. with the CD4 count >200 and common when <100.
HIV itself may also be associated with a self-limited syn-
drome of acute esophageal ulceration with oral ulcers
and a maculopapular skin rash at the time of serocon-
version. Additionally, some patients with advanced dis-
ease have deep, persistent esophageal ulcers treated with
oral glucocorticoids or thalidomide. However, with the
widespread use of protease inhibitors, 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 hemorrhage are also common. Odynopha-
gia is uncommon with reflux esophagitis, so its presence
should always raise suspicion of an alternative 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 common. Candida esophagitis
also occurs with esophageal stasis secondary to esopha-
geal motor disorders and diverticula. Patients complain
of odynophagia and dysphagia. If oral thrush is present,
empirical therapy is appropriate, but coinfection is com-
mon, and persistent symptoms should lead to prompt
Figure 13-12 endoscopy with biopsy, which is the most useful diag-
Histopathology of eosinophilic esophagitis (EoE) show- nostic evaluation. Candida esophagitis has a characteristic
ing dense infiltration of the esophageal squamous epi- appearance of white plaques with friability. Rarely,
thelium with eosinophils. Eosinophilic inflammation can Candida esophagitis is complicated by bleeding, perfo-
also be seen with gastroesophageal reflux disease (GERD); ration, stricture, or systemic invasion. Oral fluconazole
the optimal discriminatory threshold for EoE is greater than (200 mg on the first day, followed by 100 mg daily) for
15 eosinophils per high-power field. 7–14 days is the preferred treatment. Patients refractory
to fluconazole may respond to itraconazole. Alterna- rupture at the gastroesophageal junction (Boerhaave’s 125
tively, poorly responsive patients or those who cannot syndrome). More rarely, corrosive esophagitis or neo-
swallow medications can be treated with an intravenous plasms lead to perforation. Instrumental perforation
echinocandin (caspofungin 50 mg daily for 7–21 days). from endoscopy or nasogastric tube placement typically
Amphotericin B (10–15 mg IV infusion for 6 h daily to occurs in the hypopharynx or at the gastroesophageal
a total dose of 300–500 mg) is used in severe cases. junction. Perforation may also result at the site of stric-
ture in the setting of endoscopic food disimpaction or
esophageal dilation. Esophageal perforation causes pleu-
Herpetic Esophagitis ritic retrosternal pain that can be associated with pneumo-
Herpes simplex virus type 1 or 2 may cause esophagitis. mediastinum and subcutaneous emphysema. Mediastinitis
Vesicles on the nose and lips may coexist and are sug- is a major complication of esophageal perforation, and
gestive of a herpetic etiology. Varicella-zoster virus can prompt recognition is key to optimizing outcome. CT
also cause esophagitis in children with chickenpox or of the chest is most sensitive in detecting mediastinal
adults with zoster. The characteristic endoscopic find- air. Esophageal perforation is confirmed by a contrast
ings are vesicles and small, punched-out ulcerations. swallow; usually Gastrografin followed by thin barium.
Because herpes simplex infections are limited to squa- Treatment includes nasogastric suction and parenteral
mous epithelium, biopsies from the ulcer margins are broad-spectrum antibiotics with prompt surgical drain-
CHAPTER 13
most likely to reveal the characteristic ground glass age and repair in noncontained leaks. Conservative
nuclei, eosinophilic Cowdry’s type A inclusion bodies, therapy with NPO status and antibiotics without sur-
and giant cells. Culture or polymerase chain reaction gery may be appropriate in cases of minor instrumental
(PCR) assays are helpful to identify acyclovir-resistant perforation that are detected early. Endoscopic clipping
strains. The infection is often self-limited after a 1–2 week or stent placement may be indicated in nonoperable
period. Acyclovir (400 mg orally 5 times a day for cases such as perforated tumors.
than 1000 cases of pill esophagitis have been reported, eases and thought to be specific for these disorders.
suggesting that this is not an unusual occurrence. A wide However, this nomenclature subsequently proved
variety of medications are implicated with the most unfortunate and has been discarded because an esti-
common being doxycycline, tetracycline, quinidine, mated half of qualifying patients do not have an iden-
phenytoin, potassium chloride, ferrous sulfate, nonste- tifiable systemic disease, and reflux disease is often the
roidal anti-inflammatory drugs (NSAIDs), and bisphos- only identifiable association. When scleroderma esopha-
phonates. However, virtually any pill can result in pill gus occurs as a manifestation of a collagen vascular dis-
esophagitis if taken carelessly. ease, the histopathologic findings are of infiltration and
Typical symptoms of pill esophagitis are the sudden destruction of the esophageal muscularis propria with
onset of chest pain and odynophagia. Characteristi- collagen deposition and fibrosis. The pathogenesis of
cally, the pain will develop over a period of hours or absent peristalsis and LES hypotension in the absence
will awaken the individual from sleep. A classic history of a collagen vascular disease is unknown. Regardless
in the setting of ingestion of recognized pill offenders of the underlying cause, the manometric abnormalities
obviates the need for diagnostic testing in most patients. predispose patients to severe GERD due to inadequate
When endoscopy is performed, localized ulceration or LES barrier function combined with poor esopha-
inflammation is evident. Histologically, acute inflam- geal clearance of refluxed acid. Dysphagia may also be
mation is typical. Chest CT imaging will sometimes manifest but is generally mild and alleviated by eating
reveal esophageal thickening consistent with trans- in an upright position and using liquids to facilitate solid
mural inflammation. Although the condition usually emptying.
resolves within days to weeks, symptoms may persist for
months and stricture can develop in severe cases. No
specific therapy is known to hasten the healing process, Dermatologic Diseases
but antisecretory medications are frequently prescribed A host of dermatologic disorders (pemphigus vulgaris,
to remove concomitant reflux as an aggravating factor. bullous pemphigoid, cicatricial pemphigoid, Behçet’s
When healing results in stricture formation, dilatation is syndrome, epidermolysis bullosa) can affect the orophar-
indicated. ynx and esophagus, particularly the proximal esophagus,
with blisters, bullae, webs, and strictures. Glucocorti-
coid treatment is usually effective. Erosive lichen planus,
Foreign Bodies and Food Impaction
Stevens-Johnson syndrome, and graft-versus-host disease
Food or foreign bodies may lodge in the esophagus can also involve the esophagus. Esophageal dilatation
causing complete obstruction, causing an inability to may be necessary to treat strictures.
CHaPteR 14
Base
Gastric anatomy (fundus)
membranes, transforms into a dense network of apical tandem with epithelial cell renewal, formation of new
intracellular canaliculi containing long microvilli. Acid vessels (angiogenesis) within the injured microvascular
secretion, a process requiring high energy, occurs at the bed occurs. Both FGF and vascular endothelial growth
apical canalicular surface. Numerous mitochondria (30–40% factor (VEGF) are important in regulating angiogenesis
of total cell volume) generate the energy required for in the gastric mucosa.
secretion. An elaborate microvascular system within the gastric
submucosal layer is the key component of the subepi-
Gastroduodenal mucosal defense thelial defense/repair system, providing HCO3–, which
neutralizes the acid generated by the parietal cell. More-
The gastric epithelium is under constant assault by a over, this microcirculatory bed provides an adequate
series of endogenous noxious factors, including hydro- supply of micronutrients and oxygen while removing
chloric acid (HCl), pepsinogen/pepsin, and bile salts. In toxic metabolic by-products.
addition, a steady flow of exogenous substances such as Prostaglandins play a central role in gastric epithe-
medications, alcohol, and bacteria encounter the gastric lial defense/repair (Fig. 14-4). The gastric mucosa
mucosa. A highly intricate biologic system is in place to contains abundant levels of prostaglandins that regulate
provide defense from mucosal injury and to repair any the release of mucosal bicarbonate and mucus, inhibit
injury that may occur. parietal cell secretion, and are important in maintain-
The mucosal defense system can be envisioned as a ing mucosal blood flow and epithelial cell restitution.
three-level barrier, composed of preepithelial, epithelial, Prostaglandins are derived from esterified arachidonic
and subepithelial elements (Fig. 14-3). The first line acid, which is formed from phospholipids (cell mem-
of defense is a mucus-bicarbonate-phospholipid layer, brane) by the action of phospholipase A2. A key enzyme
which serves as a physicochemical barrier to multiple that controls the rate-limiting step in prostaglandin
molecules, including hydrogen ions. Mucus is secreted synthesis is cyclooxygenase (COX), which is present
in a regulated fashion by gastroduodenal surface epi- in two isoforms (COX-1, COX-2), each having dis-
thelial cells. It consists primarily of water (95%) and a tinct characteristics regarding structure, tissue distribu-
mixture of phospholipids and glycoproteins (mucin). tion, and expression. COX-1 is expressed in a host of
The mucous gel functions as a nonstirred water layer tissues, including the stomach, platelets, kidneys, and
impeding diffusion of ions and molecules such as pepsin. endothelial cells. This isoform is expressed in a consti-
Bicarbonate, secreted in a regulated manner by surface tutive manner and plays an important role in maintain-
epithelial cells of the gastroduodenal mucosa into the ing the integrity of renal function, platelet aggregation,
mucous gel, forms a pH gradient ranging from 1 to 2 at and gastrointestinal (GI) mucosal integrity. In contrast,
the gastric luminal surface and reaching 6 to 7 along the the expression of COX-2 is inducible by inflammatory
epithelial cell surface. stimuli, and it is expressed in macrophages, leukocytes,
129
fibroblasts, and synovial cells. The beneficial effects COX-1 isoform. The highly COX-2–selective NSAIDs
of nonsteroidal anti-inflammatory drugs (NSAIDs) on have the potential to provide the beneficial effect of
tissue inflammation are due to inhibition of COX-2; decreasing tissue inflammation while minimizing toxic-
the toxicity of these drugs (e.g., GI mucosal ulceration ity in the GI tract. Selective COX-2 inhibitors have had
and renal dysfunction) is related to inhibition of the adverse effects on the cardiovascular system, leading to
130 cell via direct and indirect mechanisms. Distention of
Membrane phospholipids
the stomach wall also leads to gastrin release and acid
Phospholipase A2 production. The last phase of gastric acid secretion is
initiated as food enters the intestine and is mediated by
Arachidonic acid
luminal distention and nutrient assimilation. A series of
Stomach Macrophages pathways that inhibit gastric acid production are also
Kidney COX-1 COX-2 Leukocytes
Platelets housekeeping inflammation Fibroblasts
set into motion during these phases. The GI hormone
Endothelium Endothelium somatostatin is released from endocrine cells found in the
gastric mucosa (D cells) in response to HCl. Somatostatin
can inhibit acid production by both direct (parietal cell)
TXA2, PGI2, PGE2 PGI2, PGE2
Gastrointestinal mucosal integrity Inflammation
and indirect mechanisms (decreased histamine release
Platelet aggregation Mitogenesis from ECL cells and gastrin release from G cells).
Renal function Bone formation
Other functions? Additional neural (central and peripheral) and humoral
[amylin, atrial natriuretic peptide (ANP), cholecystokinin,
Figure 14-4 ghrelin, obestatin, secretin, and serotonin] factors play a
Schematic representation of the steps involved in syn- role in counterbalancing acid secretion. Under physi-
thesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). ologic circumstances, these phases occur simultaneously.
SECTION III
Characteristics and distribution of the cyclooxygenase (COX) Ghrelin, the appetite-regulating hormone expressed in
enzymes 1 and 2 are also shown. TXA2, thromboxane A2. stomach, may stimulate gastric acid secretion through
a vagal-mediated mechanism, but this remains to be
increased risk of myocardial infarction. Therefore, the confirmed.
FDA has removed two of these agents (valdecoxib and The acid-secreting parietal cell is located in the
rofecoxib) from the market (discussed later). oxyntic gland, adjacent to other cellular elements (ECL
Disorders of the Alimentary Tract
Nitric oxide (NO) is important in the maintenance of cell, D cell) important in the gastric secretory process
gastric mucosal integrity. The key enzyme NO synthase (Fig. 14-5). This unique cell also secretes intrinsic fac-
is constitutively expressed in the mucosa and contributes tor (IF). The parietal cell expresses receptors for several
to cytoprotection by stimulating gastric mucus, increas- stimulants of acid secretion, including histamine (H2),
ing mucosal blood flow and maintaining epithelial cell gastrin (cholecystokinin B/gastrin receptor), and acetyl-
barrier function. The central nervous system (CNS) and choline (muscarinic, M3). Binding of histamine to the
hormonal factors also play a role in regulating mucosal H2 receptor leads to activation of adenylate cyclase and
defense through multiple pathways (Fig. 14-3). an increase in cyclic adenosine monophosphate (AMP).
Activation of the gastrin and muscarinic receptors results
in activation of the protein kinase C/phosphoinositide
Physiology of gastric secretion
signaling pathway. Each of these signaling pathways in
Hydrochloric acid and pepsinogen are the two principal turn regulates a series of downstream kinase cascades
gastric secretory products capable of inducing mucosal that control the acid-secreting pump, H+,K+-ATPase.
injury. Gastric acid and pepsinogen play a physiologic The discovery that different ligands and their corre-
role in protein digestion, absorption of iron and vitamin sponding receptors lead to activation of different signal-
B12 as well as killing ingested bacteria. Acid secretion ing pathways explains the potentiation of acid secretion
should be viewed as occurring under basal and stimu- that occurs when histamine and gastrin or acetylcho-
lated conditions. Basal acid production occurs in a cir- line are combined. More importantly, this observation
cadian pattern, with highest levels occurring during explains why blocking one receptor type (H2) decreases
the night and lowest levels during the morning hours. acid secretion stimulated by agents that activate a dif-
Cholinergic input via the vagus nerve and histamin- ferent pathway (gastrin, acetylcholine). Parietal cells also
ergic input from local gastric sources are the principal express receptors for ligands that inhibit acid production
contributors to basal acid secretion. Stimulated gas- (prostaglandins, somatostatin, and EGF). Histamine also
tric acid secretion occurs primarily in three phases based stimulates gastric acid secretion indirectly by activating
on the site where the signal originates (cephalic, gastric, the histamine H3 receptor on D cells, which inhibits
and intestinal). Sight, smell, and taste of food are the somatostatin release.
components of the cephalic phase, which stimu- The enzyme H+,K+-ATPase is responsible for gener-
lates gastric secretion via the vagus nerve. The gastric ating the large concentration of H+. It is a membrane-
phase is activated once food enters the stomach. This bound protein that consists of two subunits, α and β.
component of secretion is driven by nutrients (amino The active catalytic site is found within the α subunit;
acids and amines) that directly stimulate the G cell to the function of the β subunit is unclear. This enzyme
release gastrin, which in turn activates the parietal uses the chemical energy of adenosine triphosphate
131
Figure 14-5
CHAPTER 14
Regulation of gastric acid secretion at the cellular level. enterochromaffin-like; GRP, gastrin-releasing peptide; PACAP,
ACh, acetylcholine; ANP, atrial natriuretic peptide; CGRP, pituitary adenylate-cyclase activating peptide; SST, soma-
calcitonin gene-related peptide; EC, enterochromaffin; ECL, tostatin; VIP, vasoactive intestinal peptide.
Pathology
Pathophysiologic Basis of Peptic
Duodenal ulcers
Ulcer Disease
DUs occur most often in the first portion of the duo-
PUD encompasses both gastric and duodenal ulcers. denum (>95%), with ∼90% located within 3 cm of
Ulcers are defined as breaks in the mucosal surface >5 mm the pylorus. They are usually ≤1 cm in diameter but
in size, with depth to the submucosa. Duodenal ulcers can occasionally reach 3–6 cm (giant ulcer). Ulcers are
(DUs) and gastric ulcers (GUs) share many common sharply demarcated, with depth at times reaching the
features in terms of pathogenesis, diagnosis, and treat- muscularis propria. The base of the ulcer often con-
ment, but several factors distinguish them from one sists of a zone of eosinophilic necrosis with surrounding
another. fibrosis. Malignant DUs are extremely rare.
132 Gastric ulcers some GU patients. Although bile acids, lysolecithin,
In contrast to DUs, GUs can represent a malignancy and pancreatic enzymes may injure gastric mucosa,
and should be biopsied upon discovery. Benign GUs a definite role for these in GU pathogenesis has not
are most often found distal to the junction between been established. Delayed gastric emptying of solids
the antrum and the acid secretory mucosa. Benign has been described in GU patients but has not been
GUs are quite rare in the gastric fundus and are histo- reported consistently
logically similar to DUs. Benign GUs associated with
H. pylori are also associated with antral gastritis. In con- H. pylori and acid peptic disorders
trast, NSAID-related GUs are not accompanied by Gastric infection with the bacterium H. pylori accounts
chronic active gastritis but may instead have evidence of for the majority of PUD (Chap. 26). This organism
a chemical gastropathy, typified by foveolar hyperplasia, also plays a role in the development of gastric mucosa-
edema of the lamina propria, and epithelial regeneration associated lymphoid tissue (MALT) lymphoma and
in the absence of H. pylori. Extension of smooth-muscle gastric adenocarcinoma. Although the entire genome of
fibers into the upper portions of the mucosa, where H. pylori has been sequenced, it is still not clear how this
they are not typically found, may also occur. organism, which resides in the stomach, causes ulcer-
ation in the duodenum, or whether its eradication will
lead to a decrease in gastric cancer.
SECTION III
Pathophysiology
The bacterium
Duodenal ulcers
The bacterium, initially named Campylobacter pyloridis, is
H. pylori and NSAID-induced injury account for the
a gram-negative microaerophilic rod found most com-
majority of DUs. Many acid secretory abnormalities
monly in the deeper portions of the mucous gel coating
have been described in DU patients. Of these, average
the gastric mucosa or between the mucous layer and the
basal and nocturnal gastric acid secretion appears to be
gastric epithelium. It may attach to gastric epithelium
Disorders of the Alimentary Tract
Epidemiology
The prevalence of H. pylori varies throughout the
world and depends largely on the overall standard of
Bacterial factors Host factors
living in the region. In developing parts of the world, Structure Duration
80% of the population may be infected by the age of Adhesins Location
Porins Inflammatory response
20, whereas the prevalence is 20–50% in industrial- Enzymes Genetics??
ized countries. In contrast, in the United States this (urease, vac A, cag A, etc.)
organism is rare in childhood. The overall prevalence
Chronic gastritis
of H. pylori in the United States is ∼30%, with indi- Peptic ulcer disease
viduals born before 1950 having a higher rate of infec- Gastric MALT lymphoma
Gastric cancer
tion than those born later. About 10% of Americans
<30 years of age are colonized with the bacteria. The Figure 14-6
rate of infection with H. pylori in industrialized coun- Outline of the bacterial and host factors important in
tries has decreased substantially in recent decades. The determining H. pylori–induced gastrointestinal disease.
CHAPTER 14
steady increase in the prevalence of H. pylori noted MALT, mucosal-associated lymphoid tissue.
with increasing age is due primarily to a cohort effect,
reflecting higher transmission during a period in which
The particular end result of H. pylori infection (gas-
the earlier cohorts were children. It has been calculated
tritis, PUD, gastric MALT lymphoma, gastric cancer)
through mathematical models that improved sanitation
is determined by a complex interplay between bacterial
during the latter half of the nineteenth century dramat-
and host factors (Fig. 14-6).
ically decreased transmission of H. pylori. Moreover,
CHAPTER 14
(Adapted from J Scheiman et al: J Clin Outcomes Manage-
per year. It is estimated that NSAID-induced GI bleed-
ment 3:23, 1996. Copyright 2003 Turner White Communica-
ing accounts for 60,000 to 120,000 hospital admissions
tions, Inc., www.turner-white.com. Used with permission.)
per year, and deaths related to NSAID-induced tox-
icity may be as high as 16,000 per year in the United
States. Approximately 4–5% of patients develop symp-
tomatic ulcers within 1 year. Unfortunately, dyspep- leading to cell injury once trapped intracellularly in an
ionized form. Topical NSAIDs can also alter the sur-
(5) nephrolithiasis, and (6) α1-antitrypsin deficiency. nation are essential components of the approach to a
Those with a possible association are (1) hyperparathy- patient suspected of having peptic ulcers.
roidism, (2) coronary artery disease, (3) polycythemia Epigastric pain described as a burning or gnaw-
vera, and (4) chronic pancreatitis. ing discomfort can be present in both DU and
Multiple factors play a role in the pathogenesis GU. The discomfort is also described as an ill-defined,
of PUD. The two predominant causes are H. pylori aching sensation or as hunger pain. The typical pain
Disorders of the Alimentary Tract
infection and NSAID ingestion. PUD not related to pattern in DU occurs 90 min to 3 h after a meal and
H. pylori or NSAIDs is increasing. Other less com- is frequently relieved by antacids or food. Pain that
mon causes of PUD are shown in Table 14-1. These awakes the patient from sleep (between midnight and
etiologic agents should be considered as the incidence 3 a.m.) is the most discriminating symptom, with two-
thirds of DU patients describing this complaint. Unfor-
tunately, this symptom is also present in one-third of
Table 14-1 patients with NUD. The pain pattern in GU patients
Causes of Ulcers Not Caused by may be different from that in DU patients, where dis-
Helicobacter pylori and NSAIDs comfort may actually be precipitated by food. Nausea
Pathogenesis of Non-Hp and Non-NSAID Ulcer Disease
and weight loss occur more commonly in GU patients.
Endoscopy detects ulcers in <30% of patients who have
Infection
dyspepsia.
Cytomegalovirus
Herpes simplex virus
The mechanism for development of abdominal pain
H. heilmannii in ulcer patients is unknown. Several possible explana-
tions include acid-induced activation of chemical recep-
Drug/Toxin
Bisphosphonates
tors in the duodenum, enhanced duodenal sensitivity to
Chemotherapy bile acids and pepsin, or altered gastroduodenal motility.
Clopidogrel Variation in the intensity or distribution of the
Crack cocaine abdominal pain, as well as the onset of associated symp-
Glucocorticoids (when combined with NSAIDs) toms such as nausea and/or vomiting, may be indica-
Mycophenolate mofetil tive of an ulcer complication. Dyspepsia that becomes
Potassium chloride constant, is no longer relieved by food or antacids, or
Miscellaneous radiates to the back may indicate a penetrating ulcer
Basophilia in myeloproliferative disease (pancreas). Sudden onset of severe, generalized abdomi-
Duodenal obstruction (e.g., annular pancreas) nal pain may indicate perforation. Pain worsening with
Infiltrating disease
meals, nausea, and vomiting of undigested food suggest
Ischemia
Radiation therapy
gastric outlet obstruction. Tarry stools or coffee-ground
Sarcoidosis emesis indicate bleeding.
Crohn’s disease
Idiopathic hypersecretory state Physical examination
Abbreviations: Hp, H. pylori; NSAIDs, nonsteroidal anti-inflammatory Epigastric tenderness is the most frequent finding in
drugs. patients with GU or DU. Pain may be found to the
right of the midline in 20% of patients. Unfortunately, group of heterogeneous disorders typified by upper 137
the predictive value of this finding is rather low. Physi- abdominal pain without the presence of an ulcer. Dys-
cal examination is critically important for discover- pepsia has been reported to occur in up to 30% of
ing evidence of ulcer complication. Tachycardia and the U.S. population. Up to 60% of patients seeking
orthostasis suggest dehydration secondary to vomiting medical care for dyspepsia have a negative diagnostic
or active GI blood loss. A severely tender, board-like evaluation. The etiology of NUD is not established,
abdomen suggests a perforation. Presence of a succus- and the potential role of H. pylori in NUD remains
sion splash indicates retained fluid in the stomach, sug- controversial.
gesting gastric outlet obstruction. Several additional disease processes that may pres-
ent with “ulcer-like” symptoms include proximal GI
tumors, gastroesophageal reflux, vascular disease, pan-
Pud-related complications
creaticobiliary disease (biliary colic, chronic pancreatitis),
Gastrointestinal bleeding and gastroduodenal Crohn’s disease.
GI bleeding is the most common complication observed
in PUD. It occurs in ∼15% of patients and more often Diagnostic evaluation
in individuals >60 years of age. The mortality rate is as
high as 5–10%. The higher incidence in the elderly is In view of the poor predictive value of abdominal pain
CHAPTER 14
likely due to the increased use of NSAIDs in this group. for the presence of a gastroduodenal ulcer and the mul-
Up to 20% of patients with ulcer-related hemorrhage tiple disease processes that can mimic this disease, the
bleed without any preceding warning signs or symptoms. clinician is often confronted with having to establish
the presence of an ulcer. Documentation of an ulcer
Perforation requires either a radiographic (barium study) or an
The second most common ulcer-related compli- endoscopic procedure. However, a large percentage
cation is perforation, being reported in as many as of patients with symptoms suggestive of an ulcer have
A B
SECTION III
Figure 14-10
Barium study demonstrating: A. a benign duodenal ulcer; B. a benign gastric ulcer.
The methods for diagnosing H. pylori are briefly dis- in individuals with complicated or refractory PUD [see
Disorders of the Alimentary Tract
cussed here (Table 14-2). Several biopsy urease tests “Zollinger-Ellison”]. Screening for aspirin or NSAIDs
have been developed (PyloriTek, CLOtest, Hpfast, (blood or urine) may also be necessary in refractory
Pronto Dry) that have a sensitivity and specificity of H. pylori–negative PUD patients.
>90–95%. Several noninvasive methods for detect-
ing this organism have been developed. Three types
of studies routinely used include serologic testing, the Treatment Peptic Ulcer Disease
13
C- or 14C-urea breath test, and the fecal H. pylori
(Hp) antigen test. A urinary Hp antigen test, as well as a Before the discovery of H. pylori, the therapy of PUD
refined monoclonal antibody stool antigen test, appears was centered on the old dictum by Schwartz of “no
promising. acid, no ulcer.” Although acid secretion is still important
Occasionally, specialized testing such as serum gastrin in the pathogenesis of PUD, eradication of H. pylori and
and gastric acid analysis or sham feeding may be needed
Figure 14-11
Endoscopy demonstrating: A. a benign duodenal ulcer; B. a benign gastric ulcer.
Table 14-2 Table 14-3 139
Tests for Detection of H. Pylori Drugs Used in the Treatment of Peptic
Ulcer Disease
Sensitivity/
Test Specificity, % Comments Drug Type/
Mechanism Examples Dose
Invasive (Endoscopy/Biopsy Required)
Rapid 80–95/95–100 Simple, false negative with Acid-suppressing drugs
urease recent use of PPIs, Antacids Mylanta, 100–140 meq/L
antibiotics, or bismuth Maalox, Tums, 1 and 3 h after
compounds Gaviscon meals and hs
Histology 80–90/>95 Requires pathology H2 receptor Cimetidine 400 mg bid
processing and staining; antagonists Ranitidine 300 mg hs
provides histologic Famotidine 40 mg hs
information Nizatidine 300 mg hs
Culture —/— Time-consuming, Proton pump Omeprazole 20 mg/d
expensive, dependent on inhibitors Lansoprazole 30 mg/d
experience; allows deter- Rabeprazole 20 mg/d
mination of antibiotic Pantoprazole 40 mg/d
susceptibility
CHAPTER 14
Esomeprazole 20 mg/d
Noninvasive Mucosal protective agents
Serology >80/>90 Inexpensive, convenient; Sucralfate Sucralfate 1 g qid
not useful for early Prostaglandin Misoprostol 200 μg qid
follow-up analogue
Urea >90/>90 Simple, rapid; useful Bismuth- Bismuth See anti-H. pylori
breath for early follow-up; false containing subsalicylate regimens
pylori and the development of proton pump inhibitors Because the pumps need to be activated for these
(PPIs). Patients may develop tolerance to H2 blockers, a agents to be effective, their efficacy is maximized if
rare event with PPIs (discussed later). Comparable night- they are administered before a meal (except for the
time dosing regimens are ranitidine 300 mg, famotidine immediate-release formulation of omeprazole) (e.g.,
40 mg, and nizatidine 300 mg. in the morning before breakfast). Mild to moderate
Additional rare, reversible systemic toxicities reported hypergastrinemia has been observed in patients tak-
Disorders of the Alimentary Tract
with H2 receptor antagonists include pancytopenia, ing these drugs. Carcinoid tumors developed in some
neutropenia, anemia, and thrombocytopenia, with a animals given the drugs preclinically; however, exten-
prevalence rate varying from 0.01–0.2%. Cimetidine sive experience has failed to demonstrate gastric car-
and ranitidine (to a lesser extent) can bind to hepatic cinoid tumor development in humans. Serum gastrin
cytochrome P450; famotidine and nizatidine do not. levels return to normal levels within 1–2 weeks after
drug cessation. Rebound gastric acid hypersecretion
Proton Pump (H+,K+-ATPase) Inhibitors has been described in H. pylori-negative individuals
Omeprazole, esomeprazole, lansoprazole, rabepra- after discontinuation of PPIs. It occurs even after rela-
zole, and pantoprazole are substituted benzimidazole tively short-term usage (2 months) and may last for
derivatives that covalently bind and irreversibly inhibit up to 2 months after the PPI has been discontinued.
H+,K+-ATPase. Esomeprazole, the newest member of this The mechanism involves gastrin-induced hyperplasia
drug class, is the S-enantiomer of omeprazole, which and hypertrophy of histamine-secreting ECL cells. The
is a racemic mixture of both S- and R-optical isomers. clinical relevance of this observation is that individuals
These are the most potent acid inhibitory agents avail- may have worsening symptoms of gastroesophageal
able. Omeprazole and lansoprazole are the PPIs that reflux disease (GERD) or dyspepsia upon stopping the
have been used for the longest time. Both are acid- PPI. Gradual tapering of the PPI and switching to an
labile and are administered as enteric-coated granules H2 receptor antagonist may prevent this from occur-
in a sustained-release capsule that dissolves within the ring. H. pylori–induced inflammation and concomi-
small intestine at a pH of 6. Lansoprazole is available in tant decrease in acid production may explain why
an orally disintegrating tablet that can be taken with or this does not occur in H. pylori–positive patients. IF
without water, an advantage for individuals who have production is also inhibited, but vitamin B12-deficiency
significant dysphagia. Absorption kinetics are similar anemia is uncommon, probably because of the large
to the capsule. In addition, a lansoprazole-naproxen stores of the vitamin. As with any agent that leads to sig-
combination preparation that has been made available nificant hypochlorhydria, PPIs may interfere with absorp-
is targeted at decreasing NSAID-related GI injury (dis- tion of drugs such as ketoconazole, ampicillin, iron, and
cussed later). Omeprazole is available as nonenteric- digoxin. Hepatic cytochrome P450 can be inhibited by
coated granules mixed with sodium bicarbonate in a the earlier PPIs (omeprazole, lansoprazole). Rabeprazole,
powder form that can be administered orally or via gas- pantoprazole, and esomeprazole do not appear to inter-
tric tube. The sodium bicarbonate has two purposes: act significantly with drugs metabolized by the cyto-
to protect the omeprazole from acid degradation and chrome P450 system. The overall clinical significance of
to promote rapid gastric alkalinization and subsequent this observation is not definitely established. Caution
proton pump activation, which facilitates rapid action should be taken when using theophylline, warfarin,
diazepam, atazanavir, and phenytoin concomitantly may be beneficial for inhibiting nocturnal acid secre- 141
with PPIs. Long-term acid suppression, especially with tion, which has significant relevance in GERD. A second
PPIs, has been associated with a higher incidence of new class of agents is the potassium-competitive acid
community-acquired pneumonia as well as community- pump antagonists (P-CABs). These compounds inhibit
and hospital-acquired Clostridium difficile–associated gastric acid secretion via potassium competitive bind-
disease. These observations require confirmation but ing of the H+,K+-ATPase.
should alert the practitioner to take caution when rec-
ommending these agents for long-term use, especially Cytoprotective Agents
in elderly patients at risk for developing pneumonia or Sucralfate Sucralfate is a complex sucrose salt in
C. difficile infection. A population-based study revealed which the hydroxyl groups have been substituted by
that long-term use of PPIs was associated with the aluminum hydroxide and sulfate. This compound is
development of hip fractures in older women. The abso- insoluble in water and becomes a viscous paste within
lute risk of fracture remained low despite an observed the stomach and duodenum, binding primarily to sites
increase associated with the dose and duration of acid of active ulceration. Sucralfate may act by several mech-
suppression. The mechanism for this observation is not anisms: serving as a physicochemical barrier, promoting
clear and this finding must be confirmed before making a trophic action by binding growth factors such as EGF,
enhancing prostaglandin synthesis, stimulating mucus
CHAPTER 14
broad recommendations regarding the discontinuation
of these agents in patients who benefit from them. PPIs and bicarbonate secretion, and enhancing mucosal
may exert a negative effect on the anti-platelet effect of defense and repair. Toxicity from this drug is rare, with
clopidogrel. Although the evidence is mixed and incon- constipation being most common (2–3%). It should be
clusive, a small increase in mortality and readmission avoided in patients with chronic renal insufficiency to
rate for coronary events is seen in patients receiving a prevent aluminum-induced neurotoxicity. Hypophos-
PPI while on clopidogrel. The mechanism involves the phatemia and gastric bezoar formation have also been
phoma experience complete remission of the tumor Omeprazole (lansoprazole) 20 mg (30 mg) daily
in response to H. pylori eradication. Treating patients Bismuth subsalicylate 2 tablets qid
with NUD, to prevent gastric cancer or patients with Metronidazole 250 mg qid
GERD requiring long-term acid suppression, remains Tetracycline 500 mg qid
controversial. Guidelines from the American College
a
of Gastroenterology suggest eradication of H. pylori in Alternative: use prepacked Helidac (see text).
b
Alternative: use prepacked Prevpac (see text).
Disorders of the Alimentary Tract
CHAPTER 14
strains are the most common cause for treatment failure
or Duodenal Injury Medical intervention
in compliant patients. Unfortunately, in vitro resistance
for NSAID-related mucosal injury includes treatment
does not predict outcome in patients. Culture and sen-
of an active ulcer and primary prevention of future
sitivity testing of H. pylori is not performed routinely.
injury. Recommendations for the treatment and pri-
Although resistance to metronidazole has been found in
mary prevention of NSAID-related mucosal injury are
as many as 30% of isolates in North America and 80% in
listed in Table 14-5. Ideally, the injurious agent should
developing countries, triple therapy is effective in eradi-
individuals taking COX-2 inhibitors and aspirin prophy- Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID,
laxis. Finally, much of the work demonstrating the ben- nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.
Source: Adapted from AM Fendrick: Am J Manag Care 10:740,
efit of COX-2 inhibitors and PPIs on GI injury has been
2004. Reproduced with permission of INTELLISPHERE, LLC via
performed in individuals of average risk; it is unclear if Copyright Clearance Center.
the same level of benefit will be achieved in high-risk
patients. For example, concomitant use of warfarin and
Disorders of the Alimentary Tract
CHAPTER 14
Confirm eradication UBT excluded with gastric acid analysis. Although a subset
of patients have gastric acid hypersecretion of unclear
Symptoms remain or recur etiology as a contributing factor to refractory ulcers,
ZES should be excluded with a fasting gastrin or secre-
Figure 14-12 tin stimulation test (discussed later). More than 90% of
Overview of new-onset dyspepsia. Hp, Helicobacter refractory ulcers (either DUs or GUs) heal after 8 weeks
pylori; UBT, urea breath test; IBS, irritable bowel syndrome. of treatment with higher doses of PPI (omeprazole,
with the hope that a functional obstruction will reverse. cantly better clinical, endoscopic, and histologic out-
If a mechanical obstruction persists, endoscopic inter- come than Billroth II reconstruction.
vention with balloon dilation may be effective. Surgery Of these procedures, highly selective vagotomy
should be considered if all else fails. may be the one of choice in the elective setting, except
in situations where ulcer recurrence rates are high
Specific Operations for Duodenal
(prepyloric ulcers and those refractory to medical ther-
Ulcers Surgical treatment is designed to decrease
apy). Selection of vagotomy and antrectomy may be
Disorders of the Alimentary Tract
CHAPTER 14
test, gastric acid output is measured while the patient
tomy (including the ulcer) with a Billroth I anastomosis
sees, smells, and chews a meal (without swallowing).
is the treatment of choice for an antral ulcer. Vagotomy
The cephalic phase of gastric secretion, which is medi-
is performed only if a DU is present. Although ulcer exci-
ated by the vagus, is being assessed with this study.
sion with vagotomy and drainage procedure has been
An increase in gastric acid output in response to sham
proposed, the higher incidence of ulcer recurrence
feeding is evidence that the vagus nerve is intact. A rise
makes this a less desirable approach. Ulcers located
in serum pancreatic polypeptide >50% within 30 min of
some degree. Signs and symptoms often improve with symptoms. Surgical diversion of pancreaticobiliary secre-
time, but a severe protracted picture can occur in up to tions away from the gastric remnant with a Roux-en-Y
1% of patients. gastrojejunostomy consisting of a long (50–60 cm) Roux
Dietary modification is the cornerstone of therapy for limb has been used in severe cases. Bilious vomiting
patients with dumping syndrome. Small, multiple (six) improves, but early satiety and bloating may persist in
meals devoid of simple carbohydrates coupled with elimi- up to 50% of patients.
nation of liquids during meals is important. Antidiarrheals
Maldigestion and malabsorption Weight loss
and anticholinergic agents are complementary to diet.
can be observed in up to 60% of patients after partial
Guar and pectin, which increase the viscosity of intralu-
gastric resection. A significant component of this weight
minal contents, may be beneficial in more symptomatic
reduction is due to decreased oral intake. However, mild
individuals. Acarbose, an α-glucosidase inhibitor that
steatorrhea can also develop. Reasons for maldigestion/
delays digestion of ingested carbohydrates, has also been
malabsorption include decreased gastric acid produc-
shown to be beneficial in the treatment of the late phases
tion, rapid gastric emptying, decreased food dispersion
of dumping. The somatostatin analogue octreotide has
in the stomach, reduced luminal bile concentration,
been successful in diet-refractory cases. This drug is
reduced pancreatic secretory response to feeding, and
administered subcutaneously (50 μg tid), titrated accord-
rapid intestinal transit.
ing to clinical response. A long-acting depot formulation
Decreased serum vitamin B12 levels can be observed
of octreotide can be administered once every 28 days and
after partial gastrectomy. This is usually not due to defi-
provides symptom relief comparable to the short-acting
ciency of IF, since a minimal amount of parietal cells
agent. In addition, patient weight gain and quality of life
(source of IF) are removed during antrectomy. Reduced
appear to be superior with the long-acting form.
vitamin B12 may be due to competition for the vitamin
Postvagotomy diarrhea Up to 10% of patients by bacterial overgrowth or inability to split the vitamin
may seek medical attention for the treatment of post from its protein-bound source due to hypochlorhydria.
vagotomy diarrhea. This complication is most commonly Iron-deficiency anemia may be a consequence of
observed after truncal vagotomy. Patients may com- impaired absorption of dietary iron in patients with a
plain of intermittent diarrhea that occurs typically 1–2 h Billroth II gastrojejunostomy. Absorption of iron salts is
after meals. Occasionally the symptoms may be severe normal in these individuals; thus, a favorable response
and relentless. This is due to a motility disorder from to oral iron supplementation can be anticipated. Folate
interruption of the vagal fibers supplying the luminal deficiency with concomitant anemia can also develop
gut. Other contributing factors may include decreased in these patients. This deficiency may be secondary to
absorption of nutrients (discussed later), increased decreased absorption or diminished oral intake.
through gastrin receptors on parietal cells and by induc- 149
Malabsorption of vitamin D and calcium resulting in ing histamine release from ECL cells. Gastrin also has a
osteoporosis and osteomalacia is common after partial trophic action on gastric epithelial cells. Long-standing
gastrectomy and gastrojejunostomy (Billroth II). Osteo- hypergastrinemia leads to markedly increased gastric
malacia can occur as a late complication in up to 25% of acid secretion through both parietal cell stimulation and
postpartial gastrectomy patients. Bone fractures occur increased parietal cell mass. The increased gastric acid
twice as commonly in men after gastric surgery as in output leads to peptic ulcer diathesis, erosive esophagi-
a control population. It may take years before x-ray tis, and diarrhea.
findings demonstrate diminished bone density. Ele-
vated alkaline phosphatase, reduced serum calcium,
bone pain, and pathologic fractures may be seen in Tumor distribution
patients with osteomalacia. The high incidence of these Although early studies suggested that the vast majority
abnormalities in this subgroup of patients justifies treat- of gastrinomas occurred within the pancreas, a signifi-
ing them with vitamin D and calcium supplementation cant number of these lesions are extrapancreatic. Over
indefinitely. Therapy is especially important in females. 80% of these tumors are found within the hypothetical
Gastric adenocarcinoma The incidence of ade- gastrinoma triangle (confluence of the cystic and com-
nocarcinoma in the gastric stump is increased 15 years mon bile ducts superiorly, junction of the second and
CHAPTER 14
after resection. Some have reported a four- to fivefold third portions of the duodenum inferiorly, and junction
increase in gastric cancer 20–25 years after resection. The of the neck and body of the pancreas medially). Duode-
pathogenesis is unclear but may involve alkaline reflux, nal tumors constitute the most common nonpancreatic
bacterial proliferation, or hypochlorhydria. The role of lesion; between 50 and 75% of gastrinomas are found
endoscopic screening is not clear, and most guidelines here. Duodenal tumors are smaller, slower growing, and
do not support its use. less likely to metastasize than pancreatic lesions. Less-
common extrapancreatic sites include stomach, bones,
CHAPTER 14
ing the uptake of the stable somatostatin analogue
111 ing can be adjusted to achieve a BAO <10 meq/h
In-pentreotide (OctreoScan) with sensitivity and
(at the drug trough) in surgery-naive patients and to
specificity rates of >85%.
<5 meq/h in individuals who have previously under-
Up to 50% of patients have metastatic disease at
gone an acid-reducing operation. Although the soma-
diagnosis. Success in controlling gastric acid hypersecre-
tostatin analogue has inhibitory effects on gastrin
tion has shifted the emphasis of therapy toward provid-
release from receptor-bearing tumors and inhibits
ing a surgical cure. Detecting the primary tumor and
and use of agents that block the vascular endothelial supports the use of preventive measures in high-risk
growth receptor pathway (bevacizumab, sunitinib) or the patients (mechanically ventilated, coagulopathy, mul-
mammalian target of rapamycin (Chap. 52). tiorgan failure, or severe burns). Maintenance of gastric
Surgical approaches including debulking surgery and pH >3.5 with continuous infusion of H2 blockers
liver transplantation for hepatic metastasis have also or liquid antacids administered every 2–3 h are via-
produced limited benefit. ble options. Tolerance to the H2 blocker is likely to
The overall 5- and 10-year survival rates for gastrinoma
Disorders of the Alimentary Tract
CHAPTER 14
Gastric glands may undergo morphologic transfor-
inspection of the gastric mucosa is poor. Therefore, mation in chronic gastritis. Intestinal metaplasia denotes
there is no typical clinical manifestation of gastritis. the conversion of gastric glands to a small intestinal
phenotype with small-bowel mucosal glands containing
Acute gastritis goblet cells. The metaplastic changes may vary in distri-
bution from patchy to fairly extensive gastric involve-
The most common causes of acute gastritis are infec-
Gastric acid plays an important role in feedback inhi- stained microorganisms layered over the apical portion of the
surface epithelium. Note that there is no tissue invasion.
bition of gastrin release from G cells. Achlorhydria,
coupled with relative sparing of the antral mucosa (site
of G cells), leads to hypergastrinemia. Gastrin levels Seropositivity for H. pylori is associated with a three- to
can be markedly elevated (>500 pg/mL) in patients sixfold increased risk of gastric cancer. This risk may
with pernicious anemia. ECL cell hyperplasia with be as high as ninefold after adjusting for the inaccuracy
Disorders of the Alimentary Tract
frank development of gastric carcinoid tumors may of serologic testing in the elderly. The mechanism by
result from gastrin trophic effects. Hypergastrinemia and which H. pylori infection leads to cancer is unknown,
achlorhydria may also be seen in nonpernicious anemia– but it appears to be related to the chronic inflammation
associated type A gastritis. induced by the organism. Eradication of H. pylori as a
general preventative measure for gastric cancer is being
Type B gastritis
evaluated but is not yet recommended.
Type B, or antral-predominant, gastritis is the more Infection with H. pylori is also associated with devel-
common form of chronic gastritis. H. pylori infec- opment of a low-grade B cell lymphoma, gastric MALT
tion is the cause of this entity. Although described as lymphoma. The chronic T cell stimulation caused by
“antral-predominant,” this is likely a misnomer in view the infection leads to production of cytokines that pro-
of studies documenting the progression of the inflam- mote the B cell tumor. The tumor should be initially
matory process toward the body and fundus of infected staged with a CT scan of the abdomen and EUS. Tumor
individuals. The conversion to a pangastritis is time- growth remains dependent on the presence of H. pylori,
dependent, estimated to require 15–20 years. This form and its eradication is often associated with complete
of gastritis increases with age, being present in up to regression of the tumor. The tumor may take more than
100% of persons over age 70. Histology improves after a year to regress after treating the infection. Such patients
H. pylori eradication. The number of H. pylori organisms should be followed by EUS every 2–3 months. If the
decreases dramatically with progression to gastric atrophy, tumor is stable or decreasing in size, no other therapy
and the degree of inflammation correlates with the level is necessary. If the tumor grows, it may have become a
of these organisms. Early on, with antral-predominant high-grade B cell lymphoma. When the tumor becomes
findings, the quantity of H. pylori is highest and a dense a high-grade aggressive lymphoma histologically, it loses
chronic inflammatory infiltrate of the lamina propria is responsiveness to H. pylori eradication.
noted, accompanied by epithelial cell infiltration with
polymorphonuclear leukocytes (Fig. 14-14).
Multifocal atrophic gastritis, gastric atrophy with
subsequent metaplasia, has been observed in chronic Treatment Chronic Gastritis
H. pylori–induced gastritis. This may ultimately lead
Treatment in chronic gastritis is aimed at the sequelae
to development of gastric adenocarcinoma (Fig. 14-8;
and not the underlying inflammation. Patients with
Chap. 49). H. pylori infection is now considered an
pernicious anemia will require parenteral vitamin B12
independent risk factor for gastric cancer. Worldwide
supplementation on a long-term basis. Eradication of
epidemiologic studies have documented a higher inci-
H. pylori is not routinely recommended unless PUD or a
dence of H. pylori infection in patients with adenocar-
low-grade MALT lymphoma is present.
cinoma of the stomach as compared to control subjects.
Miscellaneous forms of gastritis infiltrative disorders such as sarcoidosis. The muco- 155
sal folds in Ménétrier’s disease are often most promi-
Lymphocytic gastritis is characterized histologically by nent in the body and fundus. Histologically, massive
intense infiltration of the surface epithelium with lym- foveolar hyperplasia (hyperplasia of surface and glan-
phocytes. The infiltrative process is primarily in the dular mucous cells) is noted, which replaces most of
body of the stomach and consists of mature T cells and the chief and parietal cells. This hyperplasia produces
plasmacytes. The etiology of this form of chronic gas- the prominent folds observed. The pits of the gastric
tritis is unknown. It has been described in patients with glands elongate and may become extremely tortu-
celiac sprue, but whether there is a common factor ous. Although the lamina propria may contain a mild
associating these two entities is unknown. No specific chronic inflammatory infiltrate, Ménétrier’s disease is
symptoms suggest lymphocytic gastritis. A subgroup not considered a form of gastritis. The etiology of this
of patients have thickened folds noted on endoscopy. unusual clinical picture is unknown. Overexpression
These folds are often capped by small nodules that con- of growth factors such as TGF-α may be involved in
tain a central depression or erosion; this form of the the process.
disease is called varioliform gastritis. H. pylori probably Epigastric pain, at times accompanied by nausea, vom-
plays no significant role in lymphocytic gastritis. Ther- iting, anorexia, and weight loss, are signs and symptoms
apy with glucocorticoids or sodium cromoglycate has in patients with Ménétrier’s disease. Occult GI bleed-
CHAPTER 14
obtained unclear results. ing may occur, but overt bleeding is unusual and, when
Marked eosinophilic infiltration involving any layer present, is due to superficial mucosal erosions. Twenty
of the stomach (mucosa, muscularis propria, and serosa) to 100% of patients (depending on time of presentation)
is characteristic of eosinophilic gastritis. Affected individuals develop a protein-losing gastropathy accompanied by
will often have circulating eosinophilia with clinical hypoalbuminemia and edema. Gastric acid secretion is
manifestation of systemic allergy. Involvement may range usually reduced or absent because of the replacement of
from isolated gastric disease to diffuse eosinophilic gastroen-
Ménétrier’s disease is a rare entity characterized by large, The author acknowledges the contribution of material to this
tortuous gastric mucosal folds. The differential diagnosis chapter by Dr. Lawrence Friedman and Dr. Walter Peterson
of large gastric folds includes ZES, malignancy, infec- from their chapter on this subject in the 14th edition of
tious etiologies (CMV, histoplasmosis, syphilis), and Harrison’s Principles of Internal Medicine.
cHapter 15
DISORDERS OF ABSORPTION
Henry J. Binder
Disorders of absorption constitute a broad spectrum of to increasing intracellular Ca. In addition, diarrhea per
conditions with multiple etiologies and varied clinical se may result in mild steatorrhea (<11 g fat excretion
manifestations. Almost all of these clinical problems are while on a 100-g fat diet). Second, most patients will
associated with diminished intestinal absorption of one or indicate that they have diarrhea, not that they have fat
more dietary nutrients and are often referred to as the malabsorption. Third, many intestinal disorders that
malabsorption syndrome. This term is not ideal as it repre- have diarrhea as a prominent symptom (e.g., ulcerative
sents a pathophysiologic state, does not provide an etio- colitis, traveler’s diarrhea secondary to an enterotoxin
logic explanation for the underlying problem, and should produced by Escherichia coli) do not necessarily have
not be considered an adequate final diagnosis. The only diminished absorption of any dietary nutrient.
clinical situations in which absorption is increased are Diarrhea as a symptom (i.e., when used by patients
hemochromatosis and Wilson’s disease, in which absorp- to describe their bowel movement pattern) may be a
tion of iron and copper, respectively, are increased. decrease in stool consistency, an increase in stool vol-
Most, but not all, malabsorption syndromes are associ- ume, an increase in number of bowel movements, or
ated with steatorrhea, an increase in stool fat excretion of any combination of these three changes. In contrast,
>6% of dietary fat intake. Some malabsorption disorders diarrhea as a sign is a quantitative increase in stool water
are not associated with steatorrhea: primary lactase defi- or weight of >200–225 mL or gram per 24 h, when a
ciency, a congenital absence of the small intestinal brush Western-type diet is consumed. Individuals consuming a
border disaccharidase enzyme lactase, is associated with diet with higher fiber content may normally have a stool
lactose “malabsorption,” and pernicious anemia is asso- weight of up to 400 g/24 h. Thus, the clinician must
ciated with a marked decrease in intestinal absorption clarify what an individual patient means by diarrhea.
of cobalamin (vitamin B12) due to an absence of gas- Some 10% of patients referred to gastroenterologists for
tric parietal cell intrinsic factor required for cobalamin further evaluation of unexplained diarrhea do not have
absorption. an increase in stool water when it is determined quanti-
Disorders of absorption must be included in the dif- tatively. Such patients may have small, frequent, some-
ferential diagnosis of diarrhea (Chap. 6). First, diarrhea what loose bowel movements with stool urgency that
is frequently associated with and/or is a consequence of is indicative of proctitis but do not have an increase in
the diminished absorption of one or more dietary nutri- stool weight or volume.
ents. The diarrhea may be secondary either to the intes- It is also critical to establish whether a patient’s diar-
tinal process that is responsible for the steatorrhea or to rhea is secondary to diminished absorption of one or
steatorrhea per se. Thus, celiac disease (discussed later) more dietary nutrients, in contrast to diarrhea that is
is associated with both extensive morphologic changes due to small- and/or large-intestinal fluid and electro-
in the small intestinal mucosa and reduced absorption lyte secretion. The former has often been termed osmotic
of several dietary nutrients; in contrast, the diarrhea of diarrhea, while the latter has been referred to as secre-
steatorrhea is the result of the effect of nonabsorbed tory diarrhea. Unfortunately, both secretory and osmotic
dietary fatty acids on intestinal, usually colonic, ion elements can be present simultaneously in the same
transport. For example, oleic acid and ricinoleic acid (a disorder; thus, this separation is not always precise.
bacterially hydroxylated fatty acid that is also the active Nonetheless, two studies—determination of stool elec-
ingredient in castor oil, a widely used laxative) induce trolytes and observation of the effect of a fast on stool
active colonic Cl ion secretion, most likely secondary output—can help make this distinction.
156
The demonstration of the effect of prolonged (>24 h) example. Ideally, the presence of an osmotic gap will be 157
fasting on stool output can be very effective in sug- associated with a marked decrease in stool output dur-
gesting that a dietary nutrient is responsible for the indi- ing a prolonged fast, while the absence of an osmotic
vidual’s diarrhea. A secretory diarrhea associated with gap will likely be present in an individual whose stool
enterotoxin-induced traveler’s diarrhea would not be output had not been reduced substantially during a
affected by prolonged fasting, as enterotoxin-induced period of fasting.
stimulation of intestinal fluid and electrolyte secretion
is not altered by eating. In contrast, diarrhea second-
ary to lactose malabsorption in primary lactase defi-
ciency would undoubtedly cease during a prolonged Nutrient Digestion and
fast. Thus, a substantial decrease in stool output while Absorption
fasting during a quantitative stool collection of at least The lengths of the small intestine and colon are ∼300 cm
24 h is presumptive evidence that the diarrhea is related and ∼80 cm, respectively. However, the effective func-
to malabsorption of a dietary nutrient. The persistence tional surface area is approximately 600-fold greater
of stool output while fasting indicates that the diar- than that of a hollow tube as a result of the presence of
rhea is likely secretory and that the cause of diarrhea folds, villi (in the small intestine), and microvilli. The
is not a dietary nutrient. Either a luminal (e.g., E. coli functional surface area of the small intestine is somewhat
CHAPTER 15
enterotoxin) or circulating (e.g., vasoactive intesti- greater than that of a doubles tennis court. In addi-
nal peptide) secretagogue could be responsible for tion to nutrient digestion and absorption, the intestinal
the patient’s diarrhea persisting unaltered during a epithelia have several other functions:
prolonged fast. The observed effects of fasting can be
compared and correlated with stool electrolyte and 1. Barrier and immune defense. The intestine is exposed
osmolality determinations. to a large number of potential antigens and enteric
and invasive microorganisms, and it is extremely
Disorders of Absorption
Measurement of stool electrolytes and osmolality
requires the comparison of stool Na+ and K+ concen- effective preventing the entry of almost all these
trations determined in liquid stool to the stool osmolal- agents. The intestinal mucosa also synthesizes and
ity to determine the presence or absence of a so-called secretes secretory IgA.
stool osmotic gap. The following formula is used: 2. Fluid and electrolyte absorption and secretion. The intes-
tine absorbs ∼7–8 L of fluid daily, comprising dietary
2 × (stool [Na+] + stool [K+]) ≤ stool osmolality fluid intake (1–2 L/d) and salivary, gastric, pancre-
atic, biliary, and intestinal fluid (6–7 L/d). Several
The cation concentrations are doubled to estimate
stimuli, especially bacteria and bacterial enterotoxins,
stool anion concentrations. The presence of a significant
induce fluid and electrolyte secretion that may lead
osmotic gap suggests the presence in stool water of a
to diarrhea (Chap. 23).
substance (or substances) other than Na/K anions that is
3. Synthesis and secretion of several proteins. The intestinal
presumably responsible for the patient’s diarrhea. Origi-
mucosa is a major site for the production of proteins,
nally, stool osmolality was measured, but it is almost
including apolipoproteins.
invariably greater than the required 290–300 mosmol/kg
4. Production of several bioactive amines and peptides.
H2O, reflecting bacterial degradation of nonabsorbed
The intestine is one of the largest endocrine organs
carbohydrate either immediately before defecation or
in the body and produces several amines (e.g.,
in the stool jar while awaiting chemical analysis, even
5-hydroxytryptophan) and peptides that serve as para-
when the stool is refrigerated. As a result, the stool
crine and hormonal mediators of intestinal function.
osmolality should be assumed to be 300 mosmol/kg
H2O. A low stool osmolality (<290 mosmol/kg H2O) The small and large intestines are distinct anatomi-
reflects the addition of either dilute urine or water indi- cally (villi are present in the small intestine but are
cating either collection of urine and stool together or absent in the colon) and functionally (nutrient digestion
so-called factitious diarrhea, a form of Münchausen’s and absorption take place in the small intestine but not
syndrome. When the calculated difference is >50, an in the colon). No precise anatomic characteristics sepa-
osmotic gap is present, suggesting that the diarrhea is rate duodenum, jejunum, and ileum, although certain
due to a nonabsorbed dietary nutrient, e.g., a fatty acid nutrients are absorbed exclusively in specific areas of the
and/or carbohydrate. When this difference is <25, it small intestine. However, villous cells in the small intes-
is presumed that a dietary nutrient is not responsible tine (and surface epithelial cells in the colon) and crypt
for the diarrhea. Since elements of both osmotic (i.e., cells have distinct anatomic and functional characteristics.
malabsorption of a dietary nutrient) and secretory diar- Intestinal epithelial cells are continuously renewed, with
rhea may be present, this separation at times is less new proliferating epithelial cells at the base of the crypt
clear-cut at the bedside than when used as a teaching migrating over 48–72 h to the tip of the villus (or surface
158 of the colon), where they are well-developed epithelial serum cholesterol levels by 10% before a new steady state
cells with digestive and absorptive function. This high is established. Bile acids are either primary or secondary:
rate of cell turnover explains the relatively rapid resolu- Primary bile acids are synthesized in the liver from cho-
tion of diarrhea and other digestive tract side effects dur- lesterol, and secondary bile acids are synthesized from
ing chemotherapy as new cells not exposed to these toxic primary bile acids in the intestine by colonic bacte-
agents are produced. Equally important is the paradigm rial enzymes. The two primary bile acids in humans are
of separation of villous/surface cell and crypt cell func- cholic acid and chenodeoxycholic acid; the two most
tion: Digestive hydrolytic enzymes are present primarily abundant secondary bile acids are deoxycholic acid and
in the brush border of villous epithelial cells. Absorptive lithocholic acid. Approximately 500 mg of bile acids are
and secretory functions are also separated, with villous/ synthesized in the liver daily, conjugated to either taurine
surface cells primarily, but not exclusively, being the site or glycine to form tauroconjugated or glycoconjugated
for absorptive function, while secretory function is pres- bile acids, respectively, and secreted into the duodenum
ent in crypts of both the small and large intestine. in bile. The primary functions of bile acids are (1) to pro-
Nutrients, minerals, and vitamins are absorbed by mote bile flow, (2) to solubilize cholesterol and phospho-
one or more active transport mechanisms. Active trans- lipid in the gallbladder by mixed micelle formation, and
port mechanisms are energy-dependent and mediated by (3) to enhance dietary lipid digestion and absorption by
membrane transport proteins. These processes will result forming mixed micelles in the proximal small intestine.
SECTION III
in the net movement of a substance against or in the Bile acids are primarily absorbed by an active, Na+-
absence of an electrochemical concentration gradient. dependent process that is located exclusively in the
Intestinal absorption of amino acids and monosaccha- ileum, though bile acids can also be absorbed to a lesser
rides, e.g., glucose, is also a specialized form of active extent by non-carrier-mediated transport processes in the
transport—secondary active transport. The movement of jejunum, ileum, and colon. Conjugated bile acids that
these actively transported nutrients against a concen- enter the colon are deconjugated by colonic bacte-
tration gradient is Na+-dependent and is due to a Na+
Disorders of the Alimentary Tract
CHAPTER 15
tion of bile acids. Bile acid synthesis is cholesterol catab- tion: (1) unconjugated bile acids are rapidly absorbed in
olism and occurs in the liver. Bile acids are secreted in the jejunum by nonionic diffusion, resulting in a reduced
bile and are stored in the gallbladder between meals and concentration of duodenal bile acids; and (2) the critical
at night. Food in the duodenum induces the release of micellar concentration (CMC) of unconjugated bile acids
cholecystokinin, a potent stimulus for gallbladder contrac- is higher than that of conjugated bile acids, and therefore
tion resulting in bile acid entry into the duodenum. Bile acids unconjugated bile acids are less effective than conjugated
bile acids in micelle formation.
Disorders of Absorption
are primarily absorbed via a Na-dependent transport process
that is located only in the ileum. A relatively small quantity of
bile acids (∼500 mg) is not absorbed in a 24-h period and is
Reabsorption
lost in stool. Fecal bile acid losses are matched by bile acid
synthesis. The bile acid pool (the total amount of bile acids in Ileal dysfunction caused by either Crohn’s disease or
the body) is ∼4 g and is circulated twice during each meal or surgical resection results in a decrease in bile acid reab-
six to eight times in a 24-h period. sorption in the ileum and an increase in the delivery of
bile acids to the large intestine. The resulting clinical
Secretion consequences—diarrhea with or without steatorrhea—
are determined by the degree of ileal dysfunction and
Although bile acid secretion may be reduced or absent the response of the enterohepatic circulation to bile acid
in biliary obstruction, steatorrhea is rarely a significant losses (Table 15-2). Patients with limited ileal disease
medical problem in these patients. In contrast, pri-
mary biliary cirrhosis represents a defect in canalicu- Table 15-2
lar excretion of organic anions, including bile acids,
Comparison of Bile Acid and Fatty
and not infrequently is associated with steatorrhea and Acid Diarrhea
Bile Acid Fatty Acid
Table 15-1 Diarrhea Diarrhea
or resection will often have diarrhea but not steatorrhea. greater, as substantial amounts of lipid are secreted in bile
The diarrhea, a result of bile acids in the colon stimulat- each day. (Enterohepatic circulation of bile acids is dis-
ing active Cl secretion, has been called bile acid diarrhea, cussed earlier.) Three types of fatty acids compose fats:
SECTION III
or choleretic enteropathy, and responds promptly to long-chain fatty acids (LCFAs), medium-chain fatty acids
cholestyramine, an anion-binding resin. Such patients (MCFAs), and short-chain fatty acids (SCFAs) (Table
do not develop steatorrhea because hepatic synthe- 15-3). Dietary fat is exclusively composed of long-chain
sis of bile acids increases to compensate for the rate of triglycerides (LCTs), i.e., glycerol that is bound via ester-
fecal bile acid losses, resulting in maintenance of both linkages to three LCFAs. While the majority of dietary
the bile acid pool size and the intraduodenal concen- LCFAs have carbon chain lengths of 16 or 18, fatty acids
Disorders of the Alimentary Tract
trations of bile acids. In contrast, patients with greater of carbon chain length >12 are metabolized in the same
degrees of ileal disease and/or resection will often manner; saturated and unsaturated fatty acids are handled
have diarrhea and steatorrhea that do not respond to identically.
cholestyramine. In this situation, ileal disease is also Assimilation of dietary lipid requires three integrated
associated with increased amounts of bile acids enter- processes: (1) an intraluminal, or digestive, phase; (2)
ing the colon; however, hepatic synthesis can no longer a mucosal, or absorptive, phase; and (3) a delivery, or
increase sufficiently to maintain the bile acid pool size. postabsorptive, phase. An abnormality at any site of this
As a consequence, the intraduodenal concentration of process can cause steatorrhea (Table 15-4). Therefore,
bile acids is also reduced to less than the CMC, result-
ing in impaired micelle formation and steatorrhea. This Table 15-4
second situation is often called fatty acid diarrhea. Chole- Defects in Lipid Digestion and Absorption in
styramine may not be effective (and may even increase Steatorrhea
the diarrhea by further depleting the intraduodenal bile
Phase: Pathophysiologic Disease
acid concentration); however, a low-fat diet to reduce Process Defect Example
fatty acids entering the colon can be effective. Two
clinical features, the length of ileum removed and the Digestive
degree of steatorrhea, can predict whether an individual Lipolysis Decreased lipase Chronic pancreatitis
patient will respond to cholestyramine. Unfortunately, formation secretion
these predictors are imperfect, and a therapeutic trial of Micelle Decreased See Table 15-1
cholestyramine is often necessary to establish whether formation intraduodenal
an individual patient will benefit from cholestyramine. bile acids
Table 15-2 contrasts the characteristics of bile acid diar- Absorptive
rhea (small ileal dysfunction) and fatty acid diarrhea Mucosal Mucosal Celiac disease
(large ileal dysfunction). uptake and dysfunction
reesterifica-
tion
Lipids Postabsorptive
Steatorrhea is caused by one or more defects in the diges- Chylomicron Absent Abetalipoproteinemia
tion and absorption of dietary fat. Average intake of dietary formation betalipoproteins
fat in the United States is approximately 120–150 g/d, Delivery from Abnormal Intestinal
and fat absorption is linear to dietary fat intake. The total intestine lymphatics lymphangiectasia
load of fat presented to the small intestine is considerably
Pancreas Liver Jejunal Mucosa Lymphatics 161
Lipolysis Micellar Absorption Delivery
Solubilization
with Bile Acid
(1) Esterification
Fatty acids
Fatty acids
Triglycerides
Triglycerides
To tissues
for utilization
of fat
β-Monoglyceride Cholesterol
β-Monoglyceride Phospholipid
β−Lipoprotein
(2) Chylomicron
formation
Figure 15-2
Schematic representation of lipid digestion and absorption. the duodenum; (2) an absorptive phase for mucosal uptake
Dietary lipid is in the form of long-chain triglycerides (LCTs). and reesterification; and (3) a postabsorptive phase that
The overall process can be divided into (1) a digestive phase includes chylomicron formation and exit from the intestinal
CHAPTER 15
that includes both lipolysis and micelle formation requiring epithelial cell via lymphatics. (Courtesy of John M. Dietschy,
pancreatic lipase and conjugated bile acids, respectively, in MD; with permission.)
it is essential that any patient with steatorrhea be evalu- chronic pancreatitis (who have reduced lipase secretion)
ated to identify the specific physiologic defect in over- often have a decrease in pancreatic bicarbonate secre-
all lipid digestion-absorption, as therapy will be deter- tion, which will also result in a decrease in intraduode-
Disorders of Absorption
mined by the specific cause of the steatorrhea. nal pH and inactivation of endogenous pancreatic lipase
The digestive phase has two components, lipolysis and or of therapeutically administered lipase.
micellar formation. Although dietary lipid is in the form Overlying the microvillus membrane of the small
of LCTs, the intestinal mucosa does not absorb triglyc- intestine is the so-called unstirred water layer, a relatively
erides; they must first be hydrolyzed (Fig. 15-2). The stagnant aqueous phase that must be traversed by the
initial step in lipid digestion is the formation of emul- products of lipolysis that are primarily water-insoluble.
sions of finely dispersed lipid, which is accomplished Water-soluble mixed micelles provide a mechanism for
by mastication and gastric contractions. Lipolysis, the the water-insoluble products of lipolysis to reach the
hydrolysis of triglycerides to free fatty acids, monoglyc- luminal plasma membrane of villous epithelial cells, the
erides, and glycerol by lipase, is initiated in the stomach site for lipid absorption. Mixed micelles are molecular
by lingual and gastric lipases that have a pH optimum aggregates composed of fatty acids, monoglycerides,
of 4.5–6.0. About 20–30% of total lipolysis occurs in phospholipids, cholesterol, and conjugated bile acids.
the stomach. Lipolysis is completed in the duodenum Mixed micelles are formed when the concentration of
and jejunum by pancreatic lipase, which is inactivated conjugated bile acids is greater than its CMC, which
by a pH <7.0. Pancreatic lipolysis is greatly enhanced differs among the several bile acids present in the small
by the presence of a second pancreatic enzyme, intestinal lumen. Conjugated bile acids, synthesized in
colipase, which facilitates the movement of lipase to the the liver and excreted into the duodenum in bile, are
triglyceride. regulated by the enterohepatic circulation (see above).
Impaired lipolysis can lead to steatorrhea and can Steatorrhea can result from impaired movement of fatty
occur in the presence of pancreatic insufficiency due acids across the unstirred aqueous fluid layer in two sit-
to chronic pancreatitis in adults or cystic fibrosis in uations: (1) an increase in the relative thickness of the
children and adolescents. Normal lipolysis can be unstirred water layer that occurs in bacterial overgrowth
maintained by approximately 5% of maximal pancre- syndromes (discussed later) secondary to functional
atic lipase secretion; thus, steatorrhea is a late manifes- stasis (e.g., scleroderma); and (2) a decrease in the
tation of these disorders. A reduction in intraduodenal duodenal concentration of conjugated bile acids below its
pH can also result in altered lipolysis as pancreatic lipase CMC, resulting in impaired micelle formation. Thus,
is inactivated at pH <7. Thus, ∼15% of patients with steatorrhea can be caused by one or more defects in the
gastrinoma (Chap. 14) with substantial increases in enterohepatic circulation of bile acids.
gastric acid secretion from ectopic production of gastrin Uptake and reesterification constitute the absorptive
(usually from an islet cell adenoma) have diarrhea, and phase of lipid digestion-absorption. Although passive dif-
some will have steatorrhea believed secondary to acid- fusion has been thought responsible, a carrier-mediated
inactivation of pancreatic lipase. Similarly, patients with process may mediate fatty acid and monoglyceride
162 uptake. Regardless of the uptake process, fatty acids and epithelial cells; and (5) their route of exit is via the por-
monoglycerides are reesterified by a series of enzymatic tal vein and not via lymphatics. Thus, the absorption of
steps in the endoplasmic reticulum to form triglycerides, MCTs is greater than that of LCTs in pancreatic insuffi-
the form in which lipid exits from the intestinal epithelial ciency, conditions with reduced intraduodenal bile acid
cell. Impaired lipid absorption as a result of either concentrations, small-intestinal mucosal disease, abetali-
mucosal inflammation (e.g., celiac disease) and/or intes- poproteinemia, and intestinal lymphangiectasia.
tinal resection can also lead to steatorrhea. SCFAs are not dietary lipids but are synthesized by
The reesterified triglycerides require the formation of colonic bacterial enzymes from nonabsorbed carbo-
chylomicrons to permit their exit from the small-intesti- hydrate and are the anions in highest concentration in
nal epithelial cell and their delivery to the liver via the stool (between 80 and 130 mM). The SCFAs present
lymphatics. Chylomicrons are composed of β-lipoprotein in stool are primarily acetate, propionate, and butyrate,
and contain triglycerides, cholesterol, cholesterol esters, whose carbon chain lengths are 2, 3, and 4, respec-
and phospholipids and enter the lymphatics, not the tively. Butyrate is the primary nutrient for colonic
portal vein. Defects in the postabsorptive phase of lipid epithelial cells, and its deficiency may be associated with
digestion-absorption can also result in steatorrhea, but one or more colitides. SCFAs conserve calories and
these disorders are uncommon. Abetalipoproteinemia, carbohydrate, because carbohydrates not completely
or acanthocytosis, is a rare disorder of impaired synthe- absorbed in the small intestine will not be absorbed in
SECTION III
sis of β-lipoprotein associated with abnormal erythrocytes the large intestine due to the absence of both disaccha-
(acanthocytes), neurologic problems, and steatorrhea. ridases and SGLT1, the transport protein that medi-
Lipolysis, micelle formation, and lipid uptake are all ates monosaccharide absorption. In contrast, SCFAs are
normal in patients with abetalipoproteinemia, but rapidly absorbed and stimulate colonic Na-Cl and fluid
the reesterified triglyceride cannot exit from the epi- absorption. Most non–Clostridium difficile antibiotic-
thelial cell because of the failure to produce chylomi- associated diarrhea is due to antibiotic suppression of
Disorders of the Alimentary Tract
crons. Small-intestinal biopsies of these rare patients in colonic microbiota, with a resulting decrease in SCFA
the postprandial state reveal lipid-laden small-intestinal production. As C. difficile accounts for about 15–20% of
epithelial cells that become perfectly normal in appear- all antibiotic-associated diarrhea, a relative decrease in
ance following a 72–96 h fast. Similarly, abnormalities colonic production of SCFA is likely the cause of most
of intestinal lymphatics (e.g., intestinal lymphangiectasia) antibiotic-associated diarrhea.
may also be associated with steatorrhea as well as protein The clinical manifestations of steatorrhea are a conse-
loss (discussed later). Steatorrhea can result from defects quence of both the underlying disorder responsible for
at any of the several steps in lipid digestion-absorption. the development of steatorrhea and steatorrhea per se.
The mechanism of lipid digestion-absorption out- Depending on the degree of steatorrhea and the level
lined earlier is limited to dietary lipid that is almost of dietary intake, significant fat malabsorption may lead
exclusively in the form of LCTs (Table 15-3). Medium- to weight loss. Steatorrhea per se can be responsible for
chain triglycerides (MCTs), composed of fatty acids diarrhea; if the primary cause of the steatorrhea has not
with carbon chain lengths of 8–12, are present in large been identified, a low-fat diet can often ameliorate the
amounts in coconut oil and are used as a nutritional diarrhea by decreasing fecal fat excretion. Steatorrhea
supplement. MCTs can be digested and absorbed by is often associated with fat-soluble vitamin deficiency,
a different pathway from LCTs and at one time held which will require replacement with water-soluble
promise as an important treatment of steatorrhea of preparations of these vitamins.
almost all etiologies. Unfortunately, their therapeutic Disorders of absorption may also be associated with
effects have been less than expected because their use is malabsorption of other dietary nutrients, most often
often not associated with an increase in body weight for carbohydrates, with or without a decrease in dietary
reasons that are not completely understood. lipid digestion and absorption. Therefore, knowledge of
MCTs, in contrast to LCTs, do not require pancre- the mechanism of the digestion and absorption of car-
atic lipolysis as the triglyceride can be absorbed intact by bohydrates, proteins, and other minerals and vitamins is
the intestinal epithelial cell. Further, micelle formation is useful in the evaluation of patients with altered intesti-
not necessary for the absorption of MCTs or medium- nal nutrient absorption.
chain fatty acids, if hydrolyzed by pancreatic lipase.
MCTs are absorbed more efficiently than LCTs for the
Carbohydrates
following reasons: (1) The rate of MCT absorption is
greater than that of long-chain fatty acids; (2) medium- Carbohydrates in the diet are present in the form of
chain fatty acids following absorption are not reesteri- starch, disaccharides (sucrose and lactose), and glucose.
fied; (3) following absorption, MCTs are hydrolyzed Carbohydrates are absorbed only in the small intestine
to medium-chain fatty acids; (4) MCTs do not require and only in the form of monosaccharides. Therefore,
chylomicron formation for their exit from the intestinal before their absorption, starch and disaccharides must
first be digested by pancreatic amylase and intestinal with lactose intolerance while on a strict lactose-free 163
brush border disaccharidases to monosaccharides. Mono- diet would suggest that the individual’s symptoms were
saccharide absorption occurs by a Na-dependent process related to irritable bowel syndrome.
mediated by the brush border transport protein SGLT1. Development of symptoms of lactose intolerance is
Lactose malabsorption is the only clinically impor- related to several factors:
tant disorder of carbohydrate absorption. Lactose, the
1. Amount of lactose in the diet.
disaccharide present in milk, requires digestion by brush
2. Rate of gastric emptying. Symptoms are more likely
border lactase to its two constituent monosaccharides,
when gastric emptying is rapid than when gastric
glucose and galactose. Lactase is present in almost all
emptying is slower. Therefore, it is more likely that
species in the postnatal period but then disappears
skim milk will be associated with symptoms of lac-
throughout the animal kingdom, except in humans.
tose intolerance than will whole milk, as the rate of
Lactase activity persists in many individuals throughout
gastric emptying following skim milk intake is more
life. Two different types of lactase deficiency exist—
rapid. Similarly, the diarrhea observed following
primary and secondary. In primary lactase deficiency, a
subtotal gastrectomy is often a result of lactose intol-
genetically determined decrease or absence of lactase is
erance, as gastric emptying is accelerated in patients
noted, while all other aspects of both intestinal absorp-
with a gastrojejunostomy.
tion and brush border enzymes are normal. In a number
3. Small-intestinal transit time. Although the small and
CHAPTER 15
of non-white groups, primary lactase deficiency is com-
large intestine contribute to the development of
mon in adulthood. Table 15-5 presents the incidence
symptoms, many of the symptoms of lactase defi-
of primary lactase deficiency in several ethnic groups.
ciency are related to the interaction of colonic bacteria
Northern European and North American whites are the
and nonabsorbed lactose. More rapid small-intestinal
only groups to maintain small-intestinal lactase activ-
transit makes symptoms more likely.
ity throughout adult life. The persistence of lactase is
4. Colonic compensation by production of SCFAs from non-
Disorders of Absorption
the abnormality due to a defect in the regulation of its
absorbed lactose. Reduced levels of colonic micro-
maturation. In contrast, secondary lactase deficiency occurs
flora, which can occur following antibiotic use, will
in association with small-intestinal mucosal disease with
also be associated with increased symptoms follow-
abnormalities in both structure and function of other
ing lactose ingestion, especially in a lactase-deficient
brush border enzymes and transport processes. Second-
individual.
ary lactase deficiency is often seen in celiac disease.
As lactose digestion is rate-limiting compared to Glucose-galactose or monosaccharide malabsorption
glucose/galactose absorption, lactase deficiency is associ- may also be associated with diarrhea and is due to a
ated with significant lactose malabsorption. Some indi- congenital absence of SGLT1. Diarrhea is present when
viduals with lactose malabsorption develop symptoms individuals with this disorder ingest carbohydrates that
such as diarrhea, abdominal pain, cramps, and/or flatus. contain actively transported monosaccharides (e.g., glucose,
Most individuals with primary lactase deficiency do not galactose) but not monosaccharides that are not actively
have symptoms. Since lactose intolerance may be associ- transported (e.g., fructose). Fructose is absorbed by
ated with symptoms suggestive of irritable bowel syn- the brush border transport protein GLUT 5, a facili-
drome, persistence of such symptoms in an individual tated diffusion process that is not Na-dependent and
is distinct from SGLT1. In contrast, some individuals
Table 15-5 develop diarrhea as a result of consuming large quanti-
ties of sorbitol, a sugar used in diabetic candy; sorbitol is
Primary Lactase Deficiency in Different
Adult Ethnic Groups
only minimally absorbed due to the absence of an intes-
tinal absorptive transport mechanism for sorbitol.
Prevalence of Lactase
Ethnic Group Deficiency, %
focused, and expensive laboratory and imaging studies. “gold standard” still remains a timed, quantitative stool
For example, a clinician evaluating a patient with symp- fat determination. On a practical basis, stool collections
toms suggestive of malabsorption, who recently had are invariably difficult and often incomplete, as nobody
extensive small-intestinal resection for mesenteric wants to handle stool. A qualitative test—Sudan III
ischemia, should direct the initial assessment almost stain—has long been available to establish the pres-
exclusively to define whether a short bowel syndrome ence of an increase in stool fat. This test is rapid and
might explain the entire clinical picture. Similarly, the inexpensive but, as a qualitative test, does not estab-
development of a pattern of bowel movements sugges- lish the degree of fat malabsorption and is best used
tive of steatorrhea in a patient with long-standing alco- as a preliminary screening study. Many of the blood,
hol abuse and chronic pancreatitis should lead toward breath, and isotopic tests that have been developed
assessing pancreatic exocrine function. (1) do not directly measure fat absorption; (2) have excel-
The classic picture of malabsorption is rarely seen lent sensitivity when steatorrhea is obvious and severe
today in most parts of the United States. As a conse- but have poor sensitivity when steatorrhea is mild (e.g.,
quence, diseases with malabsorption must be sus- stool chymotrypsin, elastase, that can potentially distin-
pected in individuals with less severe symptoms and guish pancreatic from nonpancreatic etiologies of steat-
signs and with subtle evidence of the altered absorption orrhea); or (3) have not survived the transition from the
of only a single nutrient rather than obvious evidence of research laboratory to commercial application.
the malabsorption of multiple nutrients. Despite this situation, the use of routine laboratory
Although diarrhea can be caused by changes in fluid studies (i.e., complete blood count, prothrombin time,
and electrolyte movement in either the small or the serum protein determination, alkaline phosphatase) may
large intestine, dietary nutrients are absorbed almost suggest the presence of dietary nutrient depletion, espe-
exclusively in the small intestine. Therefore, the dem- cially iron, folate, cobalamin, and vitamins D and K. Addi-
onstration of diminished absorption of a dietary nutri- tional studies include measurement of serum carotene,
ent provides unequivocal evidence of small-intestinal cholesterol, albumin, iron, folate, and cobalamin lev-
disease, although colonic dysfunction may also be pres- els. The serum carotene level can also be reduced if the
ent (e.g., Crohn’s disease may involve both small and patient has poor dietary intake of leafy vegetables.
large intestine). Dietary nutrient absorption may be seg- If steatorrhea and/or altered absorption of other
mental or diffuse along the small intestine and is site- nutrients are suspected, the history, clinical observa-
specific. Thus, for example, calcium, iron, and folic acid tions, and laboratory testing can help detect deficiency
are exclusively absorbed by active transport processes in of a nutrient, especially the fat-soluble vitamins A, D,
the proximal small intestine, especially the duodenum; E, or K. Thus, evidence of metabolic bone disease with
elevated alkaline phosphatase and/or reduced serum resumed or suspected malabsorption. These stud-
p
165
calcium levels would suggest vitamin D malabsorption. ies are most often performed in conjunction with the
A deficiency of vitamin K would be suggested by an examination of the esophagus, stomach, and duodenal
elevated prothrombin time in an individual without liver bulb, and insufficient barium is given to the patient to
disease who was not taking anticoagulants. Macrocytic permit an adequate examination of the small-intestinal
anemia would lead to evaluation of whether cobalamin mucosa, especially the ileum. As a result, many gastro-
or folic acid malabsorption was present. The presence of intestinal radiologists alter the procedure of a barium
iron-deficiency anemia in the absence of occult bleeding contrast examination of the small intestine by perform-
from the gastrointestinal tract in either a male or a non- ing either a small-bowel series in which a large amount
menstruating female would require evaluation of iron of barium is given by mouth without concurrent exami-
malabsorption and the exclusion of celiac disease, as iron nation of the esophagus and stomach or an enteroclysis
is absorbed exclusively in the proximal small intestine. study in which a large amount of barium is introduced
At times, however, a timed (72 h) quantitative into the duodenum via a fluoroscopically placed tube.
stool collection, preferably on a defined diet, must be In addition, many of the diagnostic features initially
obtained to determine stool fat content and establish described by radiologists to denote the presence of
the presence of steatorrhea. The presence of steatorrhea small-intestinal disease (e.g., flocculation, segmentation)
CHAPTER 15
then requires further assessment to establish the patho- are rarely seen with current barium suspensions. None-
physiologic process(es) responsible for the defect in theless, in skilled hands barium contrast examination
dietary lipid digestion-absorption (Table 15-4). Some of of the small intestine can yield important information.
the other studies include the Schilling test, d-xylose test, For example, with extensive mucosal disease, dilation
duodenal mucosal biopsy, small-intestinal radiologic of intestine can be seen, as dilution of barium from
examination, and tests of pancreatic exocrine function. increased intestinal fluid secretion (Fig. 15-3). A normal
barium contrast study does not exclude the possibil-
Disorders of Absorption
The Schilling Test This test is performed
ity of small-intestinal disease. However, a small-bowel
to determine the cause of cobalamin malabsorption.
series remains a useful examination to look for ana-
Unfortunately, the Schilling test has not been avail-
tomic abnormalities, such as strictures and fistulas (as in
able commercially in the United States for the past few
Crohn’s disease) or blind loop syndrome (e.g., multiple
years. Since understanding the physiology and patho-
jejunal diverticula), and to define the extent of a previ-
physiology of cobalamin absorption is very valuable to
ous surgical resection. Other imaging studies to assess
enhance one’s understanding of aspects of gastric, pan-
the integrity of small intestinal morphology are CT
creatic, and ileal function, discussion of the Schilling test
enteroclysis and magnetic resonance (MR) enteroclysis,
is provided in Chap. 16.
while capsule endoscopy and double-barrel enteros-
Urinary d-Xylose Test The urinary d-xylose copy are other useful aids in the diagnostic assessment
test for carbohydrate absorption provides an assess- of small-intestinal pathology.
ment of proximal small-intestinal mucosal function.
d-Xylose, a pentose, is absorbed almost exclusively in Biopsy of Small-Intestinal Mucosa
the proximal small intestine. The d-xylose test is usually A small-intestinal mucosal biopsy is essential in the
performed by giving 25 g d-xylose and collecting urine evaluation of a patient with documented steatorrhea or
for 5 h. An abnormal test (<4.5 g excretion) primar- chronic diarrhea (lasting >3 weeks) (Chap. 6). The ready
ily reflects the presence of duodenal/jejunal mucosal availability of endoscopic equipment to examine the
disease. The d-xylose test can also be abnormal in stomach and duodenum has led to its almost uniform
patients with blind loop syndrome (as a consequence use as the preferred method to obtain histologic mate-
primarily of abnormal intestinal mucosa) and, as a false- rial of proximal small-intestinal mucosa. The primary
positive study, in patients with large collections of fluid indications for a small-intestinal biopsy are (1) evaluation
in a third space (i.e., ascites, pleural fluid). The ease of of a patient either with documented or suspected steat-
obtaining a mucosal biopsy of the small intestine by orrhea or with chronic diarrhea, and (2) diffuse or focal
endoscopy and the false-negative rate of the d-xylose abnormalities of the small intestine defined on a small-
test have led to its diminished use. When small-intes- intestinal series. Lesions seen on small-bowel biopsy can
tinal mucosal disease is suspected, a small-intestinal be classified into three different categories (Table 15-6):
mucosal biopsy should be performed.
1. Diffuse, specific lesions. Relatively few diseases associ-
Radiologic Examination Radiologic exami- ated with altered nutrient absorption have specific
nation of the small intestine using barium contrast histopathologic abnormalities on small-intestinal
(small-bowel series or study) can provide impor- mucosal biopsy, and they are uncommon. Whipple’s
tant information in the evaluation of the patient with disease is characterized by the presence of periodic
166
SECTION III
Disorders of the Alimentary Tract
Figure 15-3
Barium contrast small-intestinal radiologic examinations. A. Normal individual. B. Celiac sprue. C. Jejunal diverticulosis.
D. Crohn’s disease. (Courtesy of Morton Burrell, MD, Yale University; with permission.)
acid–Schiff (PAS)–positive macrophages in the lamina As a result, biopsies obtained randomly or in the
propria, while the bacilli that are also present may absence of abnormalities visualized endoscopically
require electron-microscopic examination for identi- may not reveal the diagnostic features. Intestinal lym-
fication (Fig. 15-4). Abetalipoproteinemia is character- phoma can at times be diagnosed on mucosal biopsy
ized by a normal mucosal appearance except for the by the identification of malignant lymphoma cells in
presence of mucosal absorptive cells that contain lipid the lamina propria and submucosa. The presence of
postprandially and disappear following a prolonged dilated lymphatics in the submucosa and sometimes
period of either fat-free intake or fasting. Immune in the lamina propria indicates the presence of lym-
globulin deficiency is associated with a variety of his- phangiectasia associated with hypoproteinemia sec-
topathologic findings on small-intestinal mucosal ondary to protein loss into the intestine. Eosinophilic
biopsy. The characteristic feature is the absence of gastroenteritis comprises a heterogeneous group
or substantial reduction in the number of plasma of disorders with a spectrum of presentations and
cells in the lamina propria; the mucosal architecture symptoms with an eosinophilic infiltrate of the lam-
may be either perfectly normal or flat (i.e., villous ina propria, with or without peripheral eosinophilia.
atrophy). As patients with immune globulin defi- The patchy nature of the infiltrate as well as its pres-
ciency are often infected with Giardia lamblia, ence in the submucosa often leads to an absence of
Giardia trophozoites may also be seen in the biopsy. histopathologic findings on mucosal biopsy. As the
2. Patchy, specific lesions. Several diseases show abnor- involvement of the duodenum in Crohn’s disease is
mal small-intestinal mucosa with a patchy distribution. also submucosal and not necessarily continuous,
Table 15-6 167
giardiasis. In most other instances the infection is picked
Disease That Can Be Diagnosed by Small-
Intestinal Mucosal Biopsies up incidentally during the workup of diarrhea or other
abdominal symptoms. Many of these infections occur
Lesions Pathologic Findings
in immunocompromised patients with diarrhea and
Diffuse, Specific include Cryptosporidium, Isospora belli, Microsporidia,
Whipple’s disease Lamina propria contains Cyclospora, Toxoplasma, cytomegalovirus, adenovirus,
macrophages containing Mycobacterium avium-intracellulare, and G. lamblia. In
PAS+ material immunocompromised patients, when Candida, Asper-
Agammaglobulinemia No plasma cells; either gillus, Cryptococcus, or Histoplasma organisms are seen
normal or absent villi on duodenal biopsy, their presence generally reflects
(“flat mucosa”) systemic infection. Apart from Whipple’s disease and
Abetalipoproteinemia Normal villi; epithelial cells
infections in the immunocompromised host, the small
vacuolated with fat
postprandially bowel biopsy is seldom used as the primary mode to
diagnose infection. Even giardiasis is more easily diag-
Patchy, Specific
nosed with duodenal aspirates and/or stool antigen
Intestinal lymphoma Malignant cells in lamina studies than by duodenal biopsy.
propria and submucosa
CHAPTER 15
4. Diffuse, nonspecific lesions. Celiac disease presents with a
Intestinal Dilated lymphatics;
lymphangiectasia clubbed villi
characteristic mucosal appearance on duodenal/proxi-
Eosinophilic Eosinophil infiltration of mal jejunal mucosal biopsy that is not diagnostic of the
gastroenteritis lamina propria and mucosa disease. The diagnosis of celiac disease is established by
Amyloidosis Amyloid deposits clinical, histologic, and immunologic response to a glu-
Crohn’s disease Noncaseating granulomas ten-free diet. Tropical sprue is associated with histologic
Infection by one or Specific organisms findings similar to those of celiac disease after a tropical
Disorders of Absorption
more microorganisms or subtropical exposure but does not respond to gluten
(see text)
restriction; most often symptoms improve with antibi-
Mastocytosis Mast cell infiltration of
lamina propria otics and folate administration.
Diffuse, Nonspecific Patients with steatorrhea require assessment of pancre-
Celiac disease Short or absent villi; mono- atic exocrine function, which is often abnormal in chronic
nuclear infiltrate; epithelial pancreatitis. The secretin test that collects pancreatic
cell damage; hypertrophy secretions by duodenal intubation following intravenous
of crypts administration of secretin is the only test that directly
Tropical sprue Similar to celiac disease measures pancreatic exocrine function but is available
Bacterial overgrowth Patchy damage to villi; only at few specialized centers. Endoscopic approaches
lymphocyte infiltration
provide excellent assessment of pancreatic duct anatomy
Folate deficiency Short villi; decreased mitosis
in crypts; megalocytosis but do not assess exocrine function (Chap. 47).
Vitamin B12 deficiency Similar to folate deficiency Table 15-7 summarizes the results of the d-xylose
Radiation enteritis Similar to folate deficiency test, Schilling test, and small-intestinal mucosal biopsy
Zollinger-Ellison syn- Mucosal ulceration and in patients with five different causes of steatorrhea.
drome erosion from acid
Protein-calorie Villous atrophy; secondary
malnutrition bacterial overgrowth
Drug-induced enteritis Variable histology Specific Disease Entities
Figure 15-4
Small-intestinal mucosal biopsies. A. Normal individual. G. Giardiasis. (Courtesy of Marie Robert, MD, Yale University;
B. Untreated celiac sprue. C. Treated celiac sprue. D. Intes- with permission.)
tinal lymphangiectasia. E. Whipple’s disease. F. Lymphoma.
is not known, but environmental, immunologic, and The hallmark of celiac disease is the presence of an
genetic factors are important. Celiac disease is considered abnormal small-intestinal biopsy (Fig. 15-4) and the
an “iceberg” disease with a small number of individu- response of the condition—symptoms and the histologic
als with classical symptoms and manifestations related to changes on the small-intestinal biopsy—to the elimi-
nutrient malabsorption, and a varied natural history, with nation of gluten from the diet. The histologic changes
the onset of symptoms occurring at ages ranging from have a proximal-to-distal intestinal distribution of sever-
the first year of life through the eighth decade. A much ity, which probably reflects the exposure of the intes-
larger number of individuals have manifestations that are tinal mucosa to varied amounts of dietary gluten; the
not obviously related to intestinal malabsorption, e.g., symptoms do not necessarily correlate with histologic
anemia, osteopenia, infertility, neurologic symptoms changes especially as many newly diagnosed patients
(“atypical celiac disease”); while an even larger group is with celiac disease may be asymptomatic.
essentially asymptomatic although with abnormal small- The symptoms of celiac disease may appear with
intestinal histopathology and serologies (discussed later) the introduction of cereals in an infant’s diet, although
and as is referred to as having “silent” celiac disease. spontaneous remissions often occur during the second
Table 15-7 169
Results of Diagnostic Studies in Different Causes of Steatorrhea
d-Xylose Test Schilling Test Duodenal Mucosal Biopsy
decade of life that may be either permanent or fol- antibody is tTG, which deaminates gliadin, which is pre-
lowed by the reappearance of symptoms over several sented to HLA-DQ2 or HLA-DQ8 (discussed later).
years. Alternatively, the symptoms of celiac disease may Antibody studies are frequently used to identify patients
CHAPTER 15
first become evident at almost any age throughout with celiac disease; patients with these antibodies should
adulthood. In many patients, frequent spontaneous undergo duodenal biopsy. This autoantibody has not
remissions and exacerbations occur. The symptoms been linked to a pathogenetic mechanism (or mecha-
range from significant malabsorption of multiple nutri- nisms) responsible for celiac disease. Nonetheless, this
ents, with diarrhea, steatorrhea, weight loss, and the antibody is useful in establishing the true prevalence of
consequences of nutrient depletion (i.e., anemia and celiac disease in the general population. A 4-week treat-
Disorders of Absorption
metabolic bone disease), to the absence of any gastro- ment with prednisolone of a patient with celiac disease
intestinal symptoms but with evidence of the deple- who continues to eat gluten will induce a remission and
tion of a single nutrient (e.g., iron or folate deficiency, convert the “flat” abnormal duodenal biopsy to a more
osteomalacia, edema from protein loss). Asymptomatic normal-appearing one. In addition, gliadin peptides
relatives of patients with celiac disease have been iden- interact with gliadin-specific T cells that mediate tissue
tified as having this disease either by small-intestinal injury and induce the release of one or more cytokines
biopsy or by serologic studies [e.g., antiendomysial anti- (e.g., IFN-γ) that cause tissue injury.
bodies, tissue transglutaminase (tTG)]. The availabil- Genetic factor(s) are also involved in celiac disease.
ity of these “celiac serologies” has led to a substantial The incidence of symptomatic celiac disease varies
increase in the diagnosis of celiac disease, and the diag- widely in different population groups (high in whites,
nosis is now being made primarily in patients without low in blacks and Asians) and is 10% in first-degree rela-
“classic” symptoms but with atypical and subclinical tives of celiac disease patients; however, serologic studies
presentations. provide clear evidence that celiac disease is present
worldwide. Furthermore, all patients with celiac disease
Etiology express the HLA-DQ2 or HLA-DQ8 allele, though
only a minority of people expressing DQ2/DQ8 have
The etiology of celiac disease is not known, but envi-
celiac disease. Absence of DQ2/DQ8 excludes the diag-
ronmental, immunologic, and genetic factors all appear
nosis of celiac disease.
to contribute to the disease. One environmental factor
is the clear association of the disease with gliadin, a
Diagnosis
component of gluten that is present in wheat, barley,
and rye. In addition to the role of gluten restriction in A small-intestinal biopsy is required to establish a diag-
treatment, the instillation of gluten into both normal- nosis of celiac disease (Fig. 15-4). A biopsy should be
appearing rectum and distal ileum of patients with celiac performed in patients with symptoms and laboratory
disease results in morphologic changes within hours. findings suggestive of nutrient malabsorption and/or
An immunologic component in the pathogenesis of celiac deficiency and with a positive endomysial antibody test.
disease is critical and involves both adaptive and innate Since the presentation of celiac disease is often subtle,
immune responses. Serum antibodies—IgA antigliadin, without overt evidence of malabsorption or nutri-
IgA antiendomysial, and IgA anti-tTG antibodies—are ent deficiency, a relatively low threshold to perform
present, but it is not known whether such antibodies are a biopsy is important. It is more prudent to perform a
primary or secondary to the tissue damage. The antien- biopsy than to obtain another test of intestinal absorp-
domysial antibody has 90–95% sensitivity and 90–95% tion, which can never completely exclude or establish
specificity; the antigen recognized by the antiendomysial this diagnosis.
170 The diagnosis of celiac disease requires the presence complications of celiac disease, such as development of
of characteristic histologic changes on small-intestinal intestinal T cell lymphoma.
biopsy together with a prompt clinical and histologic
response following the institution of a gluten-free
diet. If serologic studies have detected the presence Mechanism of diarrhea
of IgA antiendomysial or tTG antibodies, they too The diarrhea in celiac disease has several pathogenetic
should disappear after a gluten-free diet is started. mechanisms. Diarrhea may be secondary to (1) steatorrhea,
With the increase in number of patients diagnosed which is primarily a result of the changes in jejunal
with celiac disease that have been largely identified by mucosal function; (2) secondary lactase deficiency, a
serologic studies, the spectrum of histologic changes consequence of changes in jejunal brush border enzy-
seen on duodenal biopsy has increased and includes matic function; (3) bile acid malabsorption resulting in
findings that are not as severe as the classic changes bile acid–induced fluid secretion in the colon, in cases
shown in Fig. 15-4. The classical changes seen on with more extensive disease involving the ileum; and
duodenal/jejunal biopsy are restricted to the mucosa (4) endogenous fluid secretion resulting from crypt
and include (1) an increase in the number of intraepi- hyperplasia. Patients with more severe involvement with
thelial lymphocytes; (2) absence or reduced height celiac disease may obtain temporary improvement with
of villi, resulting in a flat appearance with increased dietary lactose and fat restriction while awaiting the full effects
SECTION III
crypt cell proliferation, resulting in crypt hyperpla- of total gluten restriction, which is primary therapy.
sia and loss of villous structure, with consequent
villous, but not mucosal, atrophy; (3) cuboidal
appearance and nuclei that are no longer oriented Associated diseases
basally in surface epithelial cells; and (4) increased
Celiac disease is associated with dermatitis herpetiformis
lymphocytes and plasma cells in the lamina propria
(DH), though the association has not been explained.
Disorders of the Alimentary Tract
CHAPTER 15
the pathogenesis of tropical sprue requires clarification.
Chronic diarrhea in a tropical environment is most
Folic acid is absorbed exclusively in the duodenum
often caused by infectious agents including G. lamblia,
and proximal jejunum, and most patients with tropical
Yersinia enterocolitica, C. difficile, Cryptosporidium parvum,
sprue have evidence of folate malabsorption and deple-
and Cyclospora cayetanensis, among other organisms.
tion. Although folate deficiency can cause changes in
Tropical sprue should not be entertained as a possible
small-intestinal mucosa that are corrected by folate
diagnosis until the presence of cysts and trophozoites has
Disorders of Absorption
replacement, several earlier studies reporting that tropi-
been excluded in three stool samples.
cal sprue could be cured by folic acid did not provide
Chronic infections of the gastrointestinal tract and
an explanation for the “insult” that was initially respon-
diarrhea in patients with and without AIDS are dis-
sible for folate malabsorption.
cussed in Chap. 23.
The clinical pattern of tropical sprue varies in differ-
The small-intestinal mucosa in individuals living in
ent areas of the world (e.g., India vs. Puerto Rico). Not
tropical areas is not identical to that of individuals who
infrequently, individuals in South India initially will
reside in temperate climates. Biopsies reveal a mild
report the occurrence of an acute enteritis before the
alteration of villous architecture with a modest increase
development of steatorrhea and malabsorption. In con-
in mononuclear cells in the lamina propria, which on
trast, in Puerto Rico a most insidious onset of symp-
occasion can be as severe as that seen in celiac disease.
toms and a more dramatic response to antibiotics is seen
These changes are observed both in native residents and
when compared to some other locations. Tropical sprue
in expatriates living in tropical regions and are usually
in different areas of the world may not be the same
associated with mild decreases in absorptive function,
disease, and similar clinical entities may have different
but they revert to “normal” when an individual moves
etiologies.
or returns to a temperate area. Some have suggested that
the changes seen in tropical enteropathy and in tropical
sprue represent different ends of the spectrum of a single Diagnosis
entity, but convincing evidence to support this concept The diagnosis of tropical sprue is best made by the pres-
is lacking. ence of an abnormal small-intestinal mucosal biopsy
in an individual with chronic diarrhea and evidence
of malabsorption who is either residing or has recently
Etiology lived in a tropical country. The small-intestinal biopsy
Because tropical sprue responds to antibiotics, the con- in tropical sprue does not have pathognomonic features
sensus is that it may be caused by one or more infec- but resembles, and can often be indistinguishable from,
tious agents. Nonetheless, the etiology and pathogenesis that seen in celiac disease (Fig. 15-4). The biopsy in
of tropical sprue are uncertain. First, its occurrence is tropical sprue will have less villous architectural altera-
not evenly distributed in all tropical areas; rather, it is tion and more mononuclear cell infiltrate in the lamina
found in specific locations, including southern India, propria. In contrast to celiac disease, the histologic fea-
the Philippines, and several Caribbean islands (e.g., tures of tropical sprue are present with a similar degree
Puerto Rico, Haiti), but is rarely observed in Africa, of severity throughout the small intestine, and a gluten-
Jamaica, or Southeast Asia. Second, an occasional indi- free diet does not result in either clinical or histologic
vidual will not develop symptoms of tropical sprue improvement in tropical sprue.
172 diarrhea can be caused by an increase in bile acids enter-
Treatment Tropical Sprue ing the colon, leading to their stimulation of colonic
fluid and electrolyte secretion. Absence of the ileocecal
Broad-spectrum antibiotics and folic acid are most often
valve is also associated with a decrease in intestinal transit
curative, especially if the patient leaves the tropical area
time and bacterial overgrowth from the colon. The pres-
and does not return. Tetracycline should be used for up
ence of the colon (or a major portion) is associated with
to 6 months and may be associated with improvement
substantially less diarrhea and lower likelihood of intes-
within 1–2 weeks. Folic acid alone will induce a hema-
tinal failure as a result of fermentation of nonabsorbed
tologic remission as well as improvement in appetite,
carbohydrates to SCFAs. The latter are absorbed in the
weight gain, and some morphologic changes in small-
colon and stimulate Na and water absorption, improving
intestinal biopsy. Because of the presence of marked
overall fluid balance. Lactose intolerance as a result of the
folate deficiency, folic acid is most often given together
removal of lactase-containing mucosa as well as gastric
with antibiotics.
hypersecretion may also contribute to the diarrhea.
In addition to diarrhea and/or steatorrhea, a range
Short Bowel Syndrome of nonintestinal symptoms is also observed in some
patients. A significant increase in renal calcium oxalate
This is a descriptive term for the myriad clinical prob- calculi is observed in patients with a small-intestinal
lems that occur following resection of varying lengths
SECTION III
CHAPTER 15
be monitored; replacement therapy should be initi- The etiology of these different disorders is bacterial
ated if indicated. Fat-soluble vitamins, folate, cobala- proliferation in the small intestinal lumen secondary to
min, calcium, iron, magnesium, and zinc are the most either anatomic or functional stasis or to a communi-
critical factors to monitor on a regular basis. If these cation between the relatively sterile small intestine and
approaches are not successful, home PN is an estab- the colon with its high levels of aerobic and anaerobic
lished therapy that can be maintained for many years. bacteria. Several examples of anatomic stasis have been
Small intestinal transplantation is becoming established identified: (1) one or more diverticula (both duodenal
Disorders of Absorption
as a possible approach for individuals with extensive and jejunal) (Fig. 15-3C); (2) fistulas and strictures
intestinal resection who cannot be maintained with- related to Crohn’s disease (Fig. 15-3D); (3) a proximal
out PN, i.e., “intestinal failure.” Considerable attention duodenal afferent loop following a subtotal gastrectomy
has been directed to the potential effectiveness of and gastrojejunostomy; (4) a bypass of the intestine, e.g.,
trophic hormones, e.g., glucagon-like peptide 2 (GLP-2), jejunoileal bypass for obesity; and (5) dilation at the site
to improve absorptive function. of a previous intestinal anastomosis. These anatomic
derangements are often associated with the presence of
a segment (or segments) of intestine out of continuity
Bacterial Overgrowth Syndrome of propagated peristalsis, resulting in stasis and bacterial
Bacterial overgrowth syndrome comprises a group of proliferation. Bacterial overgrowth syndromes can also
disorders with diarrhea, steatorrhea, and macrocytic occur in the absence of an anatomic blind loop when
anemia whose common feature is the proliferation of functional stasis is present. Impaired peristalsis and bacte-
colonic-type bacteria within the small intestine. This rial overgrowth in the absence of a blind loop occur in
bacterial proliferation is due to stasis caused by impaired scleroderma, where motility abnormalities exist in both
peristalsis (functional stasis), changes in intestinal anatomy the esophagus and small intestine. Functional stasis and
(anatomic stasis), or direct communication between the bacterial overgrowth can also occur in association with
small and large intestine. These conditions have also diabetes mellitus and in the small intestine when a direct
been referred to as stagnant bowel syndrome or blind loop connection exists between the small and large intestine,
syndrome. including an ileocolonic resection, or occasionally fol-
lowing an enterocolic anastomosis that permits entry of
Pathogenesis bacteria into the small intestine as a result of bypassing
the ileocecal valve.
The manifestations of bacterial overgrowth syndromes
are a direct consequence of the presence of increased
Diagnosis
amounts of a colonic-type bacterial flora, such as E. coli
or Bacteroides, in the small intestine. Macrocytic anemia is The diagnosis may be suspected from the combination
due to cobalamin, not folate, deficiency. Most bacteria of a low serum cobalamin level and an elevated serum
require cobalamin for growth, and increasing concen- folate level, as enteric bacteria frequently produce folate
trations of bacteria use up the relatively small amounts compounds that will be absorbed in the duodenum.
of dietary cobalamin. Steatorrhea is due to impaired Ideally, the diagnosis of the bacterial overgrowth
micelle formation as a consequence of a reduced intra- syndrome is the demonstration of increased levels of
duodenal concentration of conjugated bile acids and the aerobic and/or anaerobic colonic-type bacteria in a
174 jejunal aspirate obtained by intubation. This special- chain reaction, the hallmark of Whipple’s disease had
ized test is rarely available. Breath hydrogen testing with been the presence of PAS-positive macrophages in the
lactulose (a nondigestible disaccharide) administration small intestine (Fig. 15-4E) and other organs with evi-
has also been used to detect bacterial overgrowth. dence of disease.
The Schilling test can also diagnose bacterial over-
growth (see Chap. 16) but is also not available rou- Etiology
tinely. Often the diagnosis is suspected clinically and
confirmed by response to treatment. Whipple’s disease is caused by a small gram-positive
bacillus, T. whipplei. The bacillus, an Actinobacteria, has
low virulence but high infectivity, and relatively mini-
mal symptoms are observed compared to the extent of
Treatment Bacterial Overgrowth Syndrome
the bacilli in multiple tissues.
Primary treatment should be directed, if at all possible,
to the surgical correction of an anatomic blind loop. Clinical presentation
In the absence of functional stasis, it is important to
The onset of Whipple’s disease is insidious and is charac-
define the anatomic relationships responsible for stasis
terized by diarrhea, steatorrhea, abdominal pain, weight
and bacterial overgrowth. For example, bacterial over-
loss, migratory large-joint arthropathy, and fever as well
SECTION III
CHAPTER 15
protein loss into the gastrointestinal tract occurs in intrinsic peripheral lymphatic disease (Milroy’s disease)
more than 65 different diseases, which can be classified will also have intestinal lymphangiectasia and hypopro-
into three groups: (1) mucosal ulceration, such that the teinemia. Other than steatorrhea and enhanced pro-
protein loss primarily represents exudation across damaged tein loss into the gastrointestinal tract, all other aspects
mucosa, e.g., ulcerative colitis, gastrointestinal carcinomas, of intestinal absorptive function are normal in intestinal
and peptic ulcer; (2) nonulcerated mucosa, but with evi- lymphangiectasia.
dence of mucosal damage so that the protein loss repre-
Disorders of Absorption
sents loss across epithelia with altered permeability, e.g.,
celiac disease and Ménétrier’s disease in the small intestine Other causes
and stomach, respectively; and (3) lymphatic dysfunction, Patients who appear to have idiopathic protein-losing
representing either primary lymphatic disease or second- enteropathy without any evidence of gastrointestinal dis-
ary to partial lymphatic obstruction that may occur as a ease should be examined for cardiac disease—especially
result of enlarged lymph nodes or cardiac disease. right-sided valvular disease and chronic pericarditis. On
occasion, hypoproteinemia can be the only presenta-
Diagnosis tion for these two types of heart disease. Ménétrier’s dis-
ease (also called hypertrophic gastropathy) is an uncommon
The diagnosis of protein-losing enteropathy is sug- entity that involves the body and fundus of the stomach
gested by the presence of peripheral edema and low and is characterized by large gastric folds, reduced gastric
serum albumin and globulin levels in the absence of acid secretion, and, at times, enhanced protein loss into the
renal and hepatic disease. An individual with protein- stomach.
losing enteropathy only rarely has selective loss of only
albumin or only globulins. Therefore, marked reduction
of serum albumin with normal serum globulins should
not initiate an evaluation for protein-losing enteropa- Treatment Protein-Losing Enteropathy
thy but should suggest the presence of renal and/or As excess protein loss into the gastrointestinal tract is
hepatic disease. Likewise, reduced serum globulins with most often secondary to a specific disease, treatment
normal serum albumin levels are more likely a result should be directed primarily to the underlying disease
of reduced globulin synthesis rather than enhanced process and not to the hypoproteinemia. For example,
globulin loss into the intestine. Documentation of an if significant hypoproteinemia with resulting peripheral
increase in protein loss into the gastrointestinal tract has edema is secondary to either celiac disease or ulcerative
been established by the administration of one of several colitis, a gluten-free diet or mesalamine, respectively,
radiolabeled proteins and its quantitation in stool dur- would be the initial therapy. When enhanced protein
ing a 24- or 48-h period. Unfortunately, none of these loss is secondary to lymphatic obstruction, it is critical
radiolabeled proteins is available for routine clinical use. to establish the nature of this obstruction. Identification
α1-Antitrypsin, a protein that accounts for ∼4% of total of mesenteric nodes or lymphoma may be possible by
serum proteins and is resistant to proteolysis, can be imaging studies. Similarly, it is important to exclude car-
used to document enhanced rates of serum protein loss diac disease as a cause of protein-losing enteropathy
into the intestinal tract but cannot be used to assess gas- either by echosonography or, on occasion, by a right-
tric protein loss due to its degradation in an acid milieu. heart catheterization.
α1-Antitrypsin clearance is measured by determining
176 Table 15-8 Table 15-9
Classification of Malabsorption Syndromes Pathophysiology of Clinical Manifestations
Inadequate digestion of Malabsorption Disorders
Postgastrectomya Symptom or Sign Mechanism
Deficiency or inactivation of pancreatic lipase
Exocrine pancreatic insufficiency Weight loss/ Anorexia, malabsorption of nutrients
Chronic pancreatitis malnutrition
Pancreatic carcinoma Diarrhea Impaired absorption or secretion of
Cystic fibrosis water and electrolytes; colonic fluid
Pancreatic insufficiency—congenital or acquired secretion secondary to unabsorbed
Gastrinoma—acid inactivation of lipasea dihydroxy bile acids and fatty acids
Drugs—orlistat
Flatus Bacterial fermentation of unabsorbed
Reduced intraduodenal bile acid concentration/impaired carbohydrate
micelle formation
Glossitis, cheilo- Deficiency of iron, vitamin B12, folate,
Liver disease
sis, stomatitis and vitamin A
Parenchymal liver disease
Cholestatic liver disease Abdominal pain Bowel distention or inflammation,
Bacterial overgrowth in small intestine: pancreatitis
SECTION III
Henry J. Binder
The Schilling test is performed to determine the cause macrocytic anemia in chronic pancreatitis is extremely
for cobalamin malabsorption. Unfortunately, this test rare. Although this probably reflects a difference in the
has not been available commercially in the United digestion/absorption of cobalamin in food versus that
States for the last few years. Since understanding the in a crystalline form, the Schilling test still can be used
physiology and pathophysiology of cobalamin absorp- to assess pancreatic exocrine function.
tion is very valuable for enhancing one’s understanding 3. Achlorhydria, or absence of another factor secreted
of aspects of gastric, pancreatic, and ileal function, dis- with acid that is responsible for splitting cobalamin
cussion of the Schilling test is provided as supplemental away from the proteins in food to which it is bound.
information to Chap. 294. Since cobalamin absorption Up to one-third of individuals>60 years of age
requires multiple steps, including gastric, pancreatic, have marginal vitamin B12 absorption because of
and ileal processes, the Schilling test also can be used to the inability to release cobalamin from food; these
assess the integrity of those other organs (Chap. 105). people have no defects in absorbing crystalline
Cobalamin is present primarily in meat. Except in strict vitamin B12.
vegans, dietary cobalamin deficiency is exceedingly 4. Bacterial overgrowth syndromes, which are most often
uncommon. Dietary cobalamin is bound in the stomach secondary to stasis in the small intestine, leading to
to a glycoprotein called R-binder protein, which is syn- bacterial utilization of cobalamin (often referred to as
thesized in both the stomach and the salivary glands. stagnant bowel syndrome; see below).
This cobalamin–R binder complex is formed in the acid 5. Ileal dysfunction (as a result of either inflammation
milieu of the stomach. Cobalamin absorption has an or prior intestinal resection) due to impaired func-
absolute requirement for intrinsic factor, another glyco- tion of the mechanism of cobalamin–intrinsic factor
protein synthesized and released by gastric parietal cells, uptake by ileal intestinal epithelial cells.
to promote its uptake by specific cobalamin receptors
The Schilling test is performed by administering
on the brush border of ileal enterocytes. Pancreatic pro- 58
Co-labeled cobalamin orally and collecting urine for
tease enzymes split the cobalamin–R binder complex to
24 h, and it is dependent on normal renal and bladder
release cobalamin in the proximal small intestine, where
function. Urinary excretion of cobalamin will reflect
cobalamin then is bound by intrinsic factor.
cobalamin absorption provided that intrahepatic bind-
As a consequence, cobalamin absorption may be
ing sites for cobalamin are fully occupied. To ensure
abnormal in the following:
saturation of hepatic cobalamin binding sites so that all
1. Pernicious anemia, a disease in which immunologi- absorbed radiolabeled cobalamin will be excreted in
cally mediated atrophy of gastric parietal cells leads urine, 1 mg of cobalamin is administered intramuscu-
to an absence of both gastric acid and intrinsic factor larly 1 h after ingestion of the radiolabeled cobalamin.
secretion. The Schilling test may be abnormal (usually defined as
2. Chronic pancreatitis as a result of deficiency of pancreatic <10% excretion in 24 h) in pernicious anemia, chronic
proteases to split the cobalamin–R binder complex. pancreatitis, blind loop syndrome, and ileal disease
Although 50% of patients with chronic pancreati- (Table 16-1). Therefore, whenever an abnormal
tis have been reported to have an abnormal Schilling Schilling test is found, 58Co-labeled cobalamin should
test that was corrected by pancreatic enzyme be administered on another occasion bound to intrinsic
replacement, the presence of a cobalamin-responsive factor, with pancreatic enzymes, or after a 5-day course
177
178 TABLE 16-1
DIFFERENTIAL RESULTS OF SCHILLING TEST IN SEVERAL DISEASES ASSOCIATED WITH COBALAMIN (CBL)
MALABSORPTION
WITH INTRINSIC WITH PANCREATIC AFTER 5 DAYS OF
58
CO-CBL FACTOR ENZYMES ANTIBIOTICS
of antibiotics (often tetracycline). A variation of the etiology for cobalamin deficiency, the Schilling test can
Schilling test can detect failure to split cobalamin from be used to help delineate the pathologic process respon-
food proteins. The labeled cobalamin is cooked together sible for steatorrhea by assessing ileal, pancreatic, and
with a scrambled egg and administered orally. People small-intestinal luminal function. Unfortunately, the
with achlorydria will excrete <10% of the labeled Schilling test is performed infrequently because of the
SECTION III
cobalamin in the urine. In addition to establishing the unavailability of human intrinsic factor.
Disorders of the Alimentary Tract
CHAPTER 17
Inflammatory bowel disease (IBD) is an immune-mediated from 26−199 cases per 100,000 person-years for CD. In
chronic intestinal condition. Ulcerative colitis (UC) and Europe, incidence ranges from 1.5–20.3 cases per
Crohn’s disease (CD) are the two major types of IBD. 100,000 person-years for UC and from 0.7–9.8 cases for
CD; prevalence ranges from 21.4–243 cases for UC and
from 8.3–214 cases per 100,000 person-years for CD.
EPIDEMIOLOGY IBD has been rare in other areas except Israel, Australia,
and South Africa. The incidence of IBD, especially UC,
The incidence of IBD varies within different is rising in Japan, South Korea, Singapore, northern
geographic areas. CD and UC both occur at India, and Latin America, areas previously thought to
the highest incidence in Europe, the United have low incidence. The incidence of UC has increased
Kingdom, and North America. In North America, sixfold in the past two decades in Hong Kong. Reports
incidence rates range from 2.2–14.3 cases per 100,000 person- from the United States, Poland, Denmark, and South
years for UC and from 3.1–14.6 cases per 100,000 person- Korea indicate that the incidence of pediatric IBD is
years for CD (Table 17-1). Prevalence ranges from increasing rapidly as well. The highest mortality is dur-
37–246 cases per 100,000 person-years for UC and ing the first years of disease and in long-duration disease
due to the risk of colon cancer. In a Danish population
study, the standardized mortality ratios for CD and UC
TABLE 17-1 were 1.31 and 1.1, respectively.
EPIDEMIOLOGY OF IBD The peak age of onset of UC and CD is between 15
ULCERATIVE and 30 years. A second peak occurs between the ages of
COLITIS CROHN’S DISEASE 60 and 80. The male to female ratio for UC is 1:1 and
Incidence (North 2.2–14.3:100,000 3.1–14.6:100,000 for CD is 1.1–1.8:1. UC and CD have two- to four-
America) per fold increased frequency in Jewish populations in the
person-years United States, Europe, and South Africa. Furthermore,
Age of onset 15–30 & 60–80 15–30 & 60–80 disease frequency differs within the Jewish populations.
The prevalence of IBD in Ashkenazi Jews is about
Ethnicity Jewish > non-Jewish white > African
American > Hispanic > Asian
twice that of Israeli-born, Sephardic, or Asian Jews. The
prevalence decreases progressively in non-Jewish white,
Male/female 1:1 1.1–1.8:1
African-American, Hispanic, and Asian populations.
ratio
Urban areas have a higher prevalence of IBD than rural
Smoking May prevent May cause areas, and high socioeconomic classes have a higher
disease disease
prevalence than lower socioeconomic classes.
Oral No increased risk Odds ratio 1.4 The effects of cigarette smoking are different in
contraceptives UC and CD. The risk of UC in smokers is 40% that
Appendectomy Protective Not protective of nonsmokers. Additionally, former smokers have a
Monozygotic 6% concordance 58% concordance 1.7-fold increased risk for UC than people who have
twins never smoked. In contrast, smoking is associated with
Dizygotic twins 0% concordance 4% concordance a twofold increased risk of CD. Oral contraceptives
are also linked to CD; the odds ratio of CD for oral
179
180 contraceptive users is about 1.4. Appendectomy is pro- a severe enteropathy and autoimmunity (Table 17-2).
tective against UC but is associated with an increased Other immunodeficiency disorders such as hypogam-
risk of CD. This elevated risk in CD is observed early maglobulinemia, selective IgA deficiency, and heredi-
after an appendectomy, which is diminished thereafter, tary angioedema, also exhibit an increased association
making it likely that it reflects diagnostic problems in with IBD.
patients with incipient CD.
IBD is a familial disease in 5–10% of patients. Some
of these patients may exhibit early onset disease dur- ETIOLOGY AND PATHOGENESIS
ing the first decade of life and, in CD, a concordance
of anatomic site and clinical type within families. In the A consensus hypothesis is that in genetically predisposed
remainder of patients, IBD is observed in the absence of individuals, both exogenous factors (e.g., composition
a family history (i.e., sporadic disease). If a patient has of normal intestinal microbiota) and endogenous host
IBD, the lifetime risk that a first-degree relative will be factors (e.g., intestinal epithelial cell barrier function,
affected is ∼10%. If two parents have IBD, each child innate and adaptive immune function) interact to cause
has a 36% chance of being affected. In twin studies, 58% a chronic state of dysregulated mucosal immune func-
of monozygotic twins are concordant for CD and tion that is further modified by specific environmental
6% are concordant for UC, whereas 4% of dizygotic factors (e.g., smoking, enteropathogens). Although
SECTION III
twins are concordant for CD and none are concordant chronic activation of the mucosal immune system may
for UC. In a recent twin study from Germany, the represent an appropriate response to an unidentified
relative risk of a monozygotic twin developing Crohn’s infectious agent, a search for such an agent has thus
disease if his or her twin was affected was 738. The risks far been unrewarding in IBD. As such, IBD is currently
of developing IBD are higher in first-degree relatives of considered an inappropriate immune response to the
Jewish versus non-Jewish patients: 7.8% versus 5.2% for endogenous commensal microbiota within the intestines,
Disorders of the Alimentary Tract
CD and 4.5% versus 1.6% for UC. with or without some component of autoimmunity.
Additional evidence for genetic predisposition to Importantly, the normal intestines contain a large num-
IBD comes from its association with certain genetic ber of immune cells in a chronic state of so-called phys-
syndromes. UC and CD are both associated with iologic inflammation, in which the gut is restrained from
Turner’s syndrome, and Hermansky-Pudlak syndrome is full immunologic responses to the commensal microbiota
associated with granulomatous colitis. Glycogen storage and dietary antigens by very powerful regulatory pathways
disease type 1b can present with Crohn’s-like lesions that function within the immune system (e.g., FoxP3+ T
of the large and small bowel. Severe immunodefi- regulatory cells). During the course of infections in the
ciency disorders such as Wiskott-Aldrich syndrome and normal host, full activation of the gut-associated lymphoid
chronic granulomatous disease are associated with IBD. tissues occurs but is rapidly superseded by dampening of
Immune dysregulation, polyendocrinopathy, enter- the immune response and tissue repair. In IBD this pro-
opathy, X-linked (IPEX) syndrome is associated with cess may not be regulated normally.
TABLE 17-2
PRIMARY GENETIC DISORDERS ASSOCIATED WITH IBD
NAME GENETIC ASSOCIATION PHENOTYPE
Turner’s syndrome Loss of part or all of X chromosome Associated with UC and colonic CD
Hermansky-Pudlak Autosomal recessive chromosome Granulomatous colitis, oculocutaneous albinism,
10q23 platelet dysfunction, pulmonary fibrosis
Wiskott-Aldrich syndrome X-linked recessive disorder, loss of Colitis, immunodeficiency, severely dysfunctional
(WAS) WAS protein function platelets, and thrombocytopenia
Glycogen Storage disease Deficiency of the glucose-6-phosphate Granulomatous colitis, presents in infancy with
transport protein type B1 hypoglycemia, growth failure, hepatomegaly,
and neutropenia
Immune dysregulation Loss of FoxP3 transcription factor and UC-like autoimmune enteropathy, with endocri-
polyendocrinopathy, T regulatory cell function nopathy (neonatal type 1 diabetes or thyroiditis),
enteropathy X-linked (IPEX) dermatitis
Early onset IBD Deficient IL-10 receptor function Severe, refractory IBD in early life
Abbreviations: CD, Crohn’s disease; IBD, inflammatory bowel disease; IL, interleukin; UC, ulcerative colitis; WASP, Wiskott-Aldrich syndrome protein.
structural or functional levels. Similarly, many of the 181
GENETIC CONSIDERATIONS
genetic risk factors identified are also observed to be
IBD is a polygenic disorder that gives rise to mul- associated with risk for other immune-mediated diseases
tiple clinical subgroups within UC and CD. A suggesting that related immunogenetic pathways are
variety of genetic approaches including candidate involved in the pathogenesis of multiple different disor-
gene studies, linkage analysis and genome-wide associa- ders accounting for the common responsiveness to simi-
tion studies that focus on the identification of disease- lar types of biologic therapies (e.g., anti-tumor necrosis
associated, single-nucleotide polymorphisms (SNP) factor therapies) and possibly the simultaneous occur-
within the human genome have identified Approxi- rence of these disorders. The diseases and the genetic
mately 100 disease-associated loci on many different risk factors that are shared with IBD include rheumatoid
chromosomes (Table 17-3). About one-third of these arthritis (TNFAIP3), psoriasis (IL23R, IL12B), ankylos-
genetic risk factors are shared between CD and UC ing spondylitis (IL23R), type 1 diabetes mellitus (IL10,
accounting for the overlapping immunopathogenesis PTPN2), asthma (ORMDL3), and systemic lupus
and consequently epidemiologic observations of both erythematosus (TNFAIP3, IL10).
diseases in the same families and similarities in response The genetic factors defined to date that are recog-
to therapies. Because the specific causal variants for each nized to mediate risk for IBD have highlighted the
gene or locus are largely unknown, it is not clear importance of several common mechanisms of
CHAPTER 17
whether the similarities in the genetic risk factors associ- disease (Table 17-3). These include the following:
ated with CD and UC that are observed are shared at Those genes that are associated with innate immunity
TABLE 17-3
GENETIC LOCI ASSOCIATED WITH CD AND/OR UC
Abbreviations: CD, Crohn’s disease; ER, endoplasmic reticulum; GTPase, guanosine triphosphatase; IL, interleukin; UC, ulcerative colitis.
Source: Adapted from Kaser et al, Ann Rev Immunol 2010
182 and autophagy (e.g., NOD2, ATG16L1, IRGM, circumstances, intestinal inflammation in these animal
JAK2, STAT3) that function in innate immune cells models requires the presence of the commensal micro-
(both parenchymal and hematopoietic) to respond biota. Thus, a variety of specific alterations can lead
to and clear bacteria, mycobacteria and viruses; those to immune activation by commensal microbiota and
that are associated with endoplasmic reticulum (ER) inflammation directed at the intestines in mice. How
and metabolic stress (e.g., XBP1, ORMDL3, OCTN), these relate to human IBD remains to be defined but
which serve to regulate the secretory activity of cells are consistent with inappropriate responses of the genet-
involved in responses to the commensal microbiota ically susceptible host to the commensal bacteria.
such as Paneth and goblet cells and the manner in In both UC and CD, an inflammatory pathway
which intestinal cells respond to the metabolic prod- thus likely emerges from the genetic predisposition
ucts of bacteria; those that are associated with the that is associated with inappropriate innate immune
regulation of adaptive immunity (e.g., IL23R, IL12B, sensing and reactivity to commensal bacteria together
IL10, PTPN2), which regulate the balance between with inadequate regulatory pathways that lead to acti-
inflammatory and regulatory cytokines; and, finally, vated CD4+ T cells in the lamina propria that secrete
those that are involved in the development and resolu- excessive quantities of inflammatory cytokines rela-
tion of inflammation (e.g., MST1, CCR6, TNFAIP3, tive to anti-inflammatory cytokines. Some cytokines
PTGER4) and ultimately leukocyte recruitment and activate other inflammatory cells (macrophages and
SECTION III
inflammatory mediator production. Some of these loci B cells) and others act indirectly to recruit other lympho-
are associated with specific subtypes of disease such as cytes, inflammatory leukocytes, and mononuclear cells
the association between NOD2 polymorphisms and from the bloodstream into the gut through interactions
fibrostenosing CD, especially within the ileum. How- between homing receptors on leukocytes (e.g., α4β7
ever, the clinical utility of these genetic risk factors for integrin) and addressins on vascular endothelium (e.g.,
the diagnosis or determination of prognosis and thera- MadCAM1). CD4+ T helper (TH) cells that promote
Disorders of the Alimentary Tract
peutic responses remains to be defined. inflammation are of three major types, all of which may
be associated with colitis in animal models and perhaps
humans: TH1 cells [secrete interferon (IFN) g], TH2
cells (secrete IL-4, IL-5, IL-13), and TH17 cells (secrete
DEFECTIVE IMMUNE REGULATION IN IBD
IL-17, IL-21). TH1 cells induce transmural granuloma-
The mucosal immune system is normally unreactive to tous inflammation that resembles CD, TH2 cells, and
luminal contents due to oral (mucosal) tolerance. When related natural killer T cells that secrete IL-13 induce
soluble antigens are administered orally rather than sub- superficial mucosal inflammation resembling UC, and
cutaneously or intramuscularly, antigen-specific non- TH17 cells may be responsible for neutrophilic recruit-
responsiveness is induced. Multiple mechanisms are ment. Each of these T cell subsets cross-regulate each
involved in the induction of oral tolerance and include other. The TH1 cytokine pathway is initiated by IL-12,
deletion or anergy of antigen-reactive T cells or induc- a key cytokine in the pathogenesis of experimen-
tion of CD4+ T cells that suppress gut inflammation tal models of mucosal inflammation. IL-4 and IL-23,
(e.g., T regulatory cells expressing the FoxP3 transcrip- together with IL-6 and TGF-β, induce TH2 and TH17
tion factor) that secrete anti-inflammatory cytokines cells, respectively. Activated macrophages secrete tumor
such as interleukin (IL) 10 and transforming growth fac- necrosis factor (TNF and IL-6). Thus, use of antibod-
tor β (TGF-β). Oral tolerance may be responsible for ies to block proinflammatory cytokines (e.g., anti-TNF,
the lack of immune responsiveness to dietary antigens anti-IL-12, anti-IL-23, anti-IL-6, anti-IFN-g) or mol-
and the commensal microbiota in the intestinal lumen. ecules associated with leukocyte recruitment (e.g., anti-
In IBD this suppression of inflammation is altered, lead- α4β7) or use of cytokines that inhibit inflammation and
ing to uncontrolled inflammation. The mechanisms of promote regulatory T cells (e.g., IL-10) or promote
this regulated immune suppression are incompletely intestinal barrier function may be beneficial to humans
known. with intestinal inflammation.
Gene knockout (−/−) or transgenic (Tg) mouse mod-
els of IBD have revealed that deleting specific cytokines
(e.g., IL-2, IL-10, TGF-β) or their receptors, deleting
THE INFLAMMATORY CASCADE IN IBD
molecules associated with T cell antigen recognition
(e.g., T cell antigen receptors) or interfering with intes- Once initiated in IBD by abnormal innate immune
tinal epithelial cell barrier function and the regulation sensing of bacteria by parenchymal cells (e.g., intesti-
of responses to commensal bacteria (e.g., XBP1, N- nal epithelial cells) and hematopoietic cells (e.g., den-
cadherin, mucus glycoprotein or NFκB) leads to dritic cells), the immune inflammatory response is
spontaneous colitis or enteritis. In the majority of perpetuated by T-cell activation. A sequential cascade of
inflammatory mediators extends the response; each step 183
PATHOLOGY
is a potential target for therapy. Inflammatory cytokines
such as IL-1, IL-6, and TNF, have diverse effects on tis- ULCERATIVE COLITIS: MACROSCOPIC
sues. They promote fibrogenesis, collagen production, FEATURES
activation of tissue metalloproteinases, and the produc-
tion of other inflammatory mediators; they also acti- UC is a mucosal disease that usually involves the rectum
vate the coagulation cascade in local blood vessels (e.g., and extends proximally to involve all or part of the
increased production of von Willebrand’s factor). These colon. About 40–50% of patients have disease limited
cytokines are normally produced in response to infec- to the rectum and rectosigmoid, 30–40% have dis-
tion but are usually turned off or inhibited at the appro- ease extending beyond the sigmoid but not involving
priate time to limit tissue damage. In IBD their activ- the whole colon, and 20% have a total colitis. Proxi-
ity is not regulated, resulting in an imbalance between mal spread occurs in continuity without areas of unin-
the proinflammatory and anti-inflammatory mediators. volved mucosa. When the whole colon is involved,
Therapies such as the 5-aminosalicylic acid (5-ASA) the inflammation extends 2–3 cm into the terminal
compounds are potent inhibitors of these inflammatory ileum in 10–20% of patients. The endoscopic changes
mediators through inhibition of transcription factors of backwash ileitis are superficial and mild and are of
such as NFκB that regulate their expression. little clinical significance. Although variations in mac-
CHAPTER 17
roscopic activity may suggest skip areas, biopsies from
normal-appearing mucosa are usually abnormal. Thus,
EXOGENOUS FACTORS it is important to obtain multiple biopsies from appar-
ently uninvolved mucosa, whether proximal or distal,
IBD may have an as yet undefined infectious etiology.
during endoscopy. One caveat is that effective medical
Observational studies suggest that multiple pathogens
therapy can change the appearance of the mucosa such
(e.g., Salmonella, Shigella, Campylobacter, Clostridium
that either skip areas or the entire colon can be micro-
limited colitis. First, the crypt architecture of the colon CD, particularly those with colonic involvement.
is distorted; crypts may be bifid and reduced in num- Rarely, CD may also involve the liver and the pancreas.
ber, often with a gap between the crypt bases and the Unlike UC, CD is a transmural process. Endoscopi-
muscularis mucosae. Second, some patients have basal cally, aphthous or small superficial ulcerations char-
plasma cells and multiple basal lymphoid aggregates. acterize mild disease; in more active disease, stellate
Mucosal vascular congestion, with edema and focal ulcerations fuse longitudinally and transversely to
Disorders of the Alimentary Tract
hemorrhage, and an inflammatory cell infiltrate of neu- demarcate islands of mucosa that frequently are histo-
trophils, lymphocytes, plasma cells, and macrophages logically normal. This “cobblestone” appearance is char-
may be present. The neutrophils invade the epithelium, acteristic of CD, both endoscopically and by barium
usually in the crypts, giving rise to cryptitis and, ulti- radiography. As in UC, pseudopolyps can form in CD.
mately, to crypt abscesses (Fig. 17-2). Ileal changes in Active CD is characterized by focal inflammation
patients with backwash ileitis include villous atrophy and formation of fistula tracts, which resolve by fibrosis
and crypt regeneration with increased inflammation, and stricturing of the bowel. The bowel wall thickens
increased neutrophil and mononuclear inflammation and becomes narrowed and fibrotic, leading to chronic,
FIGURE 17-2
Medium power view of colonic mucosa in ulcerative colitis FIGURE 17-3
showing diffuse mixed inflammation, basal lymphoplasmacy- Crohn’s disease of the colon showing thickening of the
tosis, crypt atrophy and irregularity and superficial erosion. wall, with stenosis, linear serpiginous ulcers and cobble-
These features are typical of chronic active ulcerative colitis. stoning of the mucosa. (Courtesy of Dr. R Odze, Division
(Courtesy of Dr. R Odze, Division of Gastrointestinal Pathology, of Gastrointestinal Pathology, Department of Pathology,
Department of Pathology, Brigham and Women’s Hospital, Brigham and Women’s Hospital, Boston, Massachusetts;
Boston, Massachusetts; with permission.) with permission.)
pain. The severity of symptoms correlates with the 185
extent of disease. Although UC can present acutely,
symptoms usually have been present 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 com-
monly seen in patients with distal disease.
When the disease extends beyond the rectum, blood
FIGURE 17-4
is usually mixed with stool or grossly bloody diarrhea
Medium power view of Crohn’s colitis showing mixed may be noted. Colonic motility is altered by inflamma-
CHAPTER 17
acute and chronic inflammation, crypt atrophy, and multiple tion with rapid transit through the inflamed intestine.
small epithelioid granulomas in the mucosa. (Courtesy of When the disease is severe, patients pass a liquid stool
Dr. R Odze, Division of Gastrointestinal Pathology, Depart- containing blood, pus, and fecal matter. Diarrhea is
ment of Pathology, Brigham and Women’s Hospital, Boston, often nocturnal and/or postprandial. Although severe
Massachusetts; with permission.) pain is not a prominent symptom, some patients with
active disease may experience vague lower abdominal
Bowel movements <4 per day 4–6 per day >6 per day
Blood in stool Small Moderate Severe
Fever None <37.5°C mean (<99.5°F) >37.5°C mean (>99.5°F)
Tachycardia None <90 mean pulse >90 mean pulse
Anemia Mild >75% ≤75%
Sedimentation rate <30 mm >30 mm
Endoscopic appearance Erythema, decreased Marked erythema, coarse granularity, Spontaneous bleeding,
vascular pattern, absent vascular markings, ulcerations
fine granularity contact bleeding, no ulcerations
Sigmoidoscopy is used to assess disease activity and the ulceration has penetrated the mucosa. Haustral folds
SECTION III
is usually performed before treatment. If the patient is may be normal in mild disease, but as activity progresses
not having an acute flare, colonoscopy is used to assess they become edematous and thickened. Loss of haustra-
disease extent and activity (Fig. 17-5). Endoscopically tion can occur, especially in patients with long-standing
mild disease is characterized by erythema, decreased disease. In addition, the colon becomes shortened and
vascular pattern, and mild friability. Moderate disease is narrowed. Polyps in the colon may be postinflamma-
characterized by marked erythema, absent vascular pat- tory polyps or pseudopolyps, adenomatous polyps, or
Disorders of the Alimentary Tract
CHAPTER 17
influences the clinical manifestations. semia, coagulopathy, and hyperoxaluria with nephroli-
thiasis in patients with an intact colon. Many patients
Ileocolitis need to take oral and often intravenous iron. Vertebral
Because the most common site of inflammation is the fractures are caused by a combination of vitamin D
terminal ileum, the usual presentation of ileocolitis is deficiency, hypocalcemia, and prolonged glucocorticoid
a chronic history of recurrent episodes of right lower use. Pellagra from niacin deficiency can occur in exten-
quadrant pain and diarrhea. Sometimes the initial pre- sive small bowel disease, and malabsorption of vitamin
Laboratory, endoscopic, and ing of the intestinal lumen. (Courtesy of Dr. S Reddy, Gastro-
radiographic features enterology Division, Department of Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts; with permission.)
Laboratory abnormalities include elevated ESR and
CRP. In more severe disease, findings include hypoal-
buminemia, anemia, and leukocytosis. ulcers. These small ulcers are often multiple and sepa-
Endoscopic features of CD include rectal spar- rated by normal intervening mucosa. As the disease
ing, aphthous ulcerations, fistulas, and skip lesions. progresses, aphthous ulcers become enlarged, deeper,
Colonoscopy allows examination and biopsy of mass and occasionally connected to one another, forming
lesions or strictures and biopsy of the terminal ileum. longitudinal stellate, serpiginous, and linear ulcers (see
Upper endoscopy is useful in diagnosing gastroduodenal Fig. 291-4B).
involvement in patients with upper tract symptoms. The transmural inflammation of CD leads to
Ileal or colonic strictures may be dilated with balloons decreased luminal diameter and limited distensibility.
introduced through the colonoscope. Strictures ≤ 4 cm As ulcers progress deeper, they can lead to fistula for-
and those at a anastomotic sites respond better to endo- mation. The radiographic “string sign” represents long
scopic dilation. The perforation rate is as high as 10%. areas of circumferential inflammation and fibrosis,
Most endoscopists dilate only fibrotic strictures and not resulting in long segments of luminal narrowing. The
those associated with active inflammation. Wireless cap- segmental nature of CD results in wide gaps of normal
sule endoscopy (WCE) allows direct visualization of the or dilated bowel between involved segments.
entire small bowel mucosa (Fig. 17-6). The diagnos- CT enterography combines the improved spatial
tic yield of detecting lesions suggestive of active CD and temporal resolution of multidetector-row CT with
is higher with WCE than CT enterography or small large volumes of ingested neutral enteric contrast mate-
bowel series. WCE cannot be used in the setting of a rial to permit visualization of the entire small bowel
small bowel stricture. Capsule retention occurs in <1% and lumen. Unlike routine CT, which is used to detect
of patients with suspected CD, but retention rates of the extraenteric complications of CD such as fistula
4–6% are seen in patients with established CD. and abscess, CT enterography clearly depicts the small
In CD, early radiographic findings in the small bowel inflammation associated with CD by displaying
bowel include thickened folds and aphthous ulcerations. mural hyperenhancement, stratification, and thickening;
“Cobblestoning” from longitudinal and transverse engorged vasa recta; and perienteric inflammatory
ulcerations most frequently involves the small bowel. changes (Figs. 17-7 and 17-8). CT enterography is
In more advanced disease, strictures, fistulas, inflamma- the first-line test for the evaluation of suspected CD
tory masses, and abscesses may be detected. The earliest and its complications. As an initial test in children
macroscopic findings of colonic CD are aphthous or in adults with multiple radiation exposures, MR
189
CHAPTER 17
Inflammatory Bowel Disease
FIGURE 17-8
Coronal contrast-enhanced multidetector computed
FIGURE 17-7 tomography (MDCT) image obtained after oral admin-
Coronal contrast-enhanced multidetector computed istration of 1350 cc of neutral oral contrast material shows
tomography (MDCT) image obtained after oral admin- mucosal hyperenhancement of the terminal ileum with nar-
istration of 1350 cc of neutral oral contrast material shows rowing and mild prestenotic dilatation. (Courtesy of Dr. K
dilation of small bowel loops, segmental mucosal hyperen- Mortele, Gastrointestinal Radiology, Department of Radiology,
hancement, and interloop sinus tracts (white arrow) and Brigham and Women’s Hospital, Boston, Massachusetts;
mesenteric fat stranding. (Courtesy of Dr. K Mortele, Gastro- with permission.)
intestinal Radiology, Department of Radiology, Brigham and
Women’s Hospital, Boston, Massachusetts; with permission.)
wall abscesses. Systemic glucocorticoid therapy increases
the risk of intraabdominal and pelvic abscesses in CD
enterography is comparable to CT in diagnostic accu- patients who have never had an operation. Other com-
racy. Pelvic MRI is superior to CT for demonstrating plications include intestinal obstruction in 40%, massive
pelvic lesions such as ischiorectal abscesses and perianal hemorrhage, malabsorption, and severe perianal disease.
fistulae (Fig. 17-9).
Serologic markers
Complications
Patients with Crohn’s disease show a wide variation
Because CD is a transmural process, serosal adhesions in the way they present and progress over time. Some
develop that provide direct pathways for fistula for- patients present with mild disease activity and do well
mation and reduce the incidence of free perforation. with generally safe and mild medications, but many
Perforation occurs in 1–2% of patients, usually in the others exhibit more severe disease and can develop seri-
ileum but occasionally in the jejunum or as a complica- ous complications that will require surgery. Current
tion of toxic megacolon. The peritonitis of free perfora- and developing biologic therapies can help halt pro-
tion, especially colonic, may be fatal. Intraabdominal and gression of disease and give patients with moderate to
pelvic abscesses occur in 10–30% of patients with Crohn’s severe Crohn’s disease a better quality of life. There are
disease at some time in the course of their illness. CT- potential risks of biologic therapies such as infection and
guided percutaneous drainage of the abscess is standard malignancy, and it would be optimal to determine at
therapy. Despite adequate drainage, most patients need the time of diagnosis which patients will require more
resection of the offending bowel segment. Percutaneous aggressive medical therapy. This same argument holds
drainage has an especially high failure rate in abdominal true for UC patients as well.
190 ASCA serology showed a sensitivity of 64% and a speci-
ficity of 94%. Positive and negative predictive values
(PPVs and NPVs) for pANCA/ASCA also vary based
on the prevalence of IBD in a given population. For the
patient population with a prevalence of IBD of 62%,
the PPV is 94%, and the NPV is 63%.
Combining these diagnostic assays may improve the
ability to diagnose CD. In a referral population of CD
patients, 85% had an antibody to at least one antigen
(pANCA, ASCA, OmpC, and I2); only 4% responded
to all four. Some evidence suggests that antibody
positivity may help predict disease phenotype. ASCA
positivity is associated with an increased rate of early
CD complications; OmpC–positive patients are more
likely to have internal perforating disease; and I2 posi-
tive patients are more likely to have fibrostenosing
disease. Patients positive for I2, OmpC, and ASCA
SECTION III
CHAPTER 17
Response to antibiotics No Yes Appendicitis Lymphoma Chemicals
Recurrence after No Yes Diverticulitis Metastatic NSAIDs
surgery Diversion colitis carcinoma Phosphosoda
ANCA-positive Frequently Rarely Collagenous/ Carcinoma of Cathartic colon
ASCA-positive Rarely Frequently lymphocytic the ileum Gold
Endoscopic colitis Carcinoid Oral
Ischemic colitis Familial contraceptives
Rectal sparing Rarely Frequently Radiation polyposis Cocaine
istic cellular inclusions and viral culture. HIV itself can With small bowel involvement, diarrhea is common.
cause diarrhea, nausea, vomiting, and anorexia. Small Late symptoms include malabsorption and weight loss.
intestinal biopsies show partial villous atrophy; small Stricturing with obstruction and bacterial overgrowth
bowel bacterial overgrowth and fat malabsorption may may occur. Fistulas can penetrate the bladder, vagina, or
also be noted. abdominal wall. Flexible sigmoidoscopy reveals mucosal
Protozoan parasites include Isospora belli, which can granularity, friability, numerous telangiectasias, and occa-
Disorders of the Alimentary Tract
cause a self-limited infection in healthy hosts but causes sionally discrete ulcerations. Biopsy can be diagnostic.
a chronic profuse, watery diarrhea, and weight loss Solitary rectal ulcer syndrome is uncommon and can
in AIDS patients. Entamoeba histolytica or related spe- be confused with IBD. It occurs in persons of all ages
cies infect about 10% of the world’s population; symp- and may be caused by impaired evacuation and failure
toms include abdominal pain, tenesmus, frequent loose of relaxation of the puborectalis muscle. Single or mul-
stools containing blood and mucus, and abdominal tiple ulcerations may arise from anal sphincter overac-
tenderness. Colonoscopy reveals focal punctate ulcers tivity, higher intrarectal pressures during defecation,
with normal intervening mucosa; diagnosis is made by and digital removal of stool. Patients complain of con-
biopsy or serum amebic antibodies. Fulminant amebic stipation with straining and pass blood and mucus per
colitis is rare but has a mortality rate of >50%. rectum. Other symptoms include abdominal pain, diar-
Other parasitic infections that may mimic IBD rhea, tenesmus, and perineal pain. Ulceration as large as
include hookworm (Necator americanus), whipworm 5 cm in diameter is usually seen anteriorly or anterior-
(T. trichiura), and Strongyloides stercoralis. In severely laterally 3–15 cm from the anal verge. Biopsies can be
immunocompromised patients, Candida or Aspergil- diagnostic.
lus can be identified in the submucosa. Disseminated Several types of colitis are associated with nonste-
histoplasmosis can involve the ileocecal area. roidal anti-inflammatory drugs (NSAIDs), including de
novo colitis, reactivation of IBD, and proctitis caused
NONINFECTIOUS DISEASE by use of suppositories. Most patients with NSAID-
related colitis present with diarrhea and abdominal pain,
Diverticulitis can be confused with CD clinically and and complications include stricture, bleeding, obstruc-
radiographically. Both diseases cause fever, abdomi- tion, perforation, and fistulization. Withdrawal of these
nal pain, tender abdominal mass, leukocytosis, elevated agents is crucial, and in cases of reactivated IBD, stan-
ESR, partial obstruction, and fistulas. Perianal disease dard therapies are indicated.
or ileitis on small bowel series favors the diagnosis of
CD. Significant endoscopic mucosal abnormalities are
THE ATYPICAL COLITIDES
more likely in CD than in diverticulitis. Endoscopic or
clinical recurrence following segmental resection favors Two atypical colitides—collagenous colitis and lym-
CD. Diverticular-associated colitis is similar to CD, but phocytic colitis—have completely normal endoscopic
mucosal abnormalities are limited to the sigmoid and appearances. Collagenous colitis has two main histologic
descending colon. components: increased subepithelial collagen deposition
Ischemic colitis is commonly confused with IBD. and colitis with increased intraepithelial lymphocytes.
The ischemic process can be chronic and diffuse, as in The female to male ratio is 9:1, and most patients pres-
UC, or segmental, as in CD. Colonic inflammation ent in the sixth or seventh decades of life. The main
symptom is chronic watery diarrhea. Treatments range arms, chest, stoma, and even the face. PG usually begins 193
from sulfasalazine or mesalamine and Lomotil to bis- as a pustule and then spreads concentrically to rapidly
muth to budesonide to prednisone for refractory disease. undermine healthy skin. Lesions then ulcerate, with
Lymphocytic colitis has features similar to collag- violaceous edges surrounded by a margin of erythema.
enous colitis, including age at onset and clinical pre- Centrally, they contain necrotic tissue with blood and
sentation, but it has almost equal incidence in men and exudates. Lesions may be single or multiple and grow
women and no subepithelial collagen deposition on as large as 30 cm. They are sometimes very difficult
pathologic section. However, intraepithelial lympho- to treat and often require intravenous (IV) antibiotics,
cytes are increased. The frequency of celiac disease is intravenous, glucocorticoids, dapsone, azathioprine,
increased in lymphocytic colitis and ranges from 9 to thalidomide, IV cyclosporine, or infliximab.
27%. Celiac disease should be excluded in all patients Other dermatologic manifestations include pyoderma
with lymphocytic colitis, particularly if diarrhea does vegetans, which occurs in intertriginous areas; pyos-
not respond to conventional therapy. Treatment is simi- tomatitis vegetans, which involves the mucous mem-
lar to that of collagenous colitis with the exception of a branes; Sweet’s syndrome, a neutrophilic dermatosis;
gluten-free diet for those who have celiac disease. and metastatic CD, a rare disorder defined by cutaneous
Diversion colitis is an inflammatory process that arises granuloma formation. Psoriasis affects 5–10% of patients
in segments of the large intestine that are excluded from with IBD and is unrelated to bowel activity consis-
CHAPTER 17
the fecal stream. It usually occurs in patients with ileos- tent with the potential shared immunogenetic basis of
tomy or colostomy when a mucus fistula or a Hartmann’s these diseases. Perianal skin tags are found in 75–80% of
pouch has been created. Clinically, patients have mucus patients with CD, especially those with colon involve-
or bloody discharge from the rectum. Erythema, granu- ment. Oral mucosal lesions, seen often in CD and rarely
larity, friability, and, in more severe cases, ulceration in UC, include aphthous stomatitis and “cobblestone”
can be seen on endoscopy. Histopathology shows areas lesions of the buccal mucosa.
Primary sclerosing cholangitis (PSC) is a disorder in patients with CD following small bowel resection.
characterized by both intrahepatic and extrahepatic bile Calcium oxalate stones develop secondary to hyper-
duct inflammation and fibrosis, frequently leading to oxaluria, which results from increased absorption of
biliary cirrhosis and hepatic failure; approximately 5% dietary oxalate. Normally, dietary calcium combines
of patients with UC have PSC, but 50–75% of patients with luminal oxalate to form insoluble calcium oxalate,
with PSC have IBD. PSC occurs less often in patients which is eliminated in the stool. In patients with ileal
with CD. Although it can be recognized after the diag- dysfunction, however, nonabsorbed fatty acids bind
nosis of IBD, PSC can be detected earlier or even years calcium and leave oxalate unbound. The unbound
after proctocolectomy. Consistent with this, the immu- oxalate is then delivered to the colon, where it is readily
nogenetic basis for PSC appears to be overlapping but absorbed, especially in the presence of inflammation.
distinct from UC based upon genome-wide association
studies (GWAS) although both IBD and PSC are com-
METABOLIC BONE DISORDERS
monly pANCA positive. Most patients have no symp-
toms at the time of diagnosis; when symptoms are pres- Low bone mass occurs in 3–30% of IBD patients.
ent, they consist of fatigue, jaundice, abdominal pain, The risk is increased by glucocorticoids, cyclosporine,
fever, anorexia, and malaise. The traditional gold- methotrexate and total parenteral nutrition (TPN).
standard diagnostic test is endoscopic retrograde chol- Malabsorption and inflammation mediated by IL-1,
angiopancreatography (ERCP), but magnetic resonance IL-6, TNF and other inflammatory mediators also con-
cholangiopancreatography (MRCP) is also sensitive and tribute to low bone density. An increased incidence
specific. MRCP is reasonable as an initial diagnostic test of hip, spine, wrist, and rib fractures has been noted:
in children and can visualize irregularities, multifocal 36% in CD and 45% in UC. The absolute risk of an
strictures, and dilatations of all levels of the biliary tree. osteoporotic fracture is about 1% per person per year.
In patients with PSC, both ERCP and MRCP demon- Fracture rates, particularly in the spine and hip, were
strate multiple bile duct strictures alternating with rela- highest among the elderly (age >60). One study noted
tively normal segments. an odds ratio of vertebral fracture to be 1.72 and hip
The bile acid ursodeoxycholic acid (ursodiol) may fracture 1.59. The disease severity predicted the risk of
reduce alkaline phosphatase and serum aminotransferase a fracture. Only 13% of IBD patients who had a frac-
levels, but histologic improvement has been marginal. ture were on any kind of antifracture treatment. Up
High doses (25–30 mg/kg per day) may decrease the to 20% of bone mass can be lost per year with chronic
risk of colorectal dysplasia and cancer in patients with glucocorticoid use. The effect is dosage-dependent.
UC and PSC. Endoscopic stenting may be palliative for Budesonide may also suppress the pituitary-adrenal axis
cholestasis secondary to bile duct obstruction. Patients and thus carries a risk of causing osteoporosis.
Osteonecrosis is characterized by death of osteo- 195
cytes and adipocytes and eventual bone collapse. The structure provides a convenient delivery system to the
pain is aggravated by motion and swelling of the joints. colon by allowing the intact molecule to pass through
It affects the hips more often than knees and shoulders, the small intestine after only partial absorption, and to
and in one series 4.3% of patients developed osteo- be broken down in the colon by bacterial azo reduc-
necrosis within 6 months of starting glucocorticoids. tases that cleave the azo bond linking the sulfa and
Diagnosis is made by bone scan or MRI, and treatment 5-ASA moieties. Sulfasalazine is effective treatment for
consists of pain control, cord decompression, osteot- mild to moderate UC, but its high rate of side effects
omy, and joint replacement. limits its use. Although sulfasalazine is more effective at
higher doses, at 6 or 8 g/d up to 30% of patients expe-
rience allergic reactions or intolerable side effects such
THROMBOEMBOLIC DISORDERS as headache, anorexia, nausea, and vomiting that are
attributable to the sulfapyridine moiety. Hypersensi-
Patients with IBD have an increased risk of both venous
tivity reactions, independent of sulfapyridine levels,
and arterial thrombosis even if the disease is not active.
include rash, fever, hepatitis, agranulocytosis, hypersen-
Factors responsible for the hypercoagulable state have
sitivity pneumonitis, pancreatitis, worsening of colitis,
included abnormalities of the platelet-endothelial inter-
and reversible sperm abnormalities. Sulfasalazine can
action, hyperhomocysteinemia, alterations in the coag-
CHAPTER 17
also impair folate absorption, and patients should be
ulation cascade, impaired fibrinolysis, involvement of
given folic acid supplements.
tissue factor-bearing microvesicles, disruption of the
Newer sulfa-free aminosalicylate preparations
normal coagulation system by autoantibodies, as well
deliver increased amounts of the pharmacologically
as a genetic predisposition. A spectrum of vasculitides
active ingredient of sulfasalazine (5-ASA, mesalamine)
involving small, medium, and large vessels has also been
to the site of active bowel disease while limiting sys-
observed.
temic toxicity. Peroxisome proliferator activated recep-
pounds are shown in Table 17-7. Some 50–75% of moderate-to-severe CD and induce a 60–70% remission
patients with mild to moderate UC improve when rate compared to a 30% placebo response. The systemic
treated with 5-ASA doses equivalent to 2 g/d of mesala- effects of standard glucocorticoid formulations have
mine; the dose response continues up to at least 4.8 g/d. led to the development of more potent formulations
As a general rule, 5-ASA agents act within 2–4 weeks. that are less well-absorbed and have increased first-
5-ASA doses equivalent to 1.5–4 g/d of mesalamine pass metabolism. Controlled ileal-release budesonide
maintain remission in 50–75% of patients with UC. has been nearly equal to prednisone for ileocolonic CD
Topical mesalamine enemas are effective in mild-to- with fewer glucocorticoid side effects. Budesonide is
moderate distal UC. Clinical response occurs in up to used for 2–3 months at a dose of 9 mg/d, then tapered.
TABLE 17-7
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)
Olsalazine (250 mg) (Dipentum) 5-ASA-5-ASA Colon 1–3 g
Balsalazide (750 mg) (Colazal) Aminobenzoyl-alanine-5-ASA Colon 6.75–9 g
Delayed-Release
Mesalamine (400, 800 mg) (Asacol) Eudragit S (pH 7) Distal 2.4–4.8 g (acute)
ileum-colon 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) Ethylcellulose microgranules Stomach-colon 2–4 g (acute)
(Pentasa) 1.5–4 g (maintenance)
Delayed and Extended-Release
Mesalamine (.375 g) (Apriso) Intellicor extended-release Ileum-colon 1.5 g (maintenance)
mechanism
197
Budesonide 6 mg/d is effective in reducing relapse rates as maintenance therapy in UC and CD and for treating
at 3–6 months but not at 12 months in CD patients with active perianal disease and fistulas in CD appears prom-
a medically induced remission. ising. In addition, 6-MP or azathioprine is effective for
Glucocorticoids play no role in maintenance therapy postoperative prophylaxis of CD.
in either UC or CD. Once clinical remission has been Although azathioprine and 6-MP are usually well
induced, they should be tapered according to the clinical tolerated, pancreatitis occurs in 3–4% of patients, typi-
activity, normally at a rate of no more than 5 mg/week. cally presents within the first few weeks of therapy,
They can usually be tapered to 20 mg/d within 4–5 weeks and is completely reversible when the drug is stopped.
but often take several months to be discontinued Other side effects include nausea, fever, rash, and hepa-
altogether. The side effects are numerous, including titis. Bone marrow suppression (particularly leukopenia)
fluid retention, abdominal striae, fat redistribution, is dose-related and often delayed, necessitating regu-
hyperglycemia, subcapsular cataracts, osteonecrosis, lar monitoring of the complete blood cell count (CBC).
osteoporosis, myopathy, emotional disturbances, and Additionally, 1 in 300 individuals lacks thiopurine methyl-
withdrawal symptoms. Most of these side effects, aside transferase, the enzyme responsible for drug metabolism;
from osteonecrosis, are related to the dose and duration an additional 11% of the population are heterozygotes
of therapy. with intermediate enzyme activity. Both are at increased
CHAPTER 17
risk of toxicity because of increased accumulation of
ANTIBIOTICS Antibiotics have no role in the treat- thioguanine metabolites. Although 6-thioguanine
ment of active or quiescent UC. However, pouchitis, and 6-methylmercaptopurine levels can be followed
which occurs in about a third of UC patients after colec- to determine correct drug dosing and reduce toxicity,
tomy and IPAA, usually responds to treatment with met- weight-based dosing is an acceptable alternative. CBCs
ronidazole and/or ciprofloxacin. and liver function tests should be monitored frequently
Metronidazole is effective in active inflammatory, regardless of dosing strategy. IBD patients treated with
carinii pneumonia, may occur with combination immu- or the response duration to infliximab infusion
nosuppressive treatment; prophylaxis should be given. decreases. Decreasing the dosing intervals or increas-
Major adverse events occurred in 15% of patients in one ing the dosage to 10 mg/kg may restore the efficacy of
large study including nephrotoxicity not responding to the drug.
dose adjustment, serious infections, seizures, anaphylaxis, The SONIC (Study of Biologic and Immunomodulator-
and death of two patients. This high incidence suggests Naïve Patients with Crohn’s Disease) Trial compared
that vigorous monitoring by experienced clinicians at infliximab plus azathioprine, infliximab alone and aza-
Disorders of the Alimentary Tract
tertiary care centers may be required. thioprine alone in immunomodulator and biologic
naïve patients with moderate-to-severe Crohn’s disease.
TACROLIMUS Tacrolimus is a macrolide antibiotic
At one year, of 508 randomized patients, the infliximab
with immunomodulatory properties similar to CSA. It
plus azathioprine group exhibited a steroid-free remis-
is 100 times as potent as CSA and is not dependent on
sion rate of 46% compared with 35% (infliximab alone)
bile or mucosal integrity for absorption. These phar-
and 24% (azathioprine alone). There was also increased
macologic properties enable tacrolimus to have good
complete mucosal healing at week 26 with the com-
oral absorption despite proximal small bowel Crohn’s
bined approach relative to either infliximab or azathio-
involvement. It has shown efficacy in children with
prine alone (44% vs. 30% vs. 17%). The adverse events
refractory IBD and in adults with extensive involve-
were equal between groups.
ment of the small bowel. It is also effective in adults with
The annual risk of lymphoma (e.g., Hodgkin’s and
steroid-dependent or refractory UC and CD as well as
non-Hodgkin’s lymphoma) with infliximab has been
refractory fistulizing CD.
estimated to be anywhere from 5:10,000 to 20:10,000.
BIOLOGIC THERAPIES Biologic therapy is The annual risk of lymphoma in the general popula-
often reserved for moderately to severely ill patients tion is 2:10,000. Forty-eight cases of malignancy were
with Crohn’s disease, who have failed other therapies. identified by the FDA in children and adolescents with
Patients who respond to biologic therapies enjoy an the use of TNF blockers. Etanercept and infliximab
improvement in clinical symptoms, a better quality of were the only TNF blockers included in the analysis.
life, less disability, fatigue and depression, and fewer Of the 48 cases, about 50% were lymphomas. Other
surgeries and hospitalizations. malignancies such as leukemia, melanoma, and solid
organ tumors were reported; malignancies rarely seen
Anti-TNF Therapy The first biologic therapy
in children (e.g., leiomyosarcoma, hepatic malignan-
approved for Crohn’s disease was infliximab, a chimeric
cies, and renal cell carcinoma) were also observed. Of
IgG1 antibody against TNF-alpha, which is now also
note, most of these cases (88%) were receiving other
approved for treatment of moderately to severely active
immunosuppressive medications (e.g., azathioprine
ulcerative colitis. Of active CD patients refractory to
and methotrexate).
glucocorticoids, 6-MP, or 5-ASA, 65% will respond to
Hepatosplenic T cell lymphoma is a nearly univer-
IV infliximab (5 mg/kg); one-third will enter complete
sally fatal lymphoma in patients with Crohn’s disease. At
remission. The ACCENT I (A Crohn’s Disease Clinical Trial
least 12 cases involved immunomodulators alone, and
Evaluating Infliximab in a New Long Term Treatment
19 cases received combination therapy. There have
Regimen) study showed that of the patients who expe-
been three reports in patients taking adalimumab alone
rience an initial response, 40% of these will maintain
199
without an immunomodulator. Patients tend to be naïve patients at 1 year compared with remission rates
young and almost all male. of 31–34% in the patients who had previously received
The FDA also reviewed 147 postmarketing reports of infliximab. Certolizumab pegol is a PEGylated form of
leukemia (including acute myeloid leukemia, chronic lym- an anti-TNF antibody administered SC once monthly. SC
phocytic leukemia, and chronic myeloid leukemia) and certolizumab pegol was effective for induction of clini-
69 cases of new-onset psoriasis (including pustular, palmo- cal response in patients with active inflammatory CD. In
plantar) occurring in patients using TNF blockers. The FDA the PRECISE II (The PEGylated Antibody Fragment Evalu-
concluded that there is a possible association with both leu- ation in Crohn’s Disease) trial of maintenance therapy
kemia and new-onset psoriasis with the use of TNF blockers. with certolizumab in patients who responded to certoli-
Other morbidities of infliximab include acute infusion zumab induction, the results were similar to the CHARM
reactions and severe serum sickness. All of the anti-TNF trial. At week 26, the subgroup of patients who were
drugs are associated with an increased risk of infec- infliximab naïve had a response of 69% as compared to
tions, particularly reactivation of latent tuberculosis and 44% in patients who had previously received infliximab.
opportunistic fungal infections including disseminated At least one-third of patients do not respond to inf-
histoplasmosis and coccidioidomycosis. Rarely, inflix- liximab, but no published controlled trial has examined
imab and the other anti-TNF drugs have been associ- infliximab nonresponders for a response to other anti-
CHAPTER 17
ated with optic neuritis, seizures, new-onset or exacer- TNF agents. If a patient does not have an initial response
bation of clinical symptoms, and radiographic evidence to any anti-TNF therapy, currently it must be considered
of central nervous system demyelinating disorders, futile to try another. Before the approval of natalizumab,
including multiple sclerosis. They may exacerbate symp- the only option for this group of patients was surgery.
toms in patients with New York Heart Association func-
tional class III/IV heart failure. Natalizumab Integrins are expressed on the sur-
Infliximab has also shown efficacy in UC. In two large face of leukocytes and serve as mediators of leukocyte
antibodies).
in Table 17-8. Morbidity is about 20% in elective, 30%
NUTRITIONAL THERAPIES Dietary antigens for urgent, and 40% for emergency proctocolectomy.
may stimulate the mucosal immune response. Patients The risks are primarily hemorrhage, contamination and
Disorders of the Alimentary Tract
Distal UC Extensive UC
IV IV
cyclosporine cyclosporine
or infliximab or infliximab
6-Mercaptopurine 6-Mercaptopurine
or azathioprine or azathioprine
Glucocorticoid IV Glucocorticoid IV
Inflammatory CD Fistulizing CD
IV Total
cyclosporine parenteral
or tacrolimus nutrition
natalizumab
Infliximab/adalimumab/ IV
certolizumab pegol cyclosporine or tacrolimus
natalizumab
6-Mercaptopurine or
Infliximab/adalimumab/
azathioprine/methotrexate
certolizumab pegol
Glucocorticoid IV
6-Mercaptopurine or
Prednisone azathioprine/methotrexate
FIGURE 17-10
Medical management of IBD. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis.
TABLE 17-8 201
Crohn’s Disease Most patients with CD require
INDICATIONS FOR SURGERY
at least one operation in their lifetime. The need for
ULCERATIVE COLITIS CROHN’S DISEASE surgery is related to duration of disease and the site of
Intractable disease Small Intestine involvement. Patients with small-bowel disease have
Fulminant disease Stricture and obstruction an 80% chance of requiring surgery. Those with coli-
Toxic megacolon unresponsive to medical tis alone have a 50% chance. Surgery is an option only
Colonic perforation therapy when medical treatment has failed or complications
Massive colonic Massive hemorrhage dictate its necessity. The indications for surgery are
hemorrhage Refractory fistula
shown in Table 17-8.
Extracolonic disease Abscess
Colonic obstruction Colon and rectum
Small intestinal disease Because CD is chronic
Colon cancer prophylaxis Intractable disease
Colon dysplasia or cancer Fulminant disease and recurrent, with no clear surgical cure, as little intes-
Perianal disease tine as possible is resected. Current surgical alternatives
unresponsive to medical for treatment of obstructing CD include resection of the
therapy diseased segment and strictureplasty. Surgical resec-
Refractory fistula tion of the diseased segment is the most frequently
Colonic obstruction
CHAPTER 17
performed operation, and in most cases primary anas-
Cancer prophylaxis
tomosis can be done to restore continuity. If much of
Colon dysplasia or cancer
the small bowel has already been resected and the
strictures are short, with intervening areas of normal
mucosa, strictureplasties should be done to avoid a
functionally insufficient length of bowel. The strictured
sepsis, and neural injury. The operation of choice is an
area of intestine is incised longitudinally and the inci-
treatment is stopped. In women who have had pouch foration, and megacolon refractory to medical therapy.
surgery, most studies show that the fertility rate is Total colectomy and ileostomy carry a 50–60% risk of
reduced to about one-third of normal. This is due to postoperative spontaneous abortion. Fetal mortality is
scarring or occlusion of the fallopian tubes secondary to also high in CD requiring surgery. Patients with IPAAs
pelvic inflammation. have increased nighttime stool frequency during preg-
In mild or quiescent UC and CD, fetal outcome is nancy that resolves postpartum. Transient small bowel
nearly normal. Spontaneous abortions, stillbirths, and
Disorders of the Alimentary Tract
CHAPTER 17
colonoscopy. biopsies of the surrounding mucosa are free of dysplasia.
New techniques such as high definition and magnifica-
tion colonoscopes and dye sprays have increased the rate
CROHN’S DISEASE
of dysplasia detection. In the future, endoscopists may
Risk factors for developing cancer in Crohn’s colitis be able to do targeted rather than segmental biopsies in
are long-duration and extensive disease, bypassed colon patients with chronic Crohn’s or ulcerative colitis.
Chung Owyang
Irritable bowel syndrome (IBS) is a functional bowel genetic and environmental factors, and psychosocial
disorder characterized by abdominal pain or discom- disturbances are variably involved, depending on the
fort and altered bowel habits in the absence of detect- individual. This progress may result in improved meth-
able structural abnormalities. No clear diagnostic ods of treatment.
markers exist for IBS, thus the diagnosis of the dis-
order is based on clinical presentation. In 2006, the
Rome II criteria for the diagnosis of IBS were revised CLINICAL FEATURES
(Table 18-1). Throughout the world, about 10–20%
IBS is a disorder that affects all ages, although most
of adults and adolescents have symptoms consistent with
patients have their first symptoms before age 45. Older
IBS, and most studies show a female predominance.
individuals have a lower reporting frequency. Women
IBS symptoms tend to come and go over time and
are diagnosed with IBS two to three times as often as men
often overlap with other functional disorders such as
and make up 80% of the population with severe IBS. As
fibromyalgia, headache, backache, and genitourinary
indicated in Table 18-1, pain or abdominal discomfort is
symptoms. Severity of symptoms varies and can signifi-
a key symptom for the diagnosis of IBS. These symptoms
cantly impair quality of life, resulting in high health care
should be improved with defecation and/or have their
costs. Advances in basic, mechanistic, and clinical inves-
onset associated with a change in frequency or form of
tigations have improved our understanding of this dis-
stool. Painless diarrhea or constipation does not fulfill the
order and its physiologic and psychosocial determinants.
diagnostic criteria to be classified as IBS. Supportive symp-
Altered gastrointestinal (GI) motility, visceral hyper-
toms that are not part of the diagnostic criteria include
algesia, disturbance of brain-gut interaction, abnormal
defecation straining, urgency or a feeling of incomplete
central processing, autonomic and hormonal events,
bowel movement, passing mucus, and bloating.
CHAPTER 18
ing to repeated attempts at defecation in a short time may be involved. Prolonged ambulant recordings of
span. Patients whose predominant symptom is constipa- small-bowel motility in patients with IBS show a high
tion may have weeks or months of constipation inter- incidence of abnormalities in the small bowel during
rupted with brief periods of diarrhea. In other patients, the diurnal (waking) period; nocturnal motor patterns
diarrhea may be the predominant symptom. Diarrhea are not different from those of healthy controls. The
resulting from IBS usually consists of small volumes overlap between dyspepsia and IBS is great. The prev-
of loose stools. Most patients have stool volumes of alence of IBS is higher among patients with dyspepsia
lower the thresholds for the first sensation of gas, dis- these patients demonstrated exaggerated symptoms in
comfort, and pain in IBS patients. Hence, postprandial response to visceral distention, and this abnormality per-
symptoms in IBS patients may be explained in part by a sists even after exclusion of psychological factors.
nutrient-dependent exaggerated sensory component of Psychological factors influence pain thresholds in IBS
the gastrocolonic response. In contrast to enhanced gut patients, as stress alters sensory thresholds. An association
sensitivity, IBS patients do not exhibit heightened sen- between prior sexual or physical abuse and develop-
sitivity elsewhere in the body. Thus, the afferent path- ment of IBS has been reported. Abuse is associated with
way disturbances in IBS appear to be selective for greater pain reporting, psychological distress, and poor
visceral innervation with sparing of somatic pathways. health outcome. Brain functional MRI studies show
The mechanisms responsible for visceral hypersensitivity greater activation of the posterior and middle dorsal cin-
are still under investigation. It has been proposed that gulate cortex, which is implicated in affect processing in
these exaggerated responses may be due to (1) increased IBS patients with a past history of sexual abuse.
end-organ sensitivity with recruitment of “silent” noci- Thus, patients with IBS frequently demonstrate
ceptors; (2) spinal hyperexcitability with activation of increased motor reactivity of the colon and small bowel
nitric oxide and possibly other neurotransmitters; (3) to a variety of stimuli and altered visceral sensation asso-
endogenous (cortical and brainstem) modulation of cau- ciated with lowered sensation thresholds. These may
dad nociceptive transmission; and (4) over time, the result from CNS—enteric nervous system dysregulation
possible development of long-term hyperalgesia due (Fig. 18-1).
to development of neuroplasticity, resulting in perma-
nent or semipermanent changes in neural responses to
Post-infectious IBS
chronic or recurrent visceral stimulation (Table 18-2).
IBS may be induced by GI infection. In an investigation
TABLE 18-2 of 544 patients with confirmed bacterial gastroenteritis,
PROPOSED MECHANISMS FOR VISCERAL one-quarter developed IBS subsequently. Conversely,
HYPERSENSITIVITY about a third of IBS patients experienced an acute
End-organ sensitivity Long-term hyperalgesia “gastroenteritis-like” illness at the onset of their chronic
“Silent” nociceptors Tonic cortical regulation IBS symptomatology. This group of “postinfective” IBS
CNS modulation Neuroplasticity occurs more commonly in females and affects younger
Cortex rather than older patients. Risk factors for develop-
Brainstem ing post-infectious IBS include, in order of impor-
tance, prolonged duration of initial illness, toxicity of
Abbreviation: CNS, central nervous system. infecting bacterial strain, smoking, mucosal markers
Severity Environment Brain-Gut Axis lactulose hydrogen breath test. This finding, however, 207
CNS Antidepressants, has been challenged by a number of other studies that
Psychotherapy, behavioral
Severe
Psychological
therapy, hypnotherapy,
found no increased incidence of bacterial overgrowth
Cognitive
Somatization-disorder based on jejunal aspirate culture. Abnormal H2 breath
Heightened management
Moderate sensorimotor
test can occur because of small bowel rapid transit and
activity Antispasmodics, may lead to erroneous interpretation. Hence, the role of
Gut
Antidiarrheals, testing for small intestinal bacterial overgrowth in IBS
Dietary modification,
Mild Luminal
Mucosal
Fiber supplements, patients remains unclear.
Newer gut serotonin A number of studies found significant differences
modulators
ENS between the molecular profile of the fecal microbiota
of IBS patients compared with that of healthy subjects.
FIGURE 18-1 Several bacterial genera with Lactobacillus sequence
Therapeutic targets for irritable bowel syndrome. Patients appear to be absent from IBS, and Collinsella sequences
with mild to moderate symptoms usually have intermittent were greatly reduced in this group of patients. Cur-
symptoms that correlate with altered gut physiology. Treat-
rently it is unclear whether such changes are causal,
ments include gut-acting pharmacologic agents such as
consequential, or merely the result of constipation and
antispasmodics, antidiarrheals, fiber supplements, and gut
diarrhea. In addition, the stability of the changes in the
CHAPTER 18
serotonin modulators. Patients who have severe symptoms
microbiota needs to be determined.
usually have constant pain and psychosocial difficulties.
This group of patients is best managed with antidepressants
and other psychosocial treatments. CNS, central nervous Abnormal serotonin pathways
system; ENS, enteric nervous system.
The serotonin (5HT)-containing enterochromaffin cells
in the colon are increased in a subset of IBS-D patients
compared to healthy individuals or patients with ulcer-
malabsorption, celiac sprue, hyperthyroidism, inflam- should be obtained. Laboratory features that argue
matory bowel disease, and infectious diarrhea must be against IBS include evidence of anemia, elevated sedi-
ruled out. On the other hand, constipation may be a mentation rate, presence of leukocytes or blood in stool,
side effect of many different drugs, such as anticholiner- and stool volume >200–300 mL/d. These findings would
gic, antihypertensive, and antidepressant medications. necessitate other diagnostic considerations.
Endocrinopathies such as hypothyroidism and hypo-
Disorders of the Alimentary Tract
CHAPTER 18
surprising since IBS is a heterogeneous disorder, with
some patients being constipated and other having pre- most useful if taken before anticipated stressful events
dominant diarrhea. Most investigations report increases that are known to cause diarrhea. However, not infre-
in stool weight, decreases in colonic transit times, and quently, a high dose of loperamide may cause cramping
improvement in constipation. Others have noted benefits because of increases in segmenting colonic contractions.
in patients with alternating diarrhea and constipation, Another anti-diarrhea agent that may be used in IBS
pain, and bloating. However, most studies observe no patients is the bile acid binder cholestyramine resin.
Clinical Features
Prevalence 70% 25% 5%
Correlations with gut physiology +++ ++ +
Symptoms constant 0 + +++
Psychosocial difficulties 0 + +++
Health care issues + ++ +++
Practice type Primary Specialty Referral
TABLE 18-4
POSSIBLE DRUGS FOR A DOMINANT SYMPTOM IN IBS
CHAPTER 18
SYMPTOM DRUG DOSE
∗
Available only in the United States.
Source: Adapted from Longstreth et al.
cared for in primary care practices, have little or no psy- antispasmodics, antidiarrheals, fiber supplements, and
chosocial difficulties, and do not seek health care often. the newer gut serotonin modulators (Table 18-4). A
Treatment usually involves education, reassurance, small proportion of IBS patients have severe and refrac-
and dietary/lifestyle changes. A smaller portion have tory symptoms, are usually seen in referral centers, and
moderate symptoms that are usually intermittent and frequently have constant pain and psychosocial difficul-
correlate with altered gut physiology, e.g., worsened ties (Fig. 18-1). This group of patients is best managed
with eating or stress and relieved by defecation. Treat- with antidepressants and other psychological treat-
ments include gut-acting pharmacologic agents such as ments (Table 18-4).
CHAPTER 19
Susan L. Gearhart
DIVERTICULAR DISEASE
CHAPTER 19
bleeding tend to be hypertensive, have atherosclero- patients who received >10 units of blood.
sis, and regularly use nonsteroidal anti-inflammatory
agents. Most bleeds are self-limited and stop spontane-
ously with bowel rest. The lifetime risk of rebleeding Presentation, evaluation, and staging
of diverticulitis
is 25%.
Localization of diverticular bleeding should include Acute uncomplicated diverticulitis characteristically presents
colonoscopy, which may be both diagnostic and thera- with fever, anorexia, left lower quadrant abdominal
distant abscess formation. Stage III: Noncommunicating alone, is associated with 30% less frequent recurrent
perforated diverticulitis with fecal peritonitis (the diverticular symptoms from uncomplicated diverticular disease.
neck is closed off and therefore contrast will not freely expel Furthermore, the use of probiotics has been shown to
on radiographic images). Stage IV: Perforation and free com- decrease the incidence of recurrent attacks. Culture
munication with the peritoneum, resulting in fecal peritonitis. data from patients on probiotics noted a decrease in
the presence of Clostridium species and an increase in
Lactobacillus and Bifidobacterium strains.
less commonly with a fistula (Table 19-1). Perforated SURGICAL MANAGEMENT Preoperative risk
diverticular disease is staged using the Hinchey clas- factors influencing postoperative mortality rates include
sification system (Fig. 19-2). This staging system was higher American Society of Anesthesiologists (ASA)
developed to predict outcomes following the surgi- physical status class (Table 19-2) and preexisting organ
cal management of complicated diverticular disease. In failure. In patients who are low risk (ASA P1 and P2), sur
complicated diverticular disease with fistula formation, gical therapy can be offered to those who do not rapidly
common locations include cutaneous, vaginal, or vesicle improve on medical therapy. For uncomplicated diver
fistulas. These conditions present with either passage of ticular disease, studies indicate that medical therapy can
stool through the skin or vagina or the presence of air be continued beyond two attacks without an increased
in the urinary stream (pneumaturia). Colovaginal fistulas
are more common in women who have undergone a
hysterectomy. TABLE 19-2
AMERICAN SOCIETY OF ANESTHESIOLOGISTS
PHYSICAL STATUS CLASSIFICATION SYSTEM
CHAPTER 19
tives include removal of the diseased sigmoid down to
the rectosigmoid junction. Failure to do this may result
in recurrent disease. The current options for uncom
plicated diverticular disease include an open sigmoid
resection or a laparoscopic sigmoid resection. The
benefits of laparoscopic resection over open surgical FIGURE 19-3
techniques include early discharge (by at least 1 day),
patients following inadequate surgical resection. A require the patient to manually reduce the prolapse.
retained segment of diseased rectosigmoid colon is Constipation occurs in ∼30–67% of patients with rectal
associated with twice the incidence of recurrence. IBS prolapse. Differing degrees of fecal incontinence occur
may also cause recurrence of initial symptoms. Patients in 50–70% of patients. Patients with internal rectal pro-
undergoing surgical resection for presumed diverticuli- lapse will present with symptoms of both constipation
tis and symptoms of abdominal cramping and irregular and incontinence. Other associated findings include
loose bowel movements consistent with IBS have func- outlet obstruction (anismus) in 30%, colonic inertia in
tionally poorer outcomes. 10%, and solitary rectal ulcer syndrome in 12%.
Office evaluation is best performed after the patient
has been given an enema, which enables the prolapse
to protrude. An important distinction should be made
COMMON DISEASES OF between full-thickness rectal prolapse and isolated
THE ANORECTUM mucosal prolapse associated with hemorrhoidal disease
RECTAL PROLAPSE (PROCIDENTIA) (Fig. 19-4). Mucosal prolapse is known for radial
grooves rather than circumferential folds around the
Incidence and epidemiology anus and is due to increased laxity of the connective tis-
Rectal prolapse is six times more common in women sue between the submucosa and underlying muscle of
than in men. The incidence of rectal prolapse peaks in the anal canal. The evaluation of prolapse should also
women >60 years. Women with rectal prolapse have include cystoproctography and colonoscopy. These
a higher incidence of associated pelvic floor disorders examinations evaluate for associated pelvic floor disor-
including urinary incontinence, rectocele, cystocele, ders and rule out a malignancy or a polyp as the lead
and enterocele. About 20% of children with rectal pro- point for prolapse. If rectal prolapse is associated with
lapse will have cystic fibrosis. All children presenting chronic constipation, the patient should undergo a
with prolapse should undergo a sweat chloride test. Less defecating proctogram and a sitzmark study. This will
common associations include Ehlers-Danlos syndrome, evaluate for the presence of anismus or colonic inertia.
solitary rectal ulcer syndrome, congenital hypothyroid- Anismus is the result of attempting to defecate against
ism, and Hirschsprung’s disease. a closed pelvic floor and is also known as nonrelaxing
puborectalis. This can be seen when straightening of the
rectum fails to occur on fluoroscopy while the patient
Anatomy and pathophysiology
is attempting to defecate. In colonic inertia, a sitzmark
Rectal prolapse (procidentia) is a circumferential, full- study will demonstrate retention of >20% of markers on
thickness protrusion of the rectal wall through the anal abdominal x-ray 5 days after swallowing. For patients
217
with (Frykman-Goldberg) or without resection of the
redundant sigmoid. Transabdominal procedures can
be performed effectively with laparoscopic techniques
without increased incidence of recurrence. The goal
of the transabdominal approach is to restore normal
anatomy by removing redundant bowel and reattach
ing the supportive tissue of the rectum to the presacral
fascia. The final alternative is abdominal proctectomy
with end-sigmoid colostomy. Colon resection, in gen
eral, is reserved for patients with constipation and outlet
A C obstruction. If total colonic inertia is present, as defined
by a history of constipation and a positive sitzmark
study, a subtotal colectomy with an ileosigmoid or rectal
anastomosis may be required at the time of rectopexy.
Previously, the presence of internal rectal prolapse
identified on imaging studies has been considered
CHAPTER 19
a nonsurgical disorder and biofeedback was recom
mended. However, only one-third of patients will have
successful resolution of symptoms from biofeedback.
Two surgical procedures have been shown to be more
effective than biofeedback. The STARR (stapled trans
B D anal rectal resection) procedure (Fig. 19-5) is performed
through the anus in patients with internal prolapse. A
• Severe diarrhea
CHAPTER 19
latency. Finally, ultrasound will evaluate the extent Symptomatic hemorrhoids affect >1 million individu-
of the injury to the sphincter muscles before surgical als in the Western world per year. The prevalence of
repair. Only PNTML has been shown to consistently hemorrhoidal disease is not selective for age or sex.
predict outcome following surgical intervention. However, age is known to have a deleterious effect on
Rarely does a pelvic floor disorder exist alone. The the anal canal. The prevalence of hemorrhoidal disease
majority of patients with fecal incontinence will have a is less in underdeveloped countries. The typical low-
fiber, high-fat Western diet is associated with constipa-
CHAPTER 19
Incidence and epidemiology
Common locations of anorectal abscess (left) and fistula
in ano (right). The incidence and prevalence of fistulating perianal dis-
ease parallels the incidence of anorectal abscess. Some
30–40% of abscesses will give rise to fistula in ano.
HIV. positive. These disorders should be considered in While the majority of the fistulas are cryptoglandular
patients with recurrent perianal infections. in origin, 10% are associated with IBD, tuberculosis,
rectal advancement flap in combination with a drainage proximal end of the fissure and a sentinel pile or skin
catheter or fibrin glue may be used. Very long (>2 cm) tag at the distal end. Often the circular fibers of the
and narrow tracts respond better to fibrin glue than hypertrophied internal sphincter are visible within the
shorter tracts. Simple ligation of the internal fistula tract base of the fissure. If anal manometry is performed, ele-
(LIFT procedure) has also been used in the management vation in anal resting pressure and a sawtooth deformity
of simple fistula with good success. with paradoxical contractions of the sphincter muscles
Disorders of the Alimentary Tract
Susan L. Gearhart
point, respectively, and are the most common loca- blood count, serum chemistry, coagulation profile, arte-
tions for colonic ischemia (Fig. 20-1, shaded areas). The rial blood gas, amylase, lipase, lactic acid, blood type
splanchnic circulation can receive up to 30% of the car- and cross match, and cardiac enzymes. Regardless of
SECTION III
diac output. Protective responses to prevent intestinal the need for urgent surgery, emergent admission to a
ischemia include abundant collateralization, autoregula- monitored bed or intensive care unit is recommended
tion of blood flow, and the ability to increase oxygen for resuscitation and further evaluation. If the diagnosis
extraction from the blood. of intestinal ischemia is being considered, consultation
Occlusive ischemia is a result of disruption of blood with a surgical service is necessary.
flow by an embolus or progressive thrombosis in a Other diagnostic modalities that may be useful in
major artery supplying the intestine. Emboli origi- diagnosis but should not delay surgical therapy include
Disorders of the Alimentary Tract
nate from the heart in >75% of cases and lodge pref- electrocardiogram (ECG), abdominal radiographs, CT,
erentially just distal to the origin of the middle colic and mesenteric angiography. More recently, mesentery
artery from the superior mesenteric artery. Progressive duplex scanning and visible light spectroscopy during
thrombosis of at least two of the major vessels sup- colonoscopy have been demonstrated to be beneficial.
plying the intestine is required for the development The ECG may demonstrate an arrhythmia, indicat-
of chronic intestinal angina. Nonocclusive ischemia is ing the possible source of the emboli. A plain abdomi-
disproportionate mesenteric vasoconstriction (arterio- nal film may show evidence of free intraperitoneal air,
lar vasospasm) in response to a severe physiologic stress indicating a perforated viscus and the need for emergent
such as dehydration or shock. If left untreated, early exploration. Earlier features of intestinal ischemia seen
mucosal stress ulceration will progress to full-thickness on abdominal radiographs include bowel-wall edema,
injury. known as “thumbprinting.” If the ischemia progresses,
air can be seen within the bowel wall (pneumatosis intes-
tinalis) and within the portal venous system. Other fea-
PRESENTATION, EVALUATION,
tures include calcifications of the aorta and its tributaries,
AND MANAGEMENT
indicating atherosclerotic disease. With the administra-
Intestinal ischemia remains one of the most challenging tion of oral and IV contrast, dynamic CT with three-
diagnoses. The mortality rate is >50%. The most dimensional reconstruction is a highly sensitive test for
significant indicator of survival is the timeliness of diag- intestinal ischemia. In acute embolic disease, mesenteric
nosis and treatment. An overview of diagnosis and man- angiography is best performed intraoperatively. A mes-
agement of each form of intestinal ischemia is given in enteric duplex scan demonstrating a high peak velocity
Table 20-2. of flow in the superior mesenteric artery (SMA) is asso-
Acute mesenteric ischemia resulting from arterial ciated with an ∼80% positive predictive value of mes-
embolus or thrombosis presents with severe acute, non- enteric ischemia. More significantly, a negative duplex
remitting abdominal pain strikingly out of proportion to scan virtually precludes the diagnosis of mesenteric isch-
the physical findings. Associated symptoms may include emia. Duplex imaging serves as a screening test; further
nausea and vomiting, transient diarrhea, and bloody investigations with angiography are needed. Endoscopic
stools. With the exception of minimal abdominal dis- techniques using visible light spectroscopy can be used
tention and hypoactive bowel sounds, early abdominal in the diagnosis of chronic ischemia.
examination is unimpressive. Later findings will dem- The “gold standard” for the diagnosis and manage-
onstrate peritonitis and cardiovascular collapse. In the ment of acute arterial occlusive disease is laparotomy.
evaluation of acute intestinal ischemia, routine labo- Surgical exploration should not be delayed if suspi-
ratory tests should be obtained, including complete cion of acute occlusive mesenteric ischemia is high or
TABLE 20-2 225
OVERVIEW OF THE MANAGEMENT OF ACUTE INTESTINAL ISCHEMIA
KEY TO EARLY TREATMENT OF TREATMENT OF TREATMENT OF SYSTEMIC
CONDITION DIAGNOSIS UNDERLYING CAUSE SPECIFIC LESION CONSEQUENCES
CHAPTER 20
Venous Spiral CT Anticoagulation Anticoagulation ± Give antibiotics
thrombosis Massive hydration laparotomy/ Reverse acidosis
thrombectomy/ Optimize oxygen delivery
portasystemic shunt Support cardiac output
Assess viability and Avoid vasoconstrictors
resect dead bowel
Nonocclusive Vasospasm: Ensure hydration Vasospasm Ensure hydration
Source: Modified from GB Bulkley, in JL Cameron (ed): Current Surgical Therapy, 2nd ed. Toronto, BC Decker, 1986.
evidence of clinical deterioration or frank peritoni- are obtunded, and physical findings may not assist in
tis is present. The goal of operative exploration is to the diagnosis. The presence of a leukocytosis, metabolic
resect compromised bowel and restore blood supply. acidosis, elevated amylase or creatinine phosphokinase
Intraoperative or preoperative arteriography and sys- levels, and/or lactic acidosis are useful in support of the
temic heparinization may assist the vascular surgeon diagnosis of advanced intestinal ischemia; however, these
in restoring blood supply to the compromised bowel. markers may not be indicative of either reversible isch-
The entire length of the small and large bowel begin- emia or frank necrosis. Investigational markers for intes-
ning at the ligament of Treitz should be evaluated. The tinal ischemia include D-dimer, glutathione S-transferase,
pattern of intestinal ischemia may indicate the level of platelet-activating factor (PAF), and mucosal pH moni-
arterial occlusion. In the case of SMA occlusion where toring. Regardless of the need for urgent surgery, emer-
the embolus usually lies just proximal to the origin of gent admission to a monitored bed or intensive care unit
the middle colic artery, the proximal jejunum is often is recommended for resuscitation and further evaluation.
spared while the remainder of the small bowel to the Early manifestations of intestinal ischemia include fluid
transverse colon will be ischemic. The surgical manage- sequestration within the bowel wall leading to a loss of
ment of acute mesenteric ischemia of the small bowel is interstitial volume. Aggressive fluid resuscitation may be
attempted embolectomy via intraoperative angiography necessary. To optimize oxygen delivery, nasal O2 and
or arteriotomy. Although more commonly applied to blood transfusions may be given. Broad-spectrum antibi-
chronic disease, acute thrombosis may be managed with otics should be given to provide sufficient coverage for
angioplasty, with or without endovascular stent place- enteric pathogens, including gram-negative and anaero-
ment. If this is unsuccessful, a bypass from the aorta to bic organisms. Frequent monitoring of the patient’s vital
the superior mesenteric artery is performed. signs, urine output, blood gases, and lactate levels is para-
Nonocclusive or vasospastic mesenteric ischemia pres- mount, as is frequent abdominal examination. All vaso-
ents with generalized abdominal pain, anorexia, bloody constricting agents should be avoided; fluid resuscitation
stools, and abdominal distention. Often these patients is the intervention of choice to maintain hemodynamics.
226 If ischemic colitis is a concern, colonoscopy should popularity. In the absence of obesity and an increased
be performed to assess the integrity of the colon bowel gas pattern, the radiologist may be able to iden-
mucosa. Visualization of the rectosigmoid region may tify flow disturbances within the vessels or the lack of a
demonstrate decreased mucosal integrity, associated vasodilation response to feeding. This tool is frequently
more commonly with nonocclusive mesenteric isch- used as a screening test for patients with symptoms sug-
emia, or, on occasion, occlusive disease as a result of gestive of chronic mesenteric ischemia. The gold stan-
acute loss of inferior mesenteric arterial flow following dard for confirmation of mesenteric arterial occlusion
aortic surgery. Ischemia of the colonic mucosa is graded is mesenteric angiography. Evaluation with mesenteric
as mild with minimal mucosal erythema or as moderate angiography allows for identification and possible inter-
with pale mucosal ulcerations and evidence of exten- vention for the treatment of thrombus within the vessel
sion to the muscular layer of the bowel wall. Severe isch- lumen and will also evaluate the patency of remaining
emic colitis presents with severe ulcerations resulting in mesenteric vessels. The use of mesenteric angiogra-
black or green discoloration of the mucosa, consistent phy may be limited in the presence of renal failure or
with full-thickness bowel-wall necrosis. The degree of contrast allergy. Magnetic resonance angiography is
reversibility can be predicted from the mucosal find- an alternative if the administration of contrast dye is
ings: Mild erythema is nearly 100% reversible, moderate contraindicated.
∼50%, and frank necrosis is simply dead bowel. Follow- The management of chronic intestinal ischemia
SECTION III
up colonoscopy can be performed to rule out progres- includes medical management of atherosclerotic disease
sion of ischemic colitis. by lipid-lowering medications, exercise, and cessation of
Laparotomy for nonocclusive mesenteric ischemia is smoking. A full cardiac evaluation should be performed
warranted for signs of peritonitis or worsening endoscopic before intervention. Newer endovascular procedures
findings and if the patient’s condition does not improve may avoid an operative intervention in selected patient
with aggressive resuscitation. Ischemic colitis is optimally populations. Angioplasty with endovascular stenting in
Disorders of the Alimentary Tract
treated with resection of the ischemic bowel and forma- the treatment of chronic mesenteric ischemia is asso-
tion of a proximal stoma. Primary anastomosis should not ciated with an 80% long-term success rate. In patients
be performed in patients with acute intestinal ischemia. requiring surgical exploration, the approach used is
Patients with MVT may present with a gradual or determined by the mesenteric angiogram. The entire
sudden onset. Symptoms include vague abdominal pain, length of the small and large bowel should be evalu-
nausea, and vomiting. Examination findings include ated, beginning at the ligament of Treitz. Restoration
abdominal distention with mild to moderate tender- of blood flow at the time of laparotomy is accomplished
ness and signs of dehydration. The diagnosis of mesen- with mesenteric bypass.
teric thrombosis is frequently made on abdominal spiral Determination of intestinal viability intraoperatively
CT with oral and IV contrast. Findings on CT include in patients with suspected intestinal ischemia can be chal-
bowel-wall thickening and ascites. Intravenous con- lenging. After revascularization, the bowel wall should
trast will demonstrate a delayed arterial phase and clot be observed for return of a pink color and peristalsis.
within the superior mesenteric vein. The goal of man- Palpation of major arterial vessels can be performed as
agement is to optimize hemodynamics and correct elec- well as applying a doppler flowmeter to the antimesen-
trolyte abnormalities with massive fluid resuscitation. teric border of the bowel wall, but neither is a definitive
Intravenous antibiotics as well as anticoagulation should indicator of viability. In equivocal cases, 1 g of IV sodium
be initiated. If laparotomy is performed and MVT is fluorescein is administered and the pattern of bowel
suspected, heparin anticoagulation is immediately initi- reperfusion is observed under ultraviolet illumination
ated and compromised bowel is resected. Of all acute with a standard (3600 A) Wood’s lamp. An area of non-
intestinal disorders, mesenteric venous insufficiency is fluorescence >5 mm in diameter suggests nonviability. If
associated with the best prognosis. doubt persists, reexploration performed 24–48 h follow-
Chronic intestinal ischemia presents with intesti- ing surgery will allow demarcation of nonviable bowel.
nal angina or abdominal pain associated with need for Primary intestinal anastomosis in patients with ischemic
increased blood flow to the intestine. Patients report bowel is always worrisome, and reanastomosis should be
abdominal cramping and pain following ingestion deferred to the time of second-look laparotomy.
of a meal. Weight loss and chronic diarrhea may also
be noted. Abdominal pain without weight loss is not
Acknowledgments
chronic mesenteric angina. Physical examination will
often reveal the presence of an abdominal bruit as well We thank Cory Sandore for providing some illustrations for
as other manifestations of atherosclerosis. Duplex ultra- this chapter. Gregory Bulkley contributed to this chapter in the
sound evaluation of the mesenteric vessels has gained in 16th edition.
CHAPTER 21
William Silen
SYMPTOMS
Mechanical intestinal obstruction is characterized by cramping LABORATORY AND X-RAY FINDINGS
midabdominal pain, which tends to be more severe the
Laboratory and radiographic studies are used to help
higher the obstruction. The pain occurs in paroxysms,
differentiate the two important clinical aspects of this
and the patient is relatively comfortable in the inter-
disorder: strangulation vs. nonstrangulation and par-
Disorders of the Alimentary Tract
CHAPTER 21
is nil and losses in vomitus are large. A long intestinal tube
is not indicated. Operative intervention may be under-
taken successfully by laparoscopic techniques with a
decreased incidence of wound complications. However,
laparoscopic lysis of adhesions is associated with a longer
operative time and higher conversion to open rate when
compared to other laparoscopic procedures. Alterna-
William Silen
PATHOGENESIS
CLINICAL MANIFESTATIONS
Appendicitis is believed to occur as a result of appendiceal
luminal obstruction. Obstruction is most commonly The sequence of abdominal discomfort and anorexia
caused by a fecalith, which results from accumulation associated with acute appendicitis is pathognomonic.
and inspissation of fecal matter around vegetable fibers. The pain is described as being located in the periumbili-
Enlarged lymphoid follicles associated with viral infec- cal region initially and then migrating to the right lower
tions (e.g., measles), inspissated barium, worms (e.g., quadrant. This classic sequence of symptoms occurs
pinworms, Ascaris, and Taenia), and tumors (e.g., carci- in only 66% of patients. The differential diagnoses for
noid or carcinoma) may also obstruct the lumen. Other periumbilical and right lower quadrant pain is listed in
common pathologic findings include appendiceal ulcer- Table 22-1. The periumbilical abdominal pain is of the
ation. The cause of the ulceration is unknown, although visceral type, resulting from distention of the appendi-
a viral etiology has been postulated. Infection with Yer- ceal lumen. This pain is carried on slow-conducting C
sinia organisms may cause the disease, since high com- fibers and is usually poorly localized in the periumbili-
plement fixation antibody titers have been found in up cal or epigastric region. In general, this visceral pain is
to 30% of cases of proven appendicitis. Luminal bacte- mild, often cramping and usually lasting 4–6 h, but it
ria multiply and invade the appendiceal wall as venous may not be noted by stoic individuals. As inflamma-
engorgement and subsequent arterial compromise result tion spreads to the parietal peritoneal surfaces, the pain
231
232 TABLE 22-1 hip and guarded movement by the patient are due to
THE ANATOMIC ORIGIN OF PERIUMBILICAL parietal peritoneal involvement. Hyperesthesia of the
AND RIGHT LOWER QUADRANT PAIN IN THE skin of the right lower quadrant and a positive psoas or
DIFFERENTIAL DIAGNOSIS OF APPENDICITIS obturator sign are often late findings and are rarely of
Periumbilical diagnostic value.
Appendicitis The temperature is usually normal or slightly ele-
Small-bowel obstruction vated [37.2°–38°C (99°–100.5°F)], but a temperature
Gastroenteritis >38.3°C (101°F) should suggest perforation. Tachycardia
Mesenteric ischemia is commensurate with the elevation of the temperature.
Right Lower Quadrant Rigidity and tenderness become more marked as the
Gastrointestinal causes Gynecologic causes disease progresses to perforation and localized or diffuse
Appendicitis Ovarian tumor/torsion peritonitis. Distention is rare unless severe diffuse peri-
Inflammatory bowel Pelvic inflammatory tonitis has developed. A mass may develop if localized
disease disease perforation has occurred but will not usually be detect-
Right-sided diverticulitis Renal causes able before 3 days after onset. Earlier presence of a mass
Gastroenteritis Pyelonephritis suggests carcinoma of the cecum or Crohn’s disease.
Inguinal hernia Perinephritic abscess
Perforation is rare before 24 h after onset of symptoms,
Nephrolithiasis
SECTION III
A delta fibers, which are fast-conducting and unilateral. stool suggest a primary diagnosis of carcinoma of the
These fibers localize the pain to the right lower quadrant. cecum, especially in elderly individuals. The urine may
Anorexia is very common; a hungry patient almost contain a few white or red blood cells without bacte-
invariably does not have acute appendicitis. Nausea ria if the appendix lies close to the right ureter or blad-
and vomiting occur in 50–60% of cases, but vomiting der. Urinalysis is most useful in excluding genitourinary
is usually self-limited. Change in bowel habit is of lit- conditions that may mimic acute appendicitis.
tle diagnostic value, since any or no alteration may be Radiographs are rarely of value except when an
observed, although the presence of diarrhea caused by opaque fecalith (5% of patients) is observed in the right
an inflamed appendix in juxtaposition to the sigmoid lower quadrant (especially in children). Consequently,
may cause diagnostic difficulties. Urinary frequency abdominal films are not routinely obtained unless other
and dysuria occur if the appendix lies adjacent to the conditions such as intestinal obstruction or ureteral cal-
bladder. culus may be present. The diagnosis may also be estab-
Physical findings vary with time after onset of the lished by the ultrasonic demonstration of an enlarged
illness and according to the location of the appen- and thick-walled appendix. Ultrasound is most useful to
dix, which may be situated deep in the pelvic cul-de- exclude ovarian cysts, ectopic pregnancy, or tuboovar-
sac; in the right lower quadrant in any relation to the ian abscess. Several studies have recently demonstrated
peritoneum, cecum, and small intestine; in the right the benefit of contrast-enhanced or nonenhanced CT
upper quadrant (especially during pregnancy); or even over ultrasound and plain radiographs in the diagnosis
in the left lower quadrant. The diagnosis cannot be estab- of acute appendicitis. The findings on CT will include a
lished unless tenderness can be elicited. While tenderness is thickened appendix with periappendiceal stranding and
sometimes absent in the early visceral stage of the dis- often the presence of a fecalith (Figs. 22-1 and 22-2).
ease, it ultimately always develops and is found in any The reported positive predictive value of CT is 95–97%
location corresponding to the position of the appendix. and the overall accuracy is 90–98%. Furthermore, non-
Typically, tenderness to palpation will often occur at visualization of the appendix on CT is associated with
McBurney’s point, anatomically located on a line one- the findings of a normal appendix 98% of the time.
third of the way between the anterior iliac spine and the Free peritoneal air is uncommon, even in perforated
umbilicus. Abdominal tenderness may be completely appendicitis.
absent if a retrocecal or pelvic appendix is present, in While the typical historic sequence and physical
which case the sole physical finding may be tenderness findings are present in 50–60% of cases, a wide variety
in the flank or on rectal or pelvic examination. Referred of atypical patterns of disease are encountered, espe-
rebound tenderness is often present and is most likely cially at the age extremes and during pregnancy. Infants
to be absent early in the illness. Flexion of the right under 2 years of age have a 70–80% incidence of
appendiceal abscess) or with adhesive intestinal obstruc- 233
tion 5 or 6 days after a previously undetected perforated
appendix.
Appendicitis occurs about once in every 500–2000
pregnancies and is the most common extrauterine con-
dition requiring abdominal operation. The diagno-
sis may be missed or delayed because of the frequent
occurrence of mild abdominal discomfort and nausea
and vomiting during pregnancy, and because of the
gradual shift of the appendix from the right lower quad-
rant to the right upper quadrant during the second and
third trimester of pregnancy. Appendicitis tends to be
most common during the second trimester. The diag-
nosis is best made with ultrasound, which is 80% accu-
rate; however, if perforation has already occurred, the
accuracy of ultrasound decreases to 30%. Early interven-
tion is warranted because the incidence of fetal loss with
CHAPTER 22
FIGURE 22-1 a normal appendix is 1.5%. With perforation, the inci-
CT with oral and intravenous contrast of acute appendicitis. dence of fetal loss is 20–35%.
There is thickening of the wall of the appendix and periap-
pendiceal stranding (arrow).
DIFFERENTIAL DIAGNOSIS
Acute appendicitis has been labeled the masquerader, and
the diagnosis is often more difficult to make in young
CHAPTER 22
Obstructions (indwelling catheter) elderly and immunosuppressed patients, signs of perito-
Adhesions Intraperitoneal neal irritation may be more difficult to detect.
Strangulated hernias chemotherapy
Volvulus Perinephric abscess
Intussusception Iatrogenic—postoperative, THERAPY AND PROGNOSIS
Neoplasms foreign body
Ingested foreign body,
Treatment relies on rehydration, correction of electro-
INFECTIONS OF THE
ALIMENTARY TRACT
CHAPTER 23
Ranging from a mild annoyance to a devastat- species. For Shigella, enterohemorrhagic Escherichia coli,
ing dehydrating illness, acute diarrheal disease Giardia lamblia, or Entamoeba, as few as 10–100 bacte-
is a leading cause of illness globally, with an ria or cysts can produce infection, while 105−108 Vibrio
estimated 4.6 billion episodes worldwide per year. cholerae organisms must be ingested orally to cause dis-
Diarrheal disease ranks second only to lower respiratory ease. The infective dose of Salmonella varies widely,
infection as the most common infectious cause of death depending on the species, host, and food vehicle.
worldwide. Among children <5 years old, diarrheal The ability of organisms to overcome host defenses
disease is a particularly important cause of death. Every has important implications for transmission; Shigella,
year nearly 2 million children in this age group die of enterohemorrhagic E. coli, Entamoeba, and Giardia can
diarrheal disease; the majority of these young children spread by person-to-person contact, whereas under
are impoverished and live in resource-poor areas. By some circumstances Salmonella may have to grow in
contributing to malnutrition and thereby reducing food for several hours before reaching an effective
resistance to other infectious agents, diarrheal disease is infectious dose.
also an indirect factor in a far greater burden of disease.
The wide range of clinical manifestations of acute
Adherence
gastrointestinal illnesses is matched by the wide variety
of infectious agents involved, including viruses, bacte- Many organisms must adhere to the gastrointestinal
ria, and parasitic pathogens (Table 23-1). This chapter mucosa as an initial step in the pathogenic process;
discusses factors that enable gastrointestinal pathogens thus, organisms that can compete with the normal
to cause disease, reviews host defense mechanisms, and bowel flora and colonize the mucosa have an impor-
delineates an approach to the evaluation and treatment tant advantage in causing disease. Specific cell-surface
of patients presenting with acute diarrhea. Individual proteins involved in attachment of bacteria to intestinal
organisms causing acute gastrointestinal illnesses are dis- cells are important virulence determinants. V. cholerae, for
cussed in detail in subsequent chapters. example, adheres to the brush border of small-intestinal
enterocytes via specific surface adhesins, including the
toxin-coregulated pilus and other accessory coloni-
zation factors. Enterotoxigenic E. coli, which causes
PATHOGENIC MECHANISMS
watery diarrhea, produces an adherence protein called
Enteric pathogens have developed a variety of tactics to colonization factor antigen that is necessary for coloniza-
overcome host defenses. Understanding the virulence tion of the upper small intestine by the organism prior
factors employed by these organisms is important in the to the production of enterotoxin. Enteropathogenic
diagnosis and treatment of clinical disease. E. coli, an agent of diarrhea in young children, and
enterohemorrhagic E. coli, which causes hemorrhagic
colitis and the hemolytic-uremic syndrome, produce
Inoculum size
virulence determinants that allow these organisms to
The number of microorganisms that must be ingested attach to and efface the brush border of the intestinal
to cause disease varies considerably from species to epithelium.
238
TABLE 23-1 239
GASTROINTESTINAL PATHOGENS CAUSING ACUTE DIARRHEA
MECHANISM LOCATION ILLNESS STOOL FINDINGS EXAMPLES OF PATHOGENS INVOLVED
CHAPTER 23
Toxin production Some enterotoxigenic strains of E. coli produce both
LT and ST.
The production of one or more exotoxins is important in Bacterial cytotoxins, in contrast, destroy intesti-
the pathogenesis of numerous enteric organisms. Such nal mucosal cells and produce the syndrome of dysen-
toxins include enterotoxins, which cause watery diar- tery, with bloody stools containing inflammatory cells.
rhea by acting directly on secretory mechanisms in the Enteric pathogens that produce such cytotoxins include
The composition of the intestinal flora is as important as rheal diseases. People with blood group O show
the number of organisms present. More than 99% of the increased susceptibility to disease due to V. cholerae,
normal colonic flora is made up of anaerobic bacteria, Shigella, E. coli O157, and norovirus. Polymorphisms in
and the acidic pH and volatile fatty acids produced by genes encoding inflammatory mediators have been asso-
these organisms appear to be critical elements in resis- ciated with the outcome of infection with enteroaggre-
tance to colonization. gative E. coli, enterotoxin-producing E. coli, Salmonella,
Infections of the Alimentary Tract
Symptomatic therapy
Oral rehydration therapy
(see Table 128-5)
Resolution
No
Assess:
Duration (>1 day)
Severity (see text)
Continued illness
Yes
Obtain history:
Duration1 Tenesmus6
Fever2 Vomiting7
Appearance of stool3 Common source8
Frequency of bowel Antibiotic use9
movements4 Travel10
Abdominal pain5
and
Obtain stool to be examined for WBCs
(and, if >10 days, for parasites)
CHAPTER 23
symptomatic therapy Salmonella, C. jejuni Specific antiparasitic therapy
(Table 128-5); Consider:
further evaluation C.difficile cytotoxin
if no resolution
Consider: Empirical
antimicrobial therapy
(Table 128-5)
CHAPTER 23
among children
inflammatory etiology of diarrhea and there is evidence
PARASITES 0–10 of a common-source outbreak, questions concerning
Giardia lamblia 0–5 Affects hikers and the ingestion of specific foods and the time of onset of
campers who drink the diarrhea after a meal can provide clues to the bacte-
from freshwater
rial cause of the illness. Potential causes of bacterial food
streams; contami-
nates water
poisoning are shown in Table 23-4.
1–6 h
Staphylococcus aureus Nausea, vomiting, diarrhea Ham, poultry, potato or egg salad,
mayonnaise, cream pastries
Bacillus cereus Nausea, vomiting, diarrhea Fried rice
8–16 h
Clostridium perfringens Abdominal cramps, diarrhea (vomiting rare) Beef, poultry, legumes, gravies
B. cereus Abdominal cramps, diarrhea (vomiting rare) Meats, vegetables, dried beans, cereals
>16 h
Vibrio cholerae Watery diarrhea Shellfish, water
Enterotoxigenic Escherichia coli Watery diarrhea Salads, cheese, meats, water
Enterohemorrhagic E. coli Bloody diarrhea Ground beef, roast beef, salami, raw
milk, raw vegetables, apple juice
Salmonella spp. Inflammatory diarrhea Beef, poultry, eggs, dairy products
Campylobacter jejuni Inflammatory diarrhea Poultry, raw milk
Shigella spp. Dysentery Potato or egg salad, lettuce, raw
vegetables
Vibrio parahaemolyticus Dysentery Mollusks, crustaceans
SECTION IV
spores can germinate and produce toxin. Frying before antigen enzyme immunoassays have been developed for
serving may not destroy the preformed, heat-stable toxin. the identification of norovirus. Stool specimens should
Food poisoning due to Clostridium perfringens also be examined by immunofluorescence-based rapid
has a slightly longer incubation period (8–14 h) and assays or (less sensitive) standard microscopy for Giardia
results from the survival of heat-resistant spores in cysts or Cryptosporidium if the level of clinical suspicion
inadequately cooked meat, poultry, or legumes. After regarding the involvement of these organisms is high.
Infections of the Alimentary Tract
ingestion, toxin is produced in the intestinal tract, All patients with fever and evidence of inflamma-
causing moderately severe abdominal cramps and tory disease acquired outside the hospital should have
diarrhea; vomiting is rare, as is fever. The illness is stool cultured for Salmonella, Shigella, and C ampylobacter.
self-limited, rarely lasting >24 h. Salmonella and Shigella can be selected on MacConkey
Not all food poisoning has a bacterial cause. Nonbac- agar as non-lactose-fermenting (colorless) colonies or
terial agents of short-incubation food poisoning include can be grown on Salmonella-Shigella agar or in selenite
capsaicin, which is found in hot peppers, and a variety enrichment broth, both of which inhibit most organ-
of toxins found in fish and shellfish (Chap. 396). isms except these pathogens. Evaluation of nosocomial
diarrhea should initially focus on C. difficile; stool cul-
ture for other pathogens in this setting has an extremely
LABORATORY EVALUATION low yield and is not cost-effective. Toxins A and B
produced by pathogenic strains of C. difficile can be
Many cases of noninflammatory diarrhea are self-limited detected by rapid enzyme immunoassays and latex
or can be treated empirically, and in these instances the agglutination tests (Chap. 129). Isolation of C. jejuni
clinician may not need to determine a specific etiology. requires inoculation of fresh stool onto selective growth
Potentially pathogenic E. coli cannot be distinguished medium and incubation at 42°C in a microaerophilic
from normal fecal flora by routine culture, and tests atmosphere. In many laboratories in the United States,
to detect enterotoxins are not available in most clini- E. coli O157:H7 is among the most common patho-
cal laboratories. In situations in which cholera is a con- gens isolated from visibly bloody stools. Strains of this
cern, stool should be cultured on selective media such enterohemorrhagic serotype can be identified in spe-
as thiosulfate–citrate–bile salts–sucrose (TCBS) or tel- cialized laboratories by serotyping but also can be
lurite-taurocholate-gelatin (TTG) agar. A latex agglu- identified presumptively in hospital laboratories as lac-
tination test has made the rapid detection of rotavirus tose-fermenting, indole-positive colonies of sorbitol
in stool practical for many laboratories, while reverse- nonfermenters (white colonies) on sorbitol MacConkey
transcriptase polymerase chain reaction and specific plates. If the clinical presentation suggests the possibility
of intestinal amebiasis, stool should be examined by 245
a rapid antigen detection assay or by (less sensitive) absorption of sodium and water in the small intes-
microscopy. tine remains intact in the presence of cholera toxin.
The use of ORS has reduced mortality rates for chol-
era from >50% (in untreated cases) to <1%. A number
of ORS formulas have been used. Initial preparations
TREATMENT
Infectious Diarrhea or Bacterial were based on the treatment of patients with cholera
Food Poisoning
and included a solution containing 3.5 g of sodium
In many cases, a specific diagnosis is not necessary chloride, 2.5 g of sodium bicarbonate, 1.5 g of potas-
or not available to guide treatment. The clinician sium chloride, and 20 g of glucose (or 40 g of sucrose)
can proceed with the information obtained from the per liter of water. Such a preparation can still be used
history, stool examination, and evaluation of dehy- for the treatment of severe cholera. Many causes of
dration severity. Empirical regimens for the treat- secretory diarrhea, however, are associated with less
ment of traveler’s diarrhea are listed in Table 23-5. electrolyte loss than occurs in cholera; beginning in
The mainstay of treatment is adequate rehydration. 2002, the World Health Organization recommended
The treatment of cholera and other dehydrating diar- a “reduced-osmolarity/reduced-salt” ORS that is bet-
rheal diseases was revolutionized by the promotion ter tolerated and more effective than classic ORS.
of oral rehydration solution (ORS), the efficacy of This preparation contains 2.6 g of sodium chloride,
which depends on the fact that glucose-facilitated 2.9 g of trisodium citrate, 1.5 g of potassium chloride,
TABLE 23-5
TREATMENT OF TRAVELER’S DIARRHEA ON THE BASIS OF CLINICAL FEATURESa
CLINICAL SYNDROME SUGGESTED THERAPY
CHAPTER 23
Watery diarrhea (no blood in stool, no fever), 1 or Oral fluids (oral rehydration solution, Pedialyte, Lytren, or flavored min-
2 unformed stools per day without distressing eral water) and saltine crackers
enteric symptoms
Watery diarrhea (no blood in stool, no fever), 1 or Bismuth subsalicylate (for adults): 30 mL or 2 tablets (262 mg/tablet)
2 unformed stools per day with distressing enteric every 30 min for 8 doses; or loperamideb: 4 mg initially followed by
symptoms 2 mg after passage of each unformed stool, not to exceed 8 tablets
a
All patients should take oral fluids (Pedialyte, Lytren, or flavored mineral water) plus saltine crackers. If diarrhea becomes moderate or severe, if
fever persists, or if bloody stools or dehydration develops, the patient should seek medical attention.
b
Loperamide should not be used by patients with fever or dysentery; its use may prolong diarrhea in patients with infection due to Shigella or
other invasive organisms.
c
The recommended antibacterial drugs are as follows:
Travel to high-risk country other than Thailand:
Adults: (1) A fluoroquinolone such as ciprofloxacin, 750 mg as a single dose or 500 mg bid for 3 days; levofloxacin, 500 mg as a single dose or
500 mg qd for 3 days; or norfloxacin, 800 mg as a single dose or 400 mg bid for 3 days. (2) Azithromycin, 1000 mg as a single dose or 500 mg
qd for 3 days. (3) Rifaximin, 200 mg tid or 400 mg bid for 3 days (not recommended for use in dysentery).
Children: Azithromycin, 10 mg/kg on day 1, 5 mg/kg on days 2 and 3 if diarrhea persists. Alternative agent: furazolidone, 7.5 mg/kg per day in
four divided doses for 5 days.
Travel to Thailand (with risk of fluoroquinolone-resistant Campylobacter):
Adults: Azithromycin (at above dose for adults). Alternative agent: a fluoroquinolone (at above doses for adults).
Children: Same as for children traveling to other areas (see above).
Source: After Hill et al.
246 PROPHYLAXIS
and 13.5 g of glucose (or 27 g of sucrose) per liter of
water. ORS formulations containing rice or cereal as Improvements in hygiene to limit fecal-oral spread of
the carbohydrate source may be even more effec- enteric pathogens will be necessary if the prevalence of
tive than glucose-based solutions. Patients who are diarrheal diseases is to be significantly reduced in devel-
severely dehydrated or in whom vomiting precludes oping countries. Travelers can reduce their risk of diar-
the use of oral therapy should receive IV solutions rhea by eating only hot, freshly cooked food; by avoiding
such as Ringer’s lactate. raw vegetables, salads, and unpeeled fruit; and by drinking
Although most secretory forms of traveler’s diarrhea only boiled or treated water and avoiding ice. Historically,
(usually due to enterotoxigenic or enteroaggregative few travelers to tourist destinations adhere to these dietary
E. coli or to Campylobacter) can be treated effectively restrictions. Bismuth subsalicylate is an inexpensive agent
with rehydration, bismuth subsalicylate, or antiperi- for the prophylaxis of traveler’s diarrhea; it is taken at a
staltic agents, antimicrobial agents can shorten the dosage of 2 tablets (525 mg) four times a day. Treatment
duration of illness from 3–4 days to 24–36 h. Changes appears to be effective and safe for up to 3 weeks, but
in diet have not been shown to have an impact on the adverse events such as temporary darkening of the tongue
duration of illness, while the efficacy of probiotics con- and tinnitus can occur. A meta-analysis suggests that pro-
tinues to be debated. Most individuals who present biotics may lessen the likelihood of traveler’s diarrhea by
with dysentery (bloody diarrhea and fever) should be ∼15%. Prophylactic antimicrobial agents, although effec-
treated empirically with an antimicrobial agent (e.g., a tive, are not generally recommended for the prevention of
fluoroquinolone or a macrolide) pending microbiologic traveler’s diarrhea except when travelers are immunosup-
analysis of stool. Individuals with shigellosis should be pressed or have other underlying illnesses that place them
treated with a 3- to 7-day course. Individuals with Cam- at high risk for morbidity from gastrointestinal infection.
pylobacter infection often benefit from antimicrobial The risk of side effects and the possibility of developing
treatment as well. Because of increasing resistance of an infection with a drug-resistant organism or with more
Campylobacter to fluoroquinolones, especially in parts harmful, invasive bacteria make it more reasonable to insti-
SECTION IV
of Asia, a macrolide antibiotic such as erythromycin or tute an empirical short course of treatment if symptoms
azithromycin may be preferred for this infection. develop. If prophylaxis is indicated, the nonabsorbed anti-
Treatment of salmonellosis must be tailored to the biotic rifaximin can be considered for use in regions such
individual patient. Since administration of antimi- as Latin America and Africa, where noninvasive E. coli pre-
crobial agents often prolongs intestinal colonization dominates as the cause of traveler’s diarrhea. Rifaximin is
with Salmonella, these drugs are usually reserved for not effective against invasive enteropathogens.
Infections of the Alimentary Tract
individuals at high risk of complications from dissemi- The possibility of exerting a major impact on the
nated salmonellosis, such as young children, patients worldwide morbidity and mortality associated with
with prosthetic devices, elderly patients, and immu- diarrheal diseases has led to intense efforts to develop
nocompromised persons. Antimicrobial agents should effective vaccines against the common bacterial and
not be administered to individuals (especially chil- viral enteric pathogens. An effective rotavirus vaccine is
dren) in whom enterohemorrhagic E. coli infection is currently available. Vaccines against S. typhi and V. chol-
suspected. Laboratory studies of enterohemorrhagic erae are also available, although the protection they offer
E. coli strains have demonstrated that a number of anti- is incomplete and/or short lived. At present, there is no
biotics induce replication of Shiga toxin–producing lamb- effective commercially available vaccine against Shigella,
doid bacteriophages, thereby significantly increasing enterotoxigenic E. coli, Campylobacter, nontyphoidal
toxin production by these strains. Clinical studies have Salmonella, norovirus, or intestinal parasites.
supported these laboratory results, and antibiotics
may increase by twentyfold the risk of hemolytic-ure-
Acknowledgments
mic syndrome and renal failure during enterohemor-
rhagic E. coli infection. A clinical clue in the diagnosis The substantial contributions of Joan R. Butterton, MD,
of the latter infection is bloody diarrhea with low fever an author of this chapter in previous editions, are gratefully
or none at all. acknowledged.
CHAPTER 24
CHAPTER 24
C. difficile. Stools are almost never grossly bloody and the colon. PMC is a more advanced form of CDI and is
range from soft and unformed to watery or mucoid in visualized at endoscopy in only ∼50% of patients with
consistency, with a characteristic odor. Patients may diarrhea who have a positive stool culture and toxin
have as many as 20 bowel movements per day. Clinical assay for C. difficile (Table 24-1). Endoscopy is a rapid
Stool culture for ++++ +++ Most sensitive test; specificity of ++++ if the C. difficile isolate
C. difficile tests positive for toxin; with clinical data, is diagnostic of CDI;
turnaround time too slow for practical use
Cell culture cytotoxin +++ ++++ With clinical data, is diagnostic of CDI; highly specific but
test on stool not as sensitive as stool culture; slow turnaround time
Enzyme immunoassay ++ to +++ +++ With clinical data, is diagnostic of CDI; rapid results, but
for toxin A or toxins A not as sensitive as stool culture or cell culture cytotoxin test
and B in stool
Enzyme immunoassay +++ to ++++ +++ Detects glutamate dehydrogenase found in toxigenic and
for C. difficile common nontoxigenic strains of C. difficile and other stool organisms;
antigen in stool more sensitive and less specific than enzyme immunoassay
for toxins; rapid results
PCR for C. difficile ++++ ++++ Detects toxigenic C. difficile in stool; newly approved for clinical
toxin B gene in stool testing, but appears to be more sensitive than enzyme
immunoassay toxin testing and at least as specific
Colonoscopy or + ++++ Highly specific if pseudomembranes are seen; insensitive
sigmoidoscopy compared with other tests
a
According to both clinical and test-based criteria.
Note: ++++, >90%; +++, 71–90%; ++, 51–70%; +, ∼50%.
250 diagnostic tool in seriously ill patients with suspected no controlled comparisons are available. Metronida-
PMC and an acute abdomen, but a negative result in zole is not approved for this indication by the U.S. Food
this examination does not rule out CDI. and Drug Administration (FDA), but most patients with
Despite the array of tests available for C. difficile and mild to moderate illness respond to 500 mg given by
its toxins (Table 24-1), no single test has high sensitiv- mouth three times a day for 10 days; extension of the
ity, high specificity, and rapid turnaround. Most labora- treatment period may be needed for slow responders.
tory tests for toxins, including enzyme immunoassays In addition to the reports of increases in metronidazole
(EIAs), lack sensitivity. However, testing of multiple failures, a prospective, randomized, double-blind,
additional stool specimens is not recommended. PCR placebo-controlled study has demonstrated the superi-
assays have now been approved for diagnostic testing ority of vancomycin over metronidazole for treatment of
and appear to be both rapid and sensitive while retain- severe CDI. The severity assessment score in that study
ing high specificity. Empirical treatment is appropriate if included age as well as laboratory parameters (elevated
CDI is strongly suspected on clinical grounds. Testing of temperature, low albumin level, or elevated WBC count),
asymptomatic patients is not recommended except for documentation of PMC by endoscopy, or treatment
epidemiologic study purposes. In particular, so-called of CDI in the intensive care unit. Although a validated
tests of cure following treatment are not recommended severity score is not yet available, it is important to ini-
because many patients continue to harbor the organism tiate treatment with oral vancomycin for patients who
and toxin after diarrhea has ceased and test results do appear seriously ill, particularly if they have a high WBC
not always predict recurrence of CDI. Thus these results count (>15,000/μL) or a creatinine level that is ≥1.5 times
should not be used to restrict placement of patients in higher than the premorbid value (Table 24-2). Small
long-term-care or nursing home facilities. randomized trials of nitazoxanide, bacitracin, rifaximin,
and fusidic acid for treatment of CDI have been con-
ducted. While these drugs have not yet been extensively
Treatment Clostridium difficile Infection studied, shown to be superior, or approved by the FDA
SECTION IV
deterioration of some patients, prompt initiation of spe- patients ≥65 years old, those who continue to take
cific CDI treatment has become the standard. General antibiotics while being treated for CDI, and those who
treatment guidelines include hydration and the avoid- remain in the hospital after the initial episode of CDI.
ance of antiperistaltic agents and opiates, which may Patients who have a first recurrence of CDI have a high
mask symptoms and possibly worsen disease. Neverthe- rate of second recurrence (33–65%). In the first recur-
less, antiperistaltic agents have been used safely with rence, re-treatment with metronidazole is comparable
vancomycin or metronidazole for mild to moderate CDI. to treatment with vancomycin (Table 24-2). Recurrent
All drugs, particularly vancomycin, should be given disease, once thought to be relatively mild, has now
orally if possible. When IV metronidazole is admin- been documented to pose a significant (11%) risk of
istered, fecal bactericidal drug concentrations are serious complications (shock, megacolon, perfora-
achieved during acute diarrhea, and CDI treatment tion, colectomy, or death within 30 days). There is no
has been successful; however, in the presence of ady- standard treatment for multiple recurrences, but long
namic ileus, IV metronidazole treatment of PMC has or repeated metronidazole courses should be avoided
failed. In previous randomized trials, diarrhea response because of potential neurotoxicity. Approaches include
rates to oral therapy with vancomycin or metronida- the administration of vancomycin followed by the yeast
zole were ≥94%, but four recent observational stud- Saccharomyces boulardii; the administration of vanco-
ies found that response rates for metronidazole had mycin followed by a synthetic fecal bacterial enema;
declined to 62–78%. Although the mean time to resolu- and the intentional colonization of the patient with a
tion of diarrhea is 2–4 days, the response to metroni- nontoxigenic strain of C. difficile. None of these biother-
dazole may be much slower. Treatment should not be apeutic approaches has been approved by the FDA for
deemed a failure until a drug has been given for at use in the United States. Other strategies include (1) the
least 6 days. On the basis of data for shorter courses of use of vancomycin in tapering doses or with pulse dos-
vancomycin, it is recommended that metronidazole and ing every other day for 2–8 weeks and (2) sequential
vancomycin be given for at least 10 days, although treatment with vancomycin (125 mg four times daily for
Table 24-2 251
Recommendations for the Treatment of Clostridium difficile Infection (CDI)
Clinical Setting Treatment(s) Comments
CHAPTER 24
stop vancomycin and start rifaximin
(400 mg bid × 2 weeks)
• Nitazoxanide (500 mg bid × 10 d)
• Fecal transplantation
• IV immunoglobulin (400 mg/kg)
INTRAABDOMINAL INFECTIONS
AND ABSCESSES
Intraperitoneal infections generally arise because a nor- can serve as a conduit for fluids—a property exploited
mal anatomic barrier is disrupted. This disruption may in peritoneal dialysis (Fig. 25-1). A small amount of
occur when the appendix, a diverticulum, or an ulcer serous fluid is normally present in the peritoneal space,
ruptures; when the bowel wall is weakened by ischemia, with a protein content (consisting mainly of albumin)
tumor, or inflammation (e.g., in inflammatory bowel of <30 g/L and <300 white blood cells (WBCs, gener-
disease); or with adjacent inflammatory processes, such ally mononuclear cells) per microliter. In bacterial infec-
as pancreatitis or pelvic inflammatory disease, in which tions, leukocyte recruitment into the infected peritoneal
enzymes (in the former case) or organisms (in the latter) cavity consists of an early influx of polymorphonuclear
may leak into the peritoneal cavity. Whatever the incit- leukocytes (PMNs) and a prolonged subsequent phase
ing event, once inflammation develops and organisms of mononuclear cell migration. The phenotype of the
usually contained within the bowel or another organ infiltrating leukocytes during the course of inflamma-
enter the normally sterile peritoneal space, a predictable tion is regulated primarily by resident-cell chemokine
series of events takes place. Intraabdominal infections synthesis.
occur in two stages: peritonitis and—if the patient sur-
vives this stage and goes untreated—abscess formation.
The types of microorganisms predominating in each PriMary (SPontaneoUS)
stage of infection are responsible for the pathogenesis of bacterial PeritonitiS
disease. Peritonitis is either primary (without an apparent source
of contamination) or secondary. The types of organisms
found and the clinical presentations of these two pro-
PerItonItIs cesses are different. In adults, primary bacterial perito-
nitis (PBP) occurs most commonly in conjunction with
Peritonitis is a life-threatening event that is often cirrhosis of the liver (frequently the result of alcohol-
accompanied by bacteremia and sepsis syndrome ism). However, the disease has been reported in adults
(Chap. 271). The peritoneal cavity is large but is divided with metastatic malignant disease, postnecrotic cirrhosis,
into compartments. The upper and lower peritoneal chronic active hepatitis, acute viral hepatitis, congestive
cavities are divided by the transverse mesocolon; the heart failure, systemic lupus erythematosus, and lymph-
greater omentum extends from the transverse meso- edema as well as in patients with no underlying disease.
colon and from the lower pole of the stomach to line Although PBP virtually always develops in patients
the lower peritoneal cavity. The pancreas, duodenum, with preexisting ascites, it is, in general, an uncommon
and ascending and descending colon are located in event, occurring in ≤10% of cirrhotic patients. The
the anterior retroperitoneal space; the kidneys, ureters, cause of PBP has not been established definitively but
and adrenals are found in the posterior retroperitoneal is believed to involve hematogenous spread of organ-
space. The other organs, including liver, stomach, gall- isms in a patient in whom a diseased liver and altered
bladder, spleen, jejunum, ileum, transverse and sigmoid portal circulation result in a defect in the usual filtration
colon, cecum, and appendix, are within the peritoneal function. Organisms multiply in ascites, a good medium
cavity. The cavity is lined with a serous membrane that for growth. The proteins of the complement cascade
253
254 microbiology of PBP is also distinctive. While enteric
gram-negative bacilli such as Escherichia coli are most
Right Left
subphrenic subphrenic
commonly encountered, gram-positive organisms such
as streptococci, enterococci, or even pneumococci are
sometimes found. In PBP, a single organism is typically
Lesser sac
isolated; anaerobes are found less frequently in PBP than
in secondary peritonitis, in which a mixed flora includ-
Subhepatic
ing anaerobes is the rule. In fact, if PBP is suspected and
Left multiple organisms including anaerobes are recovered
paracolic
Right from the peritoneal fluid, the diagnosis must be recon-
paracolic
sidered and a source of secondary peritonitis sought.
The diagnosis of PBP is not easy. It depends on
the exclusion of a primary intraabdominal source of
infection. Contrast-enhanced CT is useful in identify-
ing an intraabdominal source for infection. It may be
Pelvic
difficult to recover organisms from cultures of perito-
Figure 25-1 neal fluid, presumably because the burden of organisms
Diagram of the intraperitoneal spaces, showing the circula- is low. However, the yield can be improved if 10 mL
tion of fluid and potential areas for abscess formation. Some of peritoneal fluid is placed directly into a blood cul-
compartments collect fluid or pus more often than others. ture bottle. Since bacteremia frequently accompanies
These compartments include the pelvis (the lowest portion), PBP, blood should be cultured simultaneously. No spe-
the subphrenic spaces on the right and left sides, and cific radiographic studies are helpful in the diagnosis of
Morrison’s pouch, which is a posterosuperior extension of the PBP. A plain film of the abdomen would be expected
subhepatic spaces and is the lowest part of the paraverte- to show ascites. Chest and abdominal radiography
bral groove when a patient is recumbent. The falciform liga- should be performed in patients with abdominal pain to
SECTION IV
ment separating the right and left subphrenic spaces appears exclude free air, which signals a perforation (Fig. 25-2).
to act as a barrier to the spread of infection; consequently, it
is unusual to find bilateral subphrenic collections. (Reprinted
with permission from B Lorber [ed]: Atlas of Infectious Dis-
eases, vol VII: Intra-abdominal Infections, Hepatitis, and Gas-
troenteritis. Philadelphia, Current Medicine, 1996, p 1.13.)
Infections of the Alimentary Tract
CHAPTER 25
diagnoses.
tion is intense because of the heavy bacterial load.
Depending on the inciting event, local symptoms
Prevention may occur in secondary peritonitis—for example, epi-
gastric pain from a ruptured gastric ulcer. In appendi-
Primary prevention citis (Chap. 300), the initial presenting symptoms are
One observational study raises the concern that proton often vague, with periumbilical discomfort and nausea
The role of enterococci and Candida spp. in mixed infec- as Candida spp. are also found. Vancomycin-resistant
tions is controversial. Secondary peritonitis usually enterococci and vancomycin-intermediate S. aureus have
requires both surgical intervention to address the incit- been reported to produce peritonitis in CAPD patients.
ing process and antibiotics to treat early bacteremia, to The finding of more than one organism in dialysate cul-
decrease the incidence of abscess formation and wound ture should prompt evaluation for secondary peritonitis.
infection, and to prevent distant spread of infection. As with PBP, culture of dialysate fluid in blood culture
Infections of the Alimentary Tract
While surgery is rarely indicated in PBP in adults, it may bottles improves the yield. To facilitate diagnosis, several
be life-saving in secondary peritonitis. Recombinant hundred milliliters of removed dialysis fluid should be
human activated protein C has been shown to reduce concentrated by centrifugation before culture.
mortality rates among patients with severe sepsis and
may benefit some patients with secondary peritonitis.
Peritonitis may develop as a complication of abdomi- Treatment CAPD Peritonitis
nal surgeries. These infections may be accompanied by
localizing pain and/or nonlocalizing symptoms such as Empirical therapy for CAPD peritonitis should be
fever, malaise, anorexia, and toxicity. As a nosocomial directed at S. aureus, coagulase-negative Staphylococ-
infection, postoperative peritonitis may be associated cus, and gram-negative bacilli until the results of cul-
with organisms such as staphylococci, components of the tures are available. Guidelines issued in 2005 suggest
gram-negative hospital microflora, and the microbes that agents should be chosen on the basis of local
that cause PBP and secondary peritonitis, as described experience with resistant organisms. In some centers,
above. a first-generation cephalosporin such as cefazolin (for
gram-positive bacteria) and a fluoroquinolone or a
third-generation cephalosporin such as ceftazidime (for
Peritonitis in Patients gram-negative bacteria) may be reasonable; in areas
Undergoing Capd with high rates of infection with methicillin-resistant
S. aureus, vancomycin should be used instead of cefazo-
A third type of peritonitis arises in patients who are lin, and gram-negative coverage may need to be broad-
undergoing continuous ambulatory peritoneal dialysis ened. Broad coverage including vancomycin should be
(CAPD). Unlike PBP and secondary peritonitis, which particularly considered for toxic patients and for those
are caused by endogenous bacteria, CAPD-associated with exit-site infections. Loading doses are adminis-
peritonitis usually involves skin organisms. The patho- tered intraperitoneally; doses depend on the dialysis
genesis of infection is similar to that of intravascular
method and the patient’s renal function. Antibiotics (CPC) found on the bacterial surface. The CPC com- 257
are given either continuously (i.e., with each exchange) prises at least eight distinct surface polysaccharides.
or intermittently (i.e., once daily, with the dose allowed Structural analysis of these polysaccharides has shown
to remain in the peritoneal cavity for at least 6 h). If the an unusual motif of oppositely charged sugars. Polysac-
patient is severely ill, IV antibiotics should be added at charides having these zwitterionic characteristics, such as
doses appropriate for the patient’s degree of renal polysaccharide A (PSA), evoke a host response in the
failure. The clinical response to an empirical treat- peritoneal cavity that localizes bacteria into abscesses. B.
ment regimen should be rapid; if the patient has not fragilis and PSA have been found to adhere to primary
responded after 48–96 h of treatment, catheter removal mesothelial cells in vitro; this adherence, in turn, stimu-
should be considered. lates the production of tumor necrosis factor α (TNF-α)
and intercellular adhesion molecule 1 (ICAM-1) by
peritoneal macrophages. Although abscesses character-
Tuberculous Peritonitis istically contain PMNs, the process of abscess induc-
tion depends on the stimulation of T lymphocytes by
See Chap. 165. these unique zwitterionic polysaccharides. The stimu-
lated CD4+ T lymphocytes secrete leukoattractant
cytokines and chemokines. The alternative pathway of
Intraabdominal Abscesses complement and fibrinogen also participate in abscess
formation.
Intraperitoneal Abscesses While antibodies to the CPC enhance bloodstream
Abscess formation is common in untreated peritoni- clearance of B. fragilis, CD4+ T cells are critical in
tis if overt gram-negative sepsis either does not develop immunity to abscesses. When administered subcutane-
or develops but is not fatal. In experimental models of ously, B. fragilis PSA has immunomodulatory characteris-
abscess formation, mixed aerobic and anaerobic organ- tics and stimulates CD4+ T regulatory cells via an inter-
leukin (IL) 2–dependent mechanism to produce IL-10.
CHAPTER 25
isms have been implanted intraperitoneally. Without
therapy directed at anaerobes, animals develop intraab- IL-10 downregulates the inflammatory response, thereby
dominal abscesses. As in humans, these experimental preventing abscess formation.
abscesses may stud the peritoneal cavity, lie within the
omentum or mesentery, or even develop on the surface
of or within viscera such as the liver. Clinical presentation
CHAPTER 25
or a streptococcal species such as S. milleri. Results of
most reliable laboratory finding is an elevated serum cultures obtained from drain sites are not reliable for
concentration of alkaline phosphatase, which is docu- defining the etiology of infections. Liver abscesses may
mented in 70% of patients with liver abscesses. Other also be caused by Candida spp.; such abscesses usually
tests of liver function may yield normal results, but 50% follow fungemia in patients receiving chemotherapy
of patients have elevated serum levels of bilirubin, and for cancer and often present when PMNs return after
48% have elevated concentrations of aspartate amino- a period of neutropenia. Amebic liver abscesses are not
the most common associated infection (Chap. 124). hematogenous in origin, usually complicating pro-
Splenic abscesses can develop in patients who have longed bacteremia, with S. aureus most commonly recov-
received extensive immunosuppressive therapy (particu- ered. Now, in contrast, >75% of perinephric and renal
larly those with malignancy involving the spleen) and in abscesses arise from a urinary tract infection. Infection
patients with hemoglobinopathies or other hematologic ascends from the bladder to the kidney, with pyelone-
disorders (especially sickle cell anemia). phritis occurring prior to abscess development. Bacteria
While ∼50% of patients with splenic abscesses have may directly invade the renal parenchyma from medulla
abdominal pain, the pain is localized to the left upper to cortex. Local vascular channels within the kidney may
quadrant in only one-half of these cases. Splenomegaly is also facilitate the transport of organisms. Areas of abscess
found in ∼50% of cases. Fever and leukocytosis are gen- developing within the parenchyma may rupture into the
erally present; the development of fever preceded diag- perinephric space. The kidneys and adrenal glands are
nosis by an average of 20 days in one series. Left-sided surrounded by a layer of perirenal fat that, in turn, is sur-
chest findings may include abnormalities to auscultation, rounded by Gerota’s fascia, which extends superiorly to
and chest radiographic findings may include an infiltrate the diaphragm and inferiorly to the pelvic fat. Abscesses
or a left-sided pleural effusion. CT scan of the abdomen extending into the perinephric space may track through
has been the most sensitive diagnostic tool. Ultrasonog- Gerota’s fascia into the psoas or transversalis muscles, into
raphy can yield the diagnosis but is less sensitive. Liver- the anterior peritoneal cavity, superiorly to the subdia-
spleen scan or gallium scan may also be useful. Strep- phragmatic space, or inferiorly to the pelvis. Of the risk
tococcal species are the most common bacterial isolates factors that have been associated with the development
from splenic abscesses, followed by S. aureus—presum- of perinephric abscesses, the most important is concomi-
ably reflecting the associated endocarditis. An increase tant nephrolithiasis obstructing urinary flow. Of patients
in the prevalence of gram-negative aerobic isolates with perinephric abscess, 20–60% have renal stones.
from splenic abscesses has been reported; these organ- Other structural abnormalities of the urinary tract, prior
isms often derive from a urinary tract focus, with associ- urologic surgery, trauma, and diabetes mellitus have also
ated bacteremia, or from another intraabdominal source. been identified as risk factors.
The organisms most frequently encountered in peri- 261
nephric and renal abscesses are E. coli, Proteus spp., and Treatment Perinephric and Renal Abscesses
Klebsiella spp. E. coli, the aerobic species most commonly Treatment for perinephric and renal abscesses, like that
found in the colonic flora, seems to have unique viru- for other intraabdominal abscesses, includes drainage
lence properties in the urinary tract, including factors of pus and antibiotic therapy directed at the organism(s)
promoting adherence to uroepithelial cells. The urease recovered. For perinephric abscesses, percutaneous
of Proteus spp. splits urea, thereby creating a more alka- drainage is usually successful.
line and more hospitable environment for bacterial pro-
liferation. Proteus spp. are frequently found in association
with large struvite stones caused by the precipitation of Psoas abscesses
magnesium ammonium sulfate in an alkaline environ- The psoas muscle is another location in which abscesses
ment. These stones serve as a nidus for recurrent urinary are encountered. Psoas abscesses may arise from a hema-
tract infection. While a single bacterial species is usually togenous source, by contiguous spread from an intraab-
recovered from a perinephric or renal abscess, multiple dominal or pelvic process, or by contiguous spread from
species may also be found. If a urine culture is not con- nearby bony structures (e.g., vertebral bodies). Associ-
taminated with periurethral flora and is found to con- ated osteomyelitis due to spread from bone to muscle or
tain more than one organism, a perinephric abscess or from muscle to bone is common in psoas abscesses. When
renal abscess should be considered in the differential Pott’s disease was common, Mycobacterium tuberculosis was a
diagnosis. Urine cultures may also be polymicrobial in frequent cause of psoas abscess. Currently, either S. aureus
cases of bladder diverticulum. or a mixture of enteric organisms including aerobic and
Candida spp. can cause renal abscesses. This fungus anaerobic gram-negative bacilli is usually isolated from
may spread to the kidney hematogenously or by ascen- psoas abscesses in the United States. S. aureus is most likely
sion from the bladder. The hallmark of the latter route of to be isolated when a psoas abscess arises from hematog-
infection is ureteral obstruction with large fungal balls. enous spread or a contiguous focus of osteomyelitis; a
The presentation of perinephric and renal abscesses
CHAPTER 25
mixed enteric flora is the most likely etiology when the
is quite nonspecific. Flank pain and abdominal pain are abscess has an intraabdominal or pelvic source. Patients
common. At least 50% of patients are febrile. Pain may with psoas abscesses frequently present with fever, lower
be referred to the groin or leg, particularly with exten- abdominal or back pain, or pain referred to the hip or
sion of infection. The diagnosis of perinephric abscess, knee. CT is the most useful diagnostic technique.
like that of splenic abscess, is frequently delayed, and
the mortality rate in some series is appreciable, although
262
Pathology and Pathogenesis large quantities of this cytokine in response to H. pylori 263
infection are at increased risk of gastric adenocarcinoma.
H. pylori colonization induces a tissue response in the In addition, environmental cofactors are important in
stomach, chronic superficial gastritis, which includes infil- pathogenesis. Smoking increases the risks of ulcers and
tration of the mucosa by both mononuclear and poly- cancer in H. pylori–positive individuals. Diets high in
morphonuclear cells. (The term gastritis should be used salt and preserved foods increase cancer risk, whereas
specifically to describe histologic features; it has also diets high in antioxidants and vitamin C are protective.
been used to describe endoscopic appearances and The pattern of gastric inflammation is associated with
even symptoms, which do not correlate with micro- disease risk: antral-predominant gastritis is most closely
scopic findings or even with the presence of H. pylori.) linked with duodenal ulceration, whereas pangastritis is
Although H. pylori is capable of numerous adaptations linked with gastric ulceration and adenocarcinoma. This
that prevent excessive stimulation of the immune sys- difference probably explains why patients with duodenal
tem, colonization is accompanied by a considerable per- ulceration are not at high risk of developing gastric adeno-
sistent immune response, including the production of carcinoma later in life, despite being colonized by H. pylori.
both local and systemic antibodies as well as cell-medi- How gastric colonization causes duodenal ulceration
ated responses. However, these responses are ineffec- is now becoming clearer. H. pylori–induced inflammation
tive in clearing the bacterium. This inefficient clearing diminishes the number of somatostatin-producing D cells.
appears to be due in part to H. pylori’s downregulation Since somatostatin inhibits gastrin release, gastrin levels
of the immune system, which fosters its own persistence. are higher than in H. pylori–negative persons, and these
Most H. pylori–colonized persons do not develop higher levels lead to increased meal-stimulated acid secre-
clinical sequelae. That some persons develop overt dis- tion in the gastric corpus, which is only mildly inflamed
ease whereas others do not is related to a combination in antral-predominant gastritis. How this increases duode-
of factors: bacterial strain differences, host susceptibility nal ulcer risk remains controversial, but the increased acid
to disease, and environmental factors. secretion may contribute to the formation of the poten-
Several H. pylori virulence factors are more com- tially protective gastric metaplasia found in the duode-
CHAPTER 26
mon among strains that are associated with disease num of duodenal ulcer patients. Gastric metaplasia in the
than among those that are not. The cag island is a duodenum may become colonized by H. pylori and sub-
group of genes that encodes a bacterial secretion system sequently inflamed and ulcerated.
through which a specific protein, CagA, is translocated The pathogenesis of gastric ulceration and that of gas-
into epithelial cells. CagA affects host cell signal trans- tric adenocarcinoma are less well understood, although
duction, inducing proliferative, cytoskeletal, and inflam- both conditions arise in association with pan- or corpus-
matory changes; a proportion of transgenic mice
Primary
Tissue response (inflammation)
phenomenon:
Association with
3–6 6–50 3–8 0.2–0.6
H. pylori (OR):
Figure 26-1
Schematic of the relationships between colonization with (especially with cagA+ strains) protects against adenocarci-
Helicobacter pylori and diseases of the upper gastroin- noma of the esophagus (and the sometimes related gastric
testinal tract among persons in developed countries. cardia) and premalignant lesions such as Barrett’s esopha-
Essentially all persons colonized with H. pylori develop a gus (OR, <1). While the incidences of peptic ulcer disease
host response, which is generally termed chronic gastri- (cases not due to nonsteroidal anti-inflammatory drugs) and
tis. The nature of the interaction of the host with the par- noncardia gastric cancer are declining in developed coun-
ticular bacterial population determines the clinical outcome. tries, the incidence of adenocarcinoma of the esophagus is
H. pylori colonization increases the lifetime risk of peptic ulcer rapidly increasing. (Adapted from MJ Blaser: Hypothesis: The
disease, noncardia gastric cancer, and B cell non-Hodgkin’s changing relationships of Helicobacter pylori and humans:
gastric lymphoma [odds ratios (ORs) for all, >3]. In contrast, Implications for health and disease. J Infect Dis 179:1523,
SECTION IV
a growing body of evidence indicates that H. pylori colonization 1999, with permission.)
Worldwide, >80% of duodenal ulcers and >60% Chap. 293). Because H. pylori is common, some of these
of gastric ulcers are related to H. pylori coloniza- patients will be colonized with the organism. H. pylori
Infections of the Alimentary Tract
tion (Chap. 293), although the proportion of eradication leads to symptom resolution a little (7%)
ulcers due to aspirin and nonsteroidal anti-inflammatory more commonly than does placebo treatment. Whether
drugs (NSAIDs) is increasing, especially in developed such patients have peptic ulcers in remission at the time
countries. The main lines of evidence for an ulcer-promot- of endoscopy or whether a small subgroup of patients
ing role for H. pylori are that (1) the presence of the with true functional dyspepsia respond to H. pylori treat-
organism is a risk factor for the development of ulcers, (2) ment is unclear.
non-NSAID-induced ulcers rarely develop in the Much interest has focused on a possible protective role
absence of H. pylori, (3) eradication of H. pylori mark- for H. pylori against GERD (Chap. 292), Barrett’s esoph-
edly reduces rates of ulcer relapse, and (4) experimental agus (Chap. 292), and adenocarcinoma of the esophagus
H. pylori infection of gerbils causes gastric ulceration. and gastric cardia (Chap. 91). The main lines of evidence
Prospective nested case-control studies have shown that for this role are (1) that there is a temporal relationship
H. pylori colonization is a risk factor for adenocarcinomas between a falling prevalence of gastric H. pylori coloni-
of the distal (noncardia) stomach (Chap. 91). Long-term zation and a rising incidence of these conditions and
experimental infection of gerbils also may result in (2) that, in most studies, the prevalence of H. pylori colo-
gastric adenocarcinoma. Moreover, the presence of nization (especially with proinflammatory cagA+ strains)
H. pylori is strongly associated with primary gastric lym- is significantly lower among patients with these esopha-
phoma, although this condition is much less common. geal diseases than among control subjects. The mecha-
Many low-grade gastric B cell lymphomas arising from nism underlying this protective effect appears to include
MALT are driven by T cell proliferation, which in turn is H. pylori–induced hypochlorhydria. Since, at the indi-
driven by H. pylori antigen stimulation; H. pylori antigen– vidual level, GERD symptoms may decrease, worsen,
driven tumors may regress either fully or partially after H. or remain unchanged after treatment targeting H. pylori,
pylori eradication but require careful long-term monitoring. concerns about GERD should not affect decisions about
Many patients have upper gastrointestinal symp- H. pylori treatment when an indication exists.
toms but have normal results in upper gastrointestinal H. pylori has an increasingly recognized role in other
endoscopy (so-called functional or nonulcer dyspepsia; gastric pathologies. It may be one initial precipitant of
autoimmune gastritis and pernicious anemia and also which one large or two small antral biopsy specimens 265
may predispose some patients to iron deficiency through are placed into a gel containing urea and an indicator.
occult blood loss and/or hypochlorhydria and reduced The presence of H. pylori urease leads to a pH alteration
iron absorption. In addition, several extragastrointestinal and therefore to a color change, which often occurs
pathologies have been linked with H. pylori coloniza- within minutes but can require up to 24 h. Histologic
tion, although evidence of causality is less strong. Sev- examination of biopsy specimens for H. pylori also is
eral small studies of H. pylori treatment in idiopathic accurate, provided that a special stain (e.g., a modified
thrombocytopenic purpura have described improvement Giemsa or silver stain) permitting optimal visualiza-
in or even normalization of platelet counts. Potentially tion of the organism is used. If biopsy specimens are
important but even more controversial associations are obtained from both antrum and corpus, histologic study
with ischemic heart disease and cerebrovascular disease. yields additional information, including the degree and
However, the strength of these latter associations is pattern of inflammation, atrophy, metaplasia, and dys-
reduced if confounding factors are taken into account, plasia. Microbiologic culture is most specific but may be
and most authorities consider the associations to be insensitive because of difficulty with H. pylori isolation.
noncausal. Recent studies have shown an inverse asso- Once the organism is cultured, its identity as H. pylori
ciation of cagA+ H. pylori with childhood-onset asthma, can be confirmed by its typical appearance on Gram’s
hay fever, and atopic disorders. Whether H. pylori status stain and its positive reactions in oxidase, catalase, and
is merely a marker or is causally associated with protec- urease tests. Moreover, the organism’s susceptibility
tion against these diseases remains to be determined. to antibiotics can be determined, and this information
can be clinically useful in difficult cases. The occasional
biopsy specimens containing the less common non-
Diagnosis pylori gastric helicobacters give only weakly positive
Tests for the presence of H. pylori can be divided into results in the biopsy urease test. Positive identification of
two groups: invasive tests, which require upper gastro- these bacteria requires visualization of the characteristic
intestinal endoscopy and are based on the analysis of gas- long, tight spirals in histologic sections.
CHAPTER 26
tric biopsy specimens, and noninvasive tests (Table 26-1). Noninvasive H. pylori testing is the norm if gastric
Endoscopy often is not performed in the initial man- cancer does not need to be excluded by endoscopy. The
agement of young dyspeptic patients without “alarm” most consistently accurate test is the urea breath test.
symptoms but is commonly used to exclude malignancy In this simple test, the patient drinks a solution of urea
in older patients. If endoscopy is performed, the most labeled with the nonradioactive isotope 13C and then
convenient biopsy-based test is the biopsy urease test, in blows into a tube. If H. pylori urease is present, the urea
Negative H. pylori
Test for H. pylori not the cause
Positive
First-line treatment
(Table 151-2)
Figure 26-2
Algorithm for the management of Helicobacter pylori infec- in this condition, as opposed to duodenal ulceration, it is impor-
tion. *Occasionally, an endoscopy and a biopsy-based test are tant to check healing and to exclude underlying gastric adeno-
used instead of a urea breath test in follow-up after treatment. carcinoma. †Some authorities now use empirical third-line regi-
The main indication for these invasive tests is gastric ulceration; mens, several of which have been described.
or intestinal metaplasia. Other studies have found a Current regimens consist of a PPI or ranitidine bismuth
267
reduced cancer risk after treatment, but the size of this citrate and two or three antimicrobial agents given for
effect in different populations remains unclear, and 7–14 days (Table 26-2). Research on optimizing drug
the results of further large-scale prospective interven- combinations to increase efficacy continues, and it is
tional studies must be awaited. Other reasons for not likely that guidelines will change as the field develops
treating H. pylori in asymptomatic populations at pres- and as countries increasingly individualize treatment to
ent include (1) the adverse side effects of the multiple- suit local antibiotic resistance patterns and economic
antibiotic regimens used (which are common and can needs.The two most important factors in successful H.
be severe in rare cases); (2) antibiotic resistance, which pylori treatment are the patient’s close compliance with
may arise in H. pylori or other incidentally carried bac- the regimen and the use of drugs to which the patient’s
teria; (3) the anxiety that may arise in otherwise healthy strain of H. pylori has not acquired resistance. Treatment
people, especially if treatment is unsuccessful; and (4) failure following minor lapses in compliance is com-
the apparent existence of a subset of people who will mon and often leads to acquired resistance to metro-
develop GERD symptoms after treatment, although on nidazole or clarithromycin. To stress the importance of
average H. pylori treatment does not affect GERD symp- compliance, written instructions should be given to the
toms or severity. patient, and minor side effects of the regimen should be
Although H. pylori is susceptible to a wide range of explained. Resistance to clarithromycin and, to a lesser
antibiotics in vitro, monotherapy is not usually success- extent, to metronidazole are of growing concern. Clar-
ful, probably because of inadequate antibiotic delivery ithromycin resistance is less prevalent but, if present,
to the colonization niche. Failure of monotherapy has usually results in treatment failure. Strains of H. pylori
prompted the development of multidrug regimens, the that are apparently resistant to metronidazole are more
most successful of which are triple and quadruple com- common but still may be cleared by metronidazole-
binations. Initially these regimens produced H. pylori containing regimens, which have only slightly reduced
eradication rates of >90% in many trials; in recent years, efficacy. Assessment of antibiotic susceptibilities before
CHAPTER 26
however, resistance to key antibiotics has become more treatment would be optimal but is not usually under-
common, a trend leading to H. pylori eradication rates taken because endoscopy and mucosal biopsy are nec-
of only 75–80% for the most commonly used regimens. essary to obtain H. pylori for culture and because most
Table 26-2
a
Meta-analyses show that a 14-day course of therapy is slightly superior to a 7-day course. However, in populations where 7-day treatment is
known to have very high success rates, this shorter course is still often used.
b
Omeprazole may be replaced with any proton pump inhibitor at an equivalent dosage or, in regimens 1 and 2, with ranitidine bismuth citrate
(400 mg).
c
Data supporting this regimen come mainly from Europe and are based on the use of bismuth subcitrate and metronidazole (400 mg tid). This is
the most commonly used second-line regimen.
d
Data supporting this regimen come from Europe. Although the two 5-day courses of different drugs have usually been given sequentially, recent
evidence suggests no added benefit from this approach. Thus 10 days of the four drugs combined may be as good and may aid compliance.
e
Data supporting this second- or third-line regimen come from Europe. This regimen may be less effective where rates of quinolone use are high.
Theoretically, it may also be wise to avoid it in populations where Clostridium difficile infection is common after broad-spectrum antibiotic use.
268 microbiology laboratories are inexperienced in H. pylori Prevention
culture. In the absence of susceptibility information, a Carriage of H. pylori has considerable public
history of the patient’s (even distant) antibiotic use for health significance in developed countries,
other conditions should be obtained; use of the agent where it is associated with peptic ulcer disease
should then be avoided if possible, particularly in the and gastric adenocarcinoma, and in developing coun-
case of clarithromycin (e.g., previous use for upper respi- tries, where gastric adenocarcinoma may be an even
ratory infection). If initial H. pylori treatment fails, one of more common cause of cancer death late in life. If mass
two strategies may be used (Fig. 26-2). The more com- prevention were contemplated, vaccination would be
mon approach is empirical re-treatment with another the most obvious method, and experimental immuniza-
drug regimen, usually quadruple therapy (Table 26-2). tion of animals has given promising results. However,
The second approach is endoscopy, biopsy, and cul- given that H. pylori has co-evolved with its human host
ture plus treatment based on documented antibiotic over millennia, preventing or eliminating colonization
sensitivities. If re-treatment fails, susceptibility testing on a population basis may have distinct disadvantages.
should ideally be performed, although empirical third- For example, lifelong absence of H. pylori is a risk factor
line therapies are often used. for GERD complications, including esophageal adeno-
Clearance of non-pylori gastric helicobacters can fol- carcinoma. We have speculated that the disappearance of
low the use of bismuth compounds alone or of triple- H. pylori may be associated with an increased risk of
drug regimens. However, in the absence of trials, it is other emerging diseases reflecting aspects of the current
unclear whether this outcome represents successful Western lifestyle, such as asthma, obesity, and conceiv-
treatment or natural clearance of the bacterium. ably even type 2 diabetes mellitus.
SECTION IV
Infections of the Alimentary Tract
chaptEr 27
SALMONELLOSIS
Bacteria of the genus Salmonella are highly adapted addition, all salmonellae except S. gallinarum-pullorum are
for growth in both humans and animals and cause motile by means of peritrichous flagella, and all but
a wide spectrum of disease. The growth of serotypes S. typhi produce gas (H2S) on sugar fermentation. Nota-
S. typhi and S. paratyphi is restricted to human hosts, in bly, only 1% of clinical isolates ferment lactose; a high
whom these organisms cause enteric (typhoid) fever. level of suspicion must be maintained to detect these
The remaining serotypes (nontyphoidal Salmonella, or rare clinical lactose-fermenting isolates.
NTS) can colonize the gastrointestinal tracts of a broad Although serotyping of all surface antigens can be
range of animals, including mammals, reptiles, birds, used for formal identification, most laboratories per-
and insects. More than 200 serotypes are pathogenic form a few simple agglutination reactions that define
to humans, in whom they often cause gastroenteritis specific O-antigen serogroups, designated A, B, C1, C2,
and can be associated with localized infections and/or D, and E. Strains in these six serogroups cause ∼99%
bacteremia. of Salmonella infections in humans and other warm-
blooded animals. Molecular typing methods, including
pulsed-field gel electrophoresis and polymerase chain
Etiology reaction (PCR) fingerprinting, are used in epidemio-
This large genus of gram-negative bacilli within the logic investigations to differentiate Salmonella strains of
family Enterobacteriaceae consists of two species: S. enterica, a common serotype.
which contains six subspecies, and S. bongori. S. enterica
subspecies I includes almost all the serotypes patho-
pathogEnEsis
genic for humans. According to the current Salmonella
nomenclature system, the full taxonomic designation All Salmonella infections begin with ingestion of organ-
S. enterica subspecies enterica serotype typhimurium can be isms, most commonly in contaminated food or water.
shortened to Salmonella serotype typhimurium or simply The infectious dose is 103–106 colony-forming units.
S. typhimurium. Conditions that decrease either stomach acidity (an age
Members of the seven Salmonella subspecies are clas- of <1 year, antacid ingestion, or achlorhydric disease) or
sified into >2500 serotypes (serovars) according to the intestinal integrity (inflammatory bowel disease, prior
somatic O antigen [lipopolysaccharide (LPS) cell-wall gastrointestinal surgery, or alteration of the intestinal
components], the surface Vi antigen (restricted to S. typhi flora by antibiotic administration) increase susceptibility
and S. paratyphi C), and the flagellar H antigen. For sim- to Salmonella infection.
plicity, most Salmonella serotypes are named for the city Once S. typhi and S. paratyphi reach the small intestine,
where they were identified, and the serotype is often they penetrate the mucus layer of the gut and traverse
used as the species designation. the intestinal layer through phagocytic microfold (M)
Salmonellae are gram-negative, non-spore-forming, cells that reside within Peyer’s patches. Salmonellae
facultatively anaerobic bacilli that measure 2–3 by 0.4– can trigger the formation of membrane ruffles in nor-
0.6 μm. The initial identification of salmonellae in the mally nonphagocytic epithelial cells. These ruffles reach
clinical microbiology laboratory is based on growth out and enclose adherent bacteria within large vesicles
characteristics. Salmonellae, like other Enterobacte- by a process referred to as bacteria-mediated endocyto-
riaceae, produce acid on glucose fermentation, reduce sis (BME). BME is dependent on the direct delivery
nitrates, and do not produce cytochrome oxidase. In of Salmonella proteins into the cytoplasm of epithelial
269
270 cells by a specialized bacterial secretion system (type III Enteric (Typhoid) Fever
secretion). These bacterial proteins mediate alterations in
the actin cytoskeleton that are required for Salmonella Enteric (typhoid) fever is a systemic disease character-
uptake. ized by fever and abdominal pain and caused by dissemi-
After crossing the epithelial layer of the small intes- nation of S. typhi or S. paratyphi. The disease was initially
tine, S. typhi and S. paratyphi, which cause enteric called typhoid fever because of its clinical similarity to
(typhoid) fever, are phagocytosed by macrophages. These typhus. However, in the early 1800s, typhoid fever was
salmonellae survive the antimicrobial environment of clearly defined pathologically as a unique illness on the
the macrophage by sensing environmental signals that basis of its association with enlarged Peyer’s patches and
trigger alterations in regulatory systems of the phago- mesenteric lymph nodes. In 1869, given the anatomic
cytosed bacteria. For example, PhoP/PhoQ (the best- site of infection, the term enteric fever was proposed as an
characterized regulatory system) triggers the expression alternative designation to distinguish typhoid fever from
of outer-membrane proteins and mediates modifica- typhus. However, to this day, the two designations are
tions in LPS so that the altered bacterial surface can used interchangeably.
resist microbicidal activities and potentially alter host
cell signaling. In addition, salmonellae encode a second Epidemiology
type III secretion system that directly delivers bacterial
proteins across the phagosome membrane into the mac- In contrast to other Salmonella serotypes, the etiologic
rophage cytoplasm. This secretion system functions to agents of enteric fever—S. typhi and S. paratyphi sero-
remodel the Salmonella-containing vacuole, promoting types A, B, and C—have no known hosts other than
bacterial survival and replication. humans. Most commonly, food-borne or waterborne
Once phagocytosed, typhoidal salmonellae dissemi- transmission results from fecal contamination by ill or
nate throughout the body in macrophages via the lym- asymptomatic chronic carriers. Sexual transmission
phatics and colonize reticuloendothelial tissues (liver, between male partners has been described. Health care
spleen, lymph nodes, and bone marrow). Patients have workers occasionally acquire enteric fever after expo-
SECTION IV
relatively few or no signs and symptoms during this sure to infected patients or during processing of clinical
initial incubation stage. Signs and symptoms, including specimens and cultures.
fever and abdominal pain, probably result from secre- With improvements in food handling and
tion of cytokines by macrophages and epithelial cells water/sewage treatment, enteric fever has
in response to bacterial products that are recognized become rare in developed nations. Worldwide,
by innate immune receptors when a critical number of however, there are an estimated 22 million cases of
Infections of the Alimentary Tract
organisms have replicated. Over time, the development enteric fever, with 200,000 deaths annually. The inci-
of hepatosplenomegaly is likely to be related to the dence is highest (>100 cases per 100,000 population
recruitment of mononuclear cells and the development per year) in south central and Southeast Asia; medium
of a specific acquired cell-mediated immune response (10–100 cases per 100,000) in the rest of Asia, Africa,
to S. typhi colonization. The recruitment of additional Latin America, and Oceania (excluding Australia and
mononuclear cells and lymphocytes to Peyer’s patches New Zealand); and low in other parts of the world
during the several weeks after initial colonization/infec- (Fig. 27-1). A high incidence of enteric fever correlates
tion can result in marked enlargement and necrosis of with poor sanitation and lack of access to clean drinking
the Peyer’s patches, which may be mediated by bacterial water. In endemic regions, enteric fever is more com-
products that promote cell death as well as the inflam- mon in urban than rural areas and among young chil-
matory response. dren and adolescents. Risk factors include contaminated
In contrast to enteric fever, which is characterized water or ice, flooding, food and drinks purchased from
by an infiltration of mononuclear cells into the small- street vendors, raw fruits and vegetables grown in fields
bowel mucosa, NTS gastroenteritis is characterized by fertilized with sewage, ill household contacts, lack of
massive polymorphonuclear leukocyte (PMN) infiltra- hand washing and toilet access, and evidence of prior
tion into both the large- and small-bowel mucosa. This Helicobacter pylori infection (an association probably
response appears to depend on the induction of inter- related to chronically reduced gastric acidity). It is esti-
leukin (IL) 8, a strong neutrophil chemotactic factor, mated that there is one case of paratyphoid fever for
which is secreted by intestinal cells as a result of Salmonella every four cases of typhoid fever, but the incidence of
colonization and translocation of bacterial proteins into infection associated with S. paratyphi A appears to be
host cell cytoplasm. The degranulation and release of increasing, especially in India; this increase may be a
toxic substances by neutrophils may result in damage to result of vaccination for S. typhi.
the intestinal mucosa, causing the inflammatory diarrhea Multidrug-resistant (MDR) strains of S. typhi
observed with nontyphoidal gastroenteritis. emerged in 1989 in China and Southeast Asia and have
271
Figure 27-1
Annual incidence of typhoid fever per 100,000 population. (Adapted from Crump JA et al. The global burden of typhoid fever.
Bull World Health Organ 82:346, 2004.)
CHAPTER 27
of this disease—fever and abdominal pain—are variable.
fever. With the increased use of fluoroquinolones to treat
While fever is documented at presentation in >75% of
MDR enteric fever in the 1990s, strains of S. typhi and
cases, abdominal pain is reported in only 30–40%. Thus,
S. paratyphi with reduced susceptibility to ciprofloxacin
a high index of suspicion for this potentially fatal sys-
[minimal inhibitory concentration (MIC), 0.125–1 μg/mL]
temic illness is necessary when a person presents with
have emerged in the Indian subcontinent, southern
fever and a history of recent travel to a developing
Asia, and (most recently) sub-Saharan Africa and have
country.
Salmonellosis
been associated with clinical treatment failure. Testing
The incubation period for S. typhi averages 10–14 days
of isolates for resistance to the first-generation quino-
but ranges from 3–21 days, depending on the inoculum
lone nalidixic acid detects most but not all strains with
size and the host’s health and immune status. The most
reduced susceptibility to ciprofloxacin.
prominent symptom is prolonged fever (38.8°–40.5°C;
The incidence of enteric fever among U.S. travelers
101.8°–104.9°F), which can continue for up to 4 weeks
is estimated at 3–30 cases per 100,000. Of 1902 cases of
if untreated. S. paratyphi A is thought to cause milder
S. typhi–associated enteric fever reported to the Centers
disease than S. typhi, with predominantly gastrointestinal
for Disease Control and Prevention (CDC) in 1999–
symptoms. However, a prospective study of 669 consec-
2006, 79% were associated with recent international
utive cases of enteric fever in Kathmandu, Nepal, found
travel, most commonly to India (47%), Pakistan (10%),
that the infections were clinically indistinguishable. In
Bangladesh (10%), Mexico (7%), and the Philippines
this series, symptoms reported on initial medical evalu-
(4%). Only 5% of travelers diagnosed with enteric fever
ation included headache (80%), chills (35–45%), cough
had received S. typhi vaccine. Overall, 13% of S. typhi
(30%), sweating (20–25%), myalgias (20%), malaise
isolates in the United States were resistant to ampicillin,
(10%), and arthralgia (2–4%). Gastrointestinal symptoms
chloramphenicol, and trimethoprim-sulfamethoxazole
included anorexia (55%), abdominal pain (30–40%), nausea
(TMP-SMX), and the proportion of isolates resistant
(18–24%), vomiting (18%), and diarrhea (22–28%) more
to nalidixic acid increased from 19% in 1999 to 58%
commonly than constipation (13–16%). Physical find-
in 2006. Infection with nalidixic acid-resistant (NAR)
ings included coated tongue (51–56%), splenomegaly
S. typhi was associated with travel to the Indian sub-
(5–6%), and abdominal tenderness (4–5%).
continent. Of the 25–30% of reported cases of enteric
Early physical findings of enteric fever include rash
fever in the United States that are domestically acquired,
(“rose spots”; 30%), hepatosplenomegaly (3–6%), epi-
the majority are sporadic, but outbreaks linked to con-
staxis, and relative bradycardia at the peak of high fever
taminated food products and previously unrecognized
(<50%). Rose spots (Fig. 27-2; see also Fig. e7-9) make
chronic carriers continue to occur.
272 resolution and in association with the same strain type
and susceptibility profile.
Up to 10% of untreated patients with typhoid fever
excrete S. typhi in the feces for up to 3 months, and
1–4% develop chronic asymptomatic carriage, shedding
S. typhi in either urine or stool for >1 year. Chronic
carriage is more common among women, infants, and
persons who have biliary abnormalities or concur-
rent bladder infection with Schistosoma haematobium.
The anatomic abnormalities associated with the latter
conditions presumably allow prolonged colonization.
Diagnosis
Since the clinical presentation of enteric fever is relatively
Figure 27-2 nonspecific, the diagnosis needs to be considered in any
“Rose spots,” the rash of enteric fever due to S. typhi or febrile traveler returning from a developing region, espe-
S. paratyphi. cially the Indian subcontinent, the Philippines, or Latin
America. Other diagnoses that should be considered
in these travelers include malaria, hepatitis, bacterial
enteritis, dengue fever, rickettsial infections, leptospirosis,
up a faint, salmon-colored, blanching, maculopapu- amebic liver abscesses, and acute HIV infection (Chap. 123).
lar rash located primarily on the trunk and chest. The Other than a positive culture, no specific laboratory test is
rash is evident in ∼30% of patients at the end of the diagnostic for enteric fever. In 15–25% of cases, leukope-
first week and resolves without a trace after 2–5 days. nia and neutropenia are detectable. Leukocytosis is more
SECTION IV
Patients can have two or three crops of lesions, and common among children, during the first 10 days of ill-
Salmonella can be cultured from punch biopsies of these ness, and in cases complicated by intestinal perforation or
lesions. The faintness of the rash makes it difficult to secondary infection. Other nonspecific laboratory find-
detect in highly pigmented patients. ings include moderately elevated liver function tests and
The development of severe disease (which occurs in muscle enzyme levels.
∼10–15% of patients) depends on host factors (immu- The definitive diagnosis of enteric fever requires the
Infections of the Alimentary Tract
nosuppression, antacid therapy, previous exposure, and isolation of S. typhi or S. paratyphi from blood, bone
vaccination), strain virulence and inoculum, and choice marrow, other sterile sites, rose spots, stool, or intesti-
of antibiotic therapy. Gastrointestinal bleeding (10–20%) nal secretions. The sensitivity of blood culture is only
and intestinal perforation (1–3%) most commonly occur 40–80%, probably because of high rates of antibiotic use
in the third and fourth weeks of illness and result from in endemic areas and the small quantities of S. typhi (i.e.,
hyperplasia, ulceration, and necrosis of the ileocecal Pey- <15 organisms/mL) typically present in the blood. Since
er’s patches at the initial site of Salmonella infiltration. Both almost all S. typhi organisms in blood are associated with
complications are life-threatening and require immediate the mononuclear-cell/platelet fraction, centrifugation
fluid resuscitation and surgical intervention, with broad- of blood and culture of the buffy coat can substantially
ened antibiotic coverage for polymicrobial peritonitis reduce the time to isolation of the organism but do not
(Chap. 127) and treatment of gastrointestinal hemorrhages, increase sensitivity.
including bowel resection. Neurologic manifestations Bone marrow culture is 55–90% sensitive, and, unlike
occur in 2–40% of patients and include meningitis, that of blood culture, its yield is not reduced by up to
Guillain-Barré syndrome, neuritis, and neuropsychiatric 5 days of prior antibiotic therapy. Culture of intestinal
symptoms (described as “muttering delirium” or “coma secretions (best obtained by a noninvasive duodenal
vigil”), with picking at bedclothes or imaginary objects. string test) can be positive despite a negative bone mar-
Rare complications whose incidences are reduced by row culture. If blood, bone marrow, and intestinal secre-
prompt antibiotic treatment include disseminated intra- tions are all cultured, the yield is >90%. Stool cultures,
vascular coagulation, hematophagocytic syndrome, pan- while negative in 60–70% of cases during the first week,
creatitis, hepatic and splenic abscesses and granulomas, can become positive during the third week of infection
endocarditis, pericarditis, myocarditis, orchitis, hepatitis, in untreated patients.
glomerulonephritis, pyelonephritis and hemolytic- Several serologic tests, including the classic Widal test
uremic syndrome, severe pneumonia, arthritis, osteo- for “febrile agglutinins,” are available. None of these
myelitis, and parotitis. Up to 10% of patients develop tests is sufficiently sensitive or specific to replace culture-
mild relapse, usually within 2–3 weeks of fever based methods for the diagnosis of enteric fever in
developed countries. PCR and DNA probe assays to 273
detect S. typhi in blood have been identified but have rates of fecal carriage during convalescence. For NAR
not yet been developed for clinical use. strains, 10–14 days of high-dose ciprofloxacin is preferred.
Ceftriaxone, cefotaxime, and (oral) cefixime are effec-
tive for treatment of MDR enteric fever, including NAR
Treatment Enteric (Typhoid) Fever and fluoroquinolone-resistant strains. These agents
clear fever in ∼1 week, with failure rates of ∼5–10%, fecal
Prompt administration of appropriate antibiotic therapy carriage rates of <3%, and relapse rates of 3–6%. Oral
prevents severe complications of enteric fever and results azithromycin results in defervescence in 4–6 days, with
in a case-fatality rate of <1%. The initial choice of antibi- rates of relapse and convalescent stool carriage of <3%.
otics depends on the susceptibility of the S. typhi and Against NAR strains, azithromycin is associated with
S. paratyphi strains in the area of residence or travel lower rates of treatment failure and shorter durations
(Table 27-1). For treatment of drug-susceptible typhoid of hospitalization than are fluoroquinolones. Despite
fever, fluoroquinolones are the most effective class of efficient in vitro killing of Salmonella, first- and second-
agents, with cure rates of ∼98% and relapse and fecal generation cephalosporins as well as aminoglycosides
carriage rates of <2%. Experience is most extensive with are ineffective in the treatment of clinical infections.
ciprofloxacin. Short-course ofloxacin therapy is simi- Most patients with uncomplicated enteric fever
larly successful against infection caused by nalidixic can be managed at home with oral antibiotics and
acid–susceptible strains. However, the increased inci- antipyretics. Patients with persistent vomiting, diarrhea,
dence of NAR S. typhi in Asia, which is probably related and/or abdominal distension should be hospitalized and
to the widespread availability of fluoroquinolones over given supportive therapy as well as a parenteral third-
the counter, is now limiting the use of this drug class for generation cephalosporin or fluoroquinolone, depend-
empirical therapy. Patients infected with NAR S. typhi ing on the susceptibility profile. Therapy should be
strains should be treated with ceftriaxone, azithromycin, administered for at least 10 days or for 5 days after fever
or high-dose ciprofloxacin. High-dose fluoroquinolone resolution.
CHAPTER 27
therapy for 7 days for NAR enteric fever has been In a randomized, prospective, double-blind study of
associated with delayed resolution of fever and high critically ill patients with enteric fever (i.e., those with
Table 27-1
Antibiotic Therapy for Enteric Fever in Adults
Salmonellosis
Indication Agent Dosage (Route) Duration, Days
Empirical Treatment
Ceftriaxonea 1–2 g/d (IV) 7–14
Azithromycin 1 g/d (PO) 5
Fully Susceptible
Ciprofloxacinb (first line) 500 mg bid (PO) or 400 mg q12h (IV) 5–7
Amoxicillin (second line) 1 g tid (PO) or 2 g q6h (IV) 14
Chloramphenicol 25 mg/kg tid (PO or IV) 14–21
Trimethoprim-sulfamethoxazole 160/800 mg bid (PO) 7–14
Multidrug-Resistant
Ciprofloxacin 500 mg bid (PO) or 400 mg q12h (IV) 5–7
Ceftriaxone 2–3 g/d (IV) 7–14
c
Azithromycin 1 g/d (PO) 5
Nalidixic Acid–Resistant
Ceftriaxone 2–3 g/d (IV) 7–14
Azithromycin 1 g/d (PO) 5
High-dose ciprofloxacin 750 mg bid (PO) or 400 mg q8h (IV) 10–14
a
Or another third-generation cephalosporin [e.g., cefotaxime, 2 g q8h (IV); or cefixime, 400 mg bid (PO)].
b
Or ofloxacin, 400 mg bid (PO) for 2–5 days.
c
Or 1 g on day 1 followed by 500 mg/d PO for 6 days.
274 Vi CPS typhoid vaccine is poorly immunogenic in
shock and obtundation) in Indonesia in the early 1980s,
children <5 years of age because of T cell–independent
the administration of dexamethasone (an initial dose
properties. In the recently developed Vi-rEPA vaccine,
of 3 mg/kg followed by eight doses of 1 mg/kg every
Vi is bound to a nontoxic recombinant protein that is
6 h) with chloramphenicol was associated with a sub-
identical to Pseudomonas aeruginosa exotoxin A. In 2- to
stantially lower mortality rate than was treatment with
4-year-olds, two injections of Vi-rEPA induced higher
chloramphenicol alone (10% vs 55%). Although this
T cell responses and higher levels of serum IgG anti-
study has not been repeated in the “post-chlorampheni-
body to Vi than did Vi CPS in 5- to 14-year-olds. In a
col era,” severe enteric fever remains one of the few indi-
two-dose trial in 2- to 5-year-old children in Vietnam,
cations for glucocorticoid treatment of an acute bacte-
Vi-rEPA provided 91% efficacy at 27 months and 88%
rial infection.
efficacy at 43 months and was very well tolerated. This
The 1–5% of patients who develop chronic carriage
vaccine is not yet commercially available in the United
of Salmonella can be treated for 4–6 weeks with an
States. At least three new live vaccines are in clinical
appropriate oral antibiotic. Treatment with oral amoxi-
development and may prove more efficacious and longer-
cillin, TMP-SMX, ciprofloxacin, or norfloxacin is ∼80%
lasting than previous live vaccines.
effective in eradicating chronic carriage of susceptible
Typhoid vaccine is not required for international
organisms. However, in cases of anatomic abnormality
travel, but it is recommended for travelers to areas where
(e.g., biliary or kidney stones), eradication often requires
there is a moderate to high risk of exposure to S. typhi,
both antibiotic therapy and surgical correction.
especially those who are traveling to southern Asia and
other developing regions of Asia, Africa, the Caribbean,
Prevention and Control and Central and South America and who will be
exposed to potentially contaminated food and drink.
Theoretically, it is possible to eliminate the salmonel- Typhoid vaccine should be considered even for per-
lae that cause enteric fever since they survive only in sons planning <2 weeks of travel to high-risk areas. In
human hosts and are spread by contaminated food and addition, laboratory workers who deal with S. typhi and
SECTION IV
water. However, given the high prevalence of the dis- household contacts of known S. typhi carriers should be
ease in developing countries that lack adequate sewage vaccinated. Because the protective efficacy of vac-
disposal and water treatment, this goal is currently cine can be overcome by the high inocula that are
unrealistic. Thus, travelers to developing countries commonly encountered in food-borne exposures,
should be advised to monitor their food and water immunization is an adjunct and not a substitute for
intake carefully and to consider vaccination. avoiding high-risk foods and beverages. Immunization
Infections of the Alimentary Tract
Two typhoid vaccines are commercially available: is not recommended for adults residing in typhoid-
(1) Ty21a, an oral live attenuated S. typhi vaccine (given endemic areas or for the management of persons who
on days 1, 3, 5, and 7, with a booster every 5 years); and may have been exposed in a common-source outbreak.
(2) Vi CPS, a parenteral vaccine consisting of purified Enteric fever is a notifiable disease in the United
Vi polysaccharide from the bacterial capsule (given in 1 States. Individual health departments have their own
dose, with a booster every 2 years). The old parenteral guidelines for allowing ill or colonized food handlers or
whole-cell typhoid/paratyphoid A and B vaccine is no health care workers to return to their jobs. The report-
longer licensed, largely because of significant side effects ing system enables public health departments to identify
(see below). An acetone-killed whole-cell vaccine is potential source patients and to treat chronic carriers
available only for use by the U.S. military. The minimal in order to prevent further outbreaks. In addition, since
age for vaccination is 6 years for Ty21a and 2 years for Vi 1–4% of patients with S. typhi infection become chronic
CPS. Currently, there is no licensed vaccine for paraty- carriers, it is important to monitor patients (especially
phoid fever. child-care providers and food handlers) for chronic car-
A large-scale meta-analysis of vaccine trials compar- riage and to treat this condition if indicated.
ing whole-cell vaccine, Ty21a, and Vi CPS in popu-
lations in endemic areas indicates that, while all three
vaccines are similarly effective for the first year, the
3-year cumulative efficacy of the whole-cell vaccine Nontyphoidal Salmonellosis
(73%) exceeds that of both Ty21a (51%) and Vi CPS
Epidemiology
(55%). In addition, the heat-killed whole-cell vaccine
maintains its efficacy for 5 years, whereas Ty21a and Vi In the United States, the incidence of NTS infec-
CPS maintain their efficacy for 4 and 2 years, respec- tion has doubled in the past 2 decades; the 2009 figure
tively. However, the whole-cell vaccine is associated is ∼14 million cases annually. In 2007, the incidence of
with a much higher incidence of side effects (especially NTS infection in this country was 14.9 per 100,000
fever: 16% vs 1–2%) than the other two vaccines. persons—the highest rate among the 11 food-borne
enteric pathogens under active surveillance. Five sero- Other pets, including African hedgehogs, snakes, birds, 275
types accounted for one-half of U.S. infections in 2007: rodents, baby chicks, ducklings, dogs, and cats, are also
typhimurium (19%), enteritidis (14%), Newport (9%), potential sources of NTS.
Javiana (5%), and Heidelberg (4%). Increasing antibiotic resistance in NTS species is a
The incidence of nontyphoidal salmonellosis is high- global problem and has been linked to the wide-
est during the rainy season in tropical climates and spread use of antimicrobial agents in food animals
during the warmer months in temperate climates, coin- and especially in animal feed. In the early 1990s,
ciding with the peak in food-borne outbreaks. Rates of S. typhimurium definitive phage type 104 (DT104), charac-
morbidity and mortality associated with NTS are high- terized by resistance to ≥5 antibiotics (ampicillin, chloram-
est among the elderly, infants, and immunocompromised phenicol, streptomycin, sulfonamides, and tetracyclines;
individuals, including those with hemoglobinopathies, R-type ACSSuT), emerged worldwide. In 2005, resis-
HIV infection, or infections that cause blockade of the tance to at least ACSSuT was the most common MDR
reticuloendothelial system (e.g., bartonellosis, malaria, phenotype among NTS isolates in the United States.
schistosomiasis, and histoplasmosis). Acquisition is associated with exposure to ill farm animals
Unlike S. typhi and S. paratyphi, whose only res- and to various meat products, including uncooked or
ervoir is humans, NTS can be acquired from multiple undercooked ground beef. Although probably no more
animal reservoirs. Transmission is most commonly asso- virulent than susceptible S. typhimurium strains, DT104
ciated with animal food products, especially eggs, poul- strains are associated with an increased risk of bloodstream
try, undercooked ground meat, dairy products, and fresh infection and hospitalization. NAR and trimethoprim-
produce contaminated with animal waste. resistant DT104 strains are emerging, especially in the
S. enteritidis infection associated with chicken eggs United Kingdom.
emerged as a major cause of food-borne disease during Because of increased resistance to conventional
the 1980s and 1990s. S. enteritidis infection of the ovaries antibiotics such as ampicillin and TMP-SMX,
and upper oviduct tissue of hens results in contamina- extended-spectrum cephalosporins and fluoroquinolones
tion of egg contents before shell deposition. Infection have emerged as the agents of choice for the treatment of
CHAPTER 27
is spread to egg-laying hens from breeding flocks and MDR NTS infections. In 2005, 2% of all NTS strains and
through contact with rodents and manure. Of the 997 12.6% of S. Newport strains were resistant to ceftriaxone.
outbreaks of S. enteritidis with a confirmed source that Most ceftriaxone-resistant isolates were from children
were reported to the CDC in 1985–2003, 75% were <18 years of age, in whom ceftriaxone is the antibiotic
associated with raw or undercooked eggs. After peak- of choice for treatment of invasive NTS infection. These
ing at 3.9 cases per 100,000 U.S. population in 1995, strains contained plasmid-encoded AmpC β-lactamases
Salmonellosis
the incidence of S. enteritidis infection declined substan- that were probably acquired by horizontal genetic transfer
tially to 1.7 per 100,000 in 2003; this decrease probably from Escherichia coli strains in food-producing animals—
reflected improved on-farm control measures, refrig- an event linked to the widespread use of the veterinary
eration, and education of consumers and food-service cephalosporin ceftiofur.
workers. Transmission via contaminated eggs can be pre- Resistance to nalidixic acid and fluoroquino-
vented by cooking eggs until the yolk is solidified and lones also has begun to emerge and is most com-
through pasteurization of egg products. monly associated with point mutations in the
Centralization of food processing and wide- DNA gyrase genes gyrA and gyrB. Nalidixic acid resis-
spread food distribution have contributed to the tance is a good predictor of reduced susceptibility to
increased incidence of NTS in developed coun- clinically useful fluoroquinolones. From 1996–2005, the
tries. Manufactured foods to which recent Salmonella rate of NAR NTS isolates in the United States
outbreaks have been traced include peanut butter; milk increased fivefold (from 0.5–2.4%). In Denmark, infec-
products, including infant formula; and various pro- tion with NAR S. typhimurium DT104 has been linked
cessed foods, including packaged breakfast cereal, salsa, to swine and associated with a threefold higher risk of
frozen prepared meals, and snack foods. Large outbreaks invasive disease or death within 90 days. In Taiwan in
have also been linked to fresh produce, including alfalfa 2000, a strain of ciprofloxacin-resistant (MIC, ≥4 mcg/
sprouts, cantaloupe, fresh-squeezed orange juice, and mL) S. choleraesuis caused a large outbreak of invasive
tomatoes; these items become contaminated by manure infections that was linked to the use of enrofloxacin in
or water at a single site and then are widely distributed. swine feed.
An estimated 6% of sporadic Salmonella infections in
the United States are attributed to contact with rep- Clinical Manifestations
tiles and amphibians, especially iguanas, snakes, turtles,
Gastroenteritis
and lizards. Reptile-associated Salmonella infection more
commonly leads to hospitalization and more frequently Infection with NTS most often results in gastroenteritis
involves infants than do other Salmonella infections. indistinguishable from that caused by other enteric
276 pathogens. Nausea, vomiting, and diarrhea occur 6–48 h abnormalities (e.g., gallstones), abdominal malignancy,
after the ingestion of contaminated food or water. and sickle cell disease (especially with splenic abscesses).
Patients often experience abdominal cramping and Eradication of the infection often requires surgical cor-
fever (38–39°C; 100.5–102.2°F). Diarrheal stools are rection of abnormalities and percutaneous drainage of
usually loose, nonbloody, and of moderate volume. How- abscesses.
ever, large-volume watery stools, bloody stools, or symptoms
Central nervous system infections
of dysentery may occur. Rarely, NTS causes pseudoap-
pendicitis or an illness that mimics inflammatory bowel NTS meningitis most commonly develops in infants
disease. 1–4 months of age. It often results in severe sequelae
Gastroenteritis caused by NTS is usually self-lim- (including seizures, hydrocephalus, brain infarction, and
ited. Diarrhea resolves within 3–7 days and fever within mental retardation) with death in up to 60% of cases.
72 h. Stool cultures remain positive for 4–5 weeks Other rare central nervous system infections include
after infection and—in rare cases of chronic carriage ventriculitis, subdural empyema, and brain abscesses.
(<1%)—for >1 year. Antibiotic treatment usually is Pulmonary infections
not recommended and may prolong fecal carriage. NTS pulmonary infections usually present as lobar
Neonates, the elderly, and immunosuppressed patients pneumonia, and complications include lung abscess,
(e.g., transplant recipients, HIV-infected persons) empyema, and bronchopleural fistula formation. The
with NTS gastroenteritis are especially susceptible to majority of cases occur in patients with lung cancer,
dehydration and dissemination and may require hospi- structural lung disease, sickle cell disease, or glucocor-
talization and antibiotic therapy. Acute NTS gastroen- ticoid use.
teritis was associated with a threefold increased risk of
dyspepsia and irritable bowel syndrome at 1 year in a Urinary and genital tract infections
recent study from Spain. Urinary tract infections caused by NTS present as either
cystitis or pyelonephritis. Risk factors include malig-
nancy, urolithiasis, structural abnormalities, HIV infec-
SECTION IV
Bacteremia and endovascular infections tion, and renal transplantation. NTS genital infections
are rare and include ovarian and testicular abscesses,
Up to 8% of patients with NTS gastroenteritis develop
prostatitis, and epididymitis. Like other focal infections,
bacteremia; of these, 5–10% develop localized infections.
both genital and urinary tract infections can be compli-
Bacteremia and metastatic infection are most common
cated by abscess formation.
with S. choleraesuis and S. Dublin and among infants, the
elderly, and immunocompromised patients. NTS endo-
Infections of the Alimentary Tract
Table 27-2
Antibiotic Therapy for Nontyphoidal Salmonella Infection in Adults
Indication Agent Dosage (Route) Duration, Days
Preemptive Treatmenta
Ciprofloxacinb 500 mg bid (PO) 2–3
Severe Gastroenteritisc
CHAPTER 27
Ciprofloxacin 500 mg bid (PO) or 400 mg 3–7
q12h (IV)
Trimethoprim-sulfamethoxazole 160/800 mg bid (PO)
Amoxicillin 1 g tid (PO)
Ceftriaxone 1–2 g/d (IV)
Bacteremia
Salmonellosis
Ceftriaxoned 2 g/d (IV) 7–14
Ciprofloxacin 400 mg q12h (IV), then 500 mg
bid (PO)
Endocarditis or Arteritis
Ceftriaxone 2 g/d (IV) 42
Ciprofloxacin 400 mg q8h (IV), then 750 mg
bid (PO)
Ampicillin 2 g q4h (IV)
Meningitis
Ceftriaxone 2 g q12 h (IV) 14–21
Ampicillin 2 g q4h (IV)
Other Localized Infection
Ceftriaxone 2 g/d (IV) 14–28
Ciprofloxacin 500 mg bid (PO) or 400 mg
q12h (IV)
Ampicillin 2 g q6h (IV)
a
Consider for neonates; persons >50 years of age with possible atherosclerotic vascular disease; and patients with immunosuppression,
endovascular graft, or joint prosthesis.
b
Or ofloxacin, 400 mg bid (PO).
c
Consider on an individualized basis for patients with severe diarrhea and high fever who require hospitalization.
d
Or cefotaxime, 2 g q8h (IV).
278 becomes afebrile. Immunocompromised persons may course of antibiotic therapy (depending on the infection
require up to 7–14 days of therapy. The <1% of persons site) is usually recommended. In chronic osteomyelitis,
who develop chronic carriage of NTS should receive abscess, or urinary or hepatobiliary infection associated
a prolonged antibiotic course, as described above for with anatomic abnormalities, surgical resection or drain-
chronic carriage of S. typhi. age may be required in addition to prolonged antibiotic
Because of the increasing prevalence of antibiotic therapy for eradication of infection.
resistance, empirical therapy for life-threatening NTS
bacteremia or focal NTS infection should include a
third-generation cephalosporin or a fluoroquinolone Prevention and Control
(Table 27-2). If the bacteremia is low-grade (<50% of posi-
tive blood cultures), the patient should be treated for 7–14 Despite widespread efforts to prevent or reduce bacte-
days. Patients with HIV/AIDS and NTS bacteremia should rial contamination of animal-derived food products and
receive 1–2 weeks of IV antibiotic therapy followed by 4 to improve food-safety education and training, recent
weeks of oral therapy with a fluoroquinolone. Patients declines in the incidence of NTS in the United States
whose infections relapse after this regimen should receive have been modest compared with those of other food-
long-term suppressive therapy with a fluoroquinolone or borne pathogens. This observation probably reflects the
TMP-SMX, as indicated by bacterial sensitivities. complex epidemiology of NTS. Identifying effective risk-
If the patient has endocarditis or arteritis, treatment reduction strategies requires monitoring of every step of
for 6 weeks with an IV β-lactam antibiotic (such as food production, from handling of raw animal or plant
ceftriaxone or ampicillin) is indicated. IV ciprofloxacin products to preparation of finished foods. Contaminated
followed by prolonged oral therapy is an option, but food can be made safe for consumption by pasteurization,
published experience is limited. Early surgical resection irradiation, or proper cooking. All cases of NTS infection
of infected aneurysms or other infected endovascular should be reported to local public health departments,
sites is recommended. Patients with infected prosthetic since tracking and monitoring of these cases can identify
the source(s) of infection and help authorities anticipate
SECTION IV
SHIGELLOSIS
The discovery of Shigella as the etiologic agent of carriage; however, some outbreaks reflect food-borne or
dysentery—a clinical syndrome of fever, intestinal waterborne transmission. In impoverished areas, Shigella
cramps, and frequent passage of small, bloody, mucopu- can be transmitted by flies. The high-level infectivity of
rulent stools—is attributed to the Japanese microbiolo- Shigella is reflected by the very small inoculum required
gist Kiyoshi Shiga, who isolated the Shiga bacillus (now for experimental infection of volunteers [100 colony-
known as Shigella dysenteriae type 1) from patients’ stools forming units (CFU)], by the very high attack rates dur-
in 1897 during a large and devastating dysentery epi- ing outbreaks in day-care centers (33–73%), and by the
demic. Shigella cannot be distinguished from Escherichia high rates of secondary cases among family members of
coli by DNA hybridization and remains a separate spe- sick children (26–33%). Shigellosis can also be transmit-
cies only on historical and clinical grounds. ted sexually.
Throughout history, Shigella epidemics have
often occurred in settings of human crowding
definition under conditions of poor hygiene—e.g., among
Shigella is a nonspore-forming, gram-negative bacte- soldiers in campaigning armies, inhabitants of besieged
rium that, unlike E. coli, is nonmotile and does not pro- cities, groups on pilgrimages, and refugees in camps.
duce gas from sugars, decarboxylate lysine, or hydrolyze Epidemics follow a cyclical pattern in areas such as the
arginine. Some serovars produce indole, and occasional Indian subcontinent and sub-Saharan Africa. These
strains utilize sodium acetate. S. dysenteriae, S. flexneri, devastating epidemics, which are most often caused by
S. boydii, and S. sonnei (serogroups A, B, C, and D, respec- S. dysenteriae type 1, are characterized by high attack and
tively) can be differentiated on the basis of biochemi- mortality rates. In Bangladesh, for instance, an epidemic
cal and serologic characteristics. Genome sequencing of caused by S. dysenteriae type 1 was associated with a 42%
E. coli K12, S. flexneri 2a, S. sonnei, S. dysenteriae type 1, increase in mortality rate among children 1–4 years of
and S. boydii has revealed that these species have ∼93% age. Apart from these epidemics, shigellosis is mostly an
of genes in common. The three major genomic “sig- endemic disease, with 99% of cases occurring in the
natures” of Shigella are (1) a 215-kb virulence plasmid developing world and the highest prevalences in the
that carries most of the genes required for pathogenic- most impoverished areas, where personal and general
ity (particularly invasive capacity); (2) the lack or altera- hygiene is below standard. S. flexneri isolates predomi-
tion of genetic sequences encoding products (e.g., lysine nate in the least developed areas, whereas S. sonnei is
decarboxylase) that, if expressed, would attenuate patho- more prevalent in economically emerging countries and
genicity; and (3) in S. dysenteriae type 1, the presence of in the industrialized world.
genes encoding Shiga toxin, a potent cytotoxin.
Prevalence in the developing world
ePideMiology In a review published under the auspices of the World
The human intestinal tract represents the major reser- Health Organization (WHO), the total annual num-
voir of Shigella, which is also found (albeit rarely) in the ber of cases in 1966–1997 was estimated at 165 million,
higher primates. Because excretion of shigellae is greatest and 69% of these cases occurred in children <5 years
in the acute phase of disease, the bacteria are transmit- of age. In this review, the annual number of deaths was
ted most efficiently by the fecal-oral route via hand calculated to range between 500,000 and 1.1 million.
279
280 More recent data (2000–2004) from six Asian countries being poorly adapted to survive in the environment.
indicate that even though the incidence of shigellosis Resistance to low-pH conditions allows shigellae to
remains stable, mortality rates associated with this survive passage through the gastric barrier, an ability
disease may have decreased significantly, possibly as a that may explain in part why a small inoculum (as few as
result of improved nutritional status. However, extensive 100 CFU) is sufficient to cause infection.
and essentially uncontrolled use of antibiotics, which may The watery diarrhea that usually precedes the dysen-
also account for declining mortality rates, has increased teric syndrome is attributable to active secretion and
the rate of emergence of multidrug-resistant Shigella abnormal water reabsorption—a secretory effect at the
strains. An often-overlooked complication of shigellosis jejunal level described in experimentally infected rhesus
is the short- and long-term impairment of the nutri- monkeys. This initial purge is probably due to the com-
tional status of infected children in endemic areas. Com- bined action of an enterotoxin (ShET-1) and mucosal
bined with anorexia, the exudative enteropathy resulting inflammation. The dysenteric syndrome, manifested by
from mucosal abrasions contributes to rapid deteriora- bloody and mucopurulent stools, reflects invasion of the
tion of the patient’s nutritional status. Shigellosis is thus mucosa.
a major contributor to stunted growth among children The pathogenesis of Shigella is essentially deter-
in developing countries. mined by a large virulence plasmid of 214 kb compris-
Peaking in incidence in the pediatric population, ing ∼100 genes, of which 25 encode a type III secretion
endemic shigellosis is rare in young and middle-aged system that inserts into the membrane of the host cell to
adults, probably because of naturally acquired immunity. allow effectors to transit from the bacterial cytoplasm to
Incidence then increases again in the elderly population. the host cell cytoplasm (Fig. 28-1). Bacteria are thereby
able to invade intestinal epithelial cells by inducing
Prevalence in the industrialized world their own uptake after the initial crossing of the epithe-
In pediatric populations, local outbreaks occur when lial barrier through M cells (the specialized translocat-
proper and adapted hygiene policies are not imple- ing epithelial cells in the follicle-associated epithelium
mented in group facilities like day-care centers and that covers mucosal lymphoid nodules). The organisms
SECTION IV
institutions for the mentally retarded. In adults, as in induce apoptosis of subepithelial resident macrophages.
children, sporadic cases occur among travelers returning Once inside the cytoplasm of intestinal epithelial cells,
from endemic areas, and rare outbreaks of varying size Shigella effectors trigger the cytoskeletal rearrangements
can follow waterborne or food-borne infections. necessary to direct uptake of the organism into the
epithelial cell. The Shigella-containing vacuole is then
quickly lysed, releasing bacteria into the cytosol.
Pathogenesis and Pathology
Infections of the Alimentary Tract
Shigella
M cell
Epithelial cells
Activation of
NF-gB caused by IcsA
IL-1` and Cell-to-cell
intracellular spread
NLR activation
IpaB type III
IL-8 Macrophages IpaC + secretion
IL-1` IpaA
Disruption of epithelial
permeability barrier by PMNs
Macrophage apoptosis
Caspase-I activation by IpaB
Massive invasion of Bacterial survival
epithelium Initiation of inflammation
IL-18
Figure 28-1
Invasive strategy of Shigella flexneri. IL, interleukin; NF-κB, nuclear factor κB; NLR, NOD-like receptor; PMN, polymorpho-
nuclear leukocyte.
into contact, cellular protrusions form and are engulfed Unlike most diarrheal syndromes, dysenteric syn- 281
by neighboring cells. This series of events permits bacte- dromes rarely present with dehydration as a major fea-
rial cell-to-cell spread. ture. Endoscopy shows an edematous and hemorrhagic
Cytokines released by a growing number of infected mucosa, with ulcerations and possibly overlying exu-
intestinal epithelial cells attract increased numbers of dates resembling pseudomembranes. The extent of the
immune cells [particularly polymorphonuclear leukocytes lesions correlates with the number and frequency of
(PMNs)] to the infected site, thus further destabilizing stools and with the degree of protein loss by exudative
the epithelial barrier, exacerbating inflammation, and mechanisms. Most episodes are self-limited and resolve
leading to the acute colitis that characterizes shigellosis. without treatment in 1 week. With appropriate treat-
Evidence indicates that some type III secretion system– ment, recovery takes place within a few days to a week,
injected effectors can control the extent of inflamma- with no sequelae.
tion, thus facilitating bacterial survival. Acute life-threatening complications are seen most
Shiga toxin produced by S. dysenteriae type 1 increases often in children <5 years of age (particularly those who
disease severity. This toxin belongs to a group of A1-B5 are malnourished) and in elderly patients. Risk factors
protein toxins whose B subunit binds to the recep- for death in a clinically severe case include nonbloody
tor globotriaosylceramide on the target cell surface and diarrhea, moderate to severe dehydration, bacteremia,
whose catalytic A subunit is internalized by receptor- absence of fever, abdominal tenderness, and rectal
mediated endocytosis and interacts with the subcellu- prolapse. Major complications are predominantly intes-
lar machinery to inhibit protein synthesis by expressing tinal (e.g., toxic megacolon, intestinal perforations, rectal
RNA N-glycosidase activity on 28S ribosomal RNA. prolapse) or metabolic (e.g., hypoglycemia, hyponatre-
This process leads to inhibition of binding of the mia, dehydration). Bacteremia is rare and is reported most
amino-acyl-tRNA to the 60S ribosomal subunit and frequently in severely malnourished and HIV-infected
thus to a general shutoff of cell protein biosynthesis. patients. Alterations of consciousness, including seizures,
Shiga toxins are translocated from the bowel into the delirium, and coma, may occur, especially in children <5
circulation. After binding of the toxins to target cells in years old, and are associated with a poor prognosis; fever
CHAPTER 28
the kidney, pathophysiologic alterations may result in and severe metabolic alterations are more often the major
hemolytic-uremic syndrome (HUS; see below). causes of altered consciousness than is meningitis or the
Ekiri syndrome (toxic encephalopathy associated with
bizarre posturing, cerebral edema, and fatty degeneration
Clinical Manifestations of viscera), which has been reported mostly in Japanese
The presentation and severity of shigellosis depend to children. Pneumonia, vaginitis, and keratoconjunctivitis
Shigellosis
some extent on the infecting serotype but even more due to Shigella are rarely reported. In the absence of seri-
on the age and the immunologic and nutritional status ous malnutrition, severe and very unusual clinical mani-
of the host. Poverty and poor standards of hygiene are festations, such as meningitis, may be linked to genetic
strongly related to the number and severity of diarrheal defects in innate immune functions [i.e., deficiency in
episodes, especially in children <5 years old who have interleukin 1 receptor–associated kinase 4 (IRAK-4)] and
been weaned. may require genetic investigation.
Shigellosis typically evolves through four phases: Two complications of particular importance are
incubation, watery diarrhea, dysentery, and the postin- toxic megacolon and HUS. Toxic megacolon is a con-
fectious phase. The incubation period usually lasts 1–4 sequence of severe inflammation extending to the
days but may be as long as 8 days. Typical initial mani- colonic smooth-muscle layer and causing paralysis and
festations are transient fever, limited watery diarrhea, dilatation. The patient presents with abdominal disten-
malaise, and anorexia. Signs and symptoms may range tion and tenderness, with or without signs of localized
from mild abdominal discomfort to severe cramps, or generalized peritonitis. The abdominal x-ray char-
diarrhea, fever, vomiting, and tenesmus. The manifes- acteristically shows marked dilatation of the transverse
tations are usually exacerbated in children, with tem- colon (with the greatest distention in the ascending and
peratures up to 40°–41°C (104.0°–105.8°F) and more descending segments); thumbprinting caused by muco-
severe anorexia and watery diarrhea. This initial phase sal inflammatory edema; and loss of the normal haustral
may represent the only clinical manifestation of shigellosis, pattern associated with pseudopolyps, often extending
especially in developed countries. Otherwise, dysentery into the lumen. Pneumatosis coli is an occasional find-
follows within hours or days and is characterized by ing. If perforation occurs, radiographic signs of pneumo-
uninterrupted excretion of small volumes of bloody peritoneum may be apparent. Predisposing factors (e.g.,
mucopurulent stools with increased tenesmus and hypokalemia and use of opioids, anticholinergics,
abdominal cramps. At this stage, Shigella produces acute loperamide, psyllium seeds, and antidepressants) should
colitis involving mainly the distal colon and the rectum. be investigated.
282 Shiga toxin produced by S. dysenteriae type 1 has because shigellosis often manifests only as watery diarrhea,
been linked to HUS in developing countries but systematic attempts to isolate Shigella are necessary.
rarely in industrialized countries, where enterohe- The “gold standard” for the diagnosis of Shigella
morrhagic E. coli (EHEC) predominates as the etiologic infection remains the isolation and identification of the
agent of this syndrome. HUS is an early complication pathogen from fecal material. One major difficulty, par-
that most often develops after several days of diarrhea. ticularly in endemic areas where laboratory facilities are
Clinical examination shows pallor, asthenia, and irrita- not immediately available, is the fragility of Shigella and its
bility and, in some cases, bleeding of the nose and gums, common disappearance during transport, especially with
oliguria, and increasing edema. HUS is a nonimmune rapid changes in temperature and pH. In the absence of
(Coombs test–negative) hemolytic anemia defined by a a reliable enrichment medium, buffered glycerol saline
diagnostic triad: microangiopathic hemolytic anemia or Cary-Blair medium can be used as a holding medium,
[hemoglobin level typically <80 g/L (<8 g/dL)], throm- but prompt inoculation onto isolation medium is essen-
bocytopenia (mild to moderate in severity; typically tial. The probability of isolation is higher if the portion of
<60,000 platelets/μL), and acute renal failure due to stools that contains bloody and/or mucopurulent mate-
thrombosis of the glomerular capillaries (with markedly rial is directly sampled. Rectal swabs can be used, as they
elevated creatinine levels). Anemia is severe, with frag- offer the highest rate of successful isolation during the
mented red blood cells (schizocytes) in the peripheral acute phase of disease. Blood cultures are positive in <5%
smear, high serum concentrations of lactate dehydroge- of cases but should be done when a patient presents with
nase and free circulating hemoglobin, and elevated retic- a clinical picture of severe sepsis.
ulocyte counts. Acute renal failure occurs in 55–70% of In addition to quick processing, the use of several
cases; however, renal function recovers in most of these media increases the likelihood of successful isolation: a
cases (up to 70% in various series). Leukemoid reactions, nonselective medium such as bromocresol-purple agar
with leukocyte counts of 50,000/μL, are sometimes lactose; a low-selectivity medium such as MacConkey
noted in association with HUS. or eosin-methylene blue; and a high-selectivity medium
The postinfectious immunologic complication known such as Hektoen, Salmonella-Shigella, or xylose-lysine-
SECTION IV
as reactive arthritis can develop weeks or months after deoxycholate agar. After incubation on these media
shigellosis, especially in patients expressing the histo- for 12–18 h at 37°C (98.6°F), shigellae appear as
compatibility antigen HLA-B27. About 3% of patients nonlactose-fermenting colonies that measure 0.5–1 mm
infected with S. flexneri later develop this syndrome, with in diameter and have a convex, translucent, smooth
arthritis, ocular inflammation, and urethritis—a condi- surface. Suspected colonies on nonselective or low-
tion that can last for months or years and can progress to selectivity medium can be subcultured on a high-
Infections of the Alimentary Tract
difficult-to-treat chronic arthritis. Postinfectious arthrop- selectivity medium before being specifically identified
athy occurs only after infection with S. flexneri and not or can be identified directly by standard commercial sys-
after infection with the other Shigella serotypes. tems on the basis of four major characteristics: glucose
positivity (usually without production of gas), lactose
Laboratory Diagnosis negativity, H2S negativity, and lack of motility. The four
Shigella serogroups (A–D) can then be differentiated by
The differential diagnosis in patients with a dysen- additional characteristics. This approach adds time and
teric syndrome depends on the clinical and envi- difficulty to the identification process; however, after
ronmental context. In developing areas, infectious presumptive diagnosis, the use of serologic methods
diarrhea caused by other invasive pathogenic bacteria (e.g., slide agglutination, with group- and then type-spe-
(Salmonella, Campylobacter jejuni, Clostridium difficile, Yersinia cific antisera) should be considered. Group-specific anti-
enterocolitica) or parasites (Entamoeba histolytica) should be sera are widely available; in contrast, because of the large
considered. Only bacteriologic and parasitologic examina- number of serotypes and sub-serotypes, type-specific
tions of stool can truly differentiate among these pathogens. antisera are rare and more expensive and thus are often
A first flare of inflammatory bowel disease, such as restricted to reference laboratories.
Crohn’s disease or ulcerative colitis (Chap. 295), should be
considered in patients in industrialized countries. Despite
similar symptoms, anamnesis discriminates between shig-
Treatment Shigellosis
ellosis, which usually follows recent travel in an endemic
zone, and these other conditions.
Antibiotic Susceptibility of Shigella
Microscopic examination of stool smears shows the
As an enteroinvasive disease, shigellosis requires antibiotic
presence of erythrophagocytic trophozoites with very few
treatment. Since the mid-1960s, however, increasing
PMNs in E. histolytica infection, whereas bacterial entero-
resistance to multiple drugs has been a dominant fac-
invasive infections (particularly shigellosis) are characterized
tor in treatment decisions. Resistance rates are highly
by high PMN counts in each microscopic field. However,
Table 28-1 283
dependent on the geographic area. Clonal spread of
Recommended Antimicrobial Therapy for
particular strains and horizontal transfer of resistance Shigellosis
determinants, particularly via plasmids and transpo-
Treatment
sons, contribute to multidrug resistance. The current Schedule
global status—i.e., high rates of resistance to classic Antimicrobial
first-line antibiotics such as amoxicillin—has led to a Agent Children Adults Limitations
rapid switch to quinolones such as nalidixic acid. How- First line
ever, resistance to such early-generation quinolones
Ciprofloxacin 15 mg/kg 500 mg
has also emerged and spread quickly as a result of chro-
2 times per day
mosomal mutations affecting DNA gyrase and topoi- for 3 days, PO
somerase IV; this resistance has necessitated the use of
Second line
later-generation quinolones as first-line antibiotics in
many areas. For instance, a review of the antibiotic resis- Pivmecillinam 20 mg/kg 100 mg Cost
4 times per day No pediatric
tance history of Shigella in India found that, after their
for 5 days, PO formulation
introduction in the late 1980s, the second-generation
quinolones norfloxacin, ciprofloxacin, and ofloxacin were Frequent
administration
highly effective in the treatment of shigellosis, including
Resistance
cases caused by multidrug-resistant strains of S. dysenteriae emerging
type 1. However, investigations of subsequent outbreaks
Ceftriaxone 50–100 – Efficacy not
in India and Bangladesh detected resistance to norfloxacin,
mg/kg validated
ciprofloxacin, and ofloxacin in 5% of isolates. The inci- Once a day IM Must be injected
dence of multidrug resistance parallels the widespread, for 2–5 days
uncontrolled use of antibiotics and calls for the rational
Azithromycin 6–20 mg/kg 1–1.5 g Cost
use of effective drugs. Once a day for Efficacy not
CHAPTER 28
1–5 days, PO validated
Antibiotic Treatment of Shigellosis
MIC near serum
(Table 28-1) Because of the ready transmissibility of concentration
Shigella, current public health recommendations in the Rapid emer-
United States are that every case be treated with antibiot- gence of
ics. Ciprofloxacin is recommended as first-line treatment. resistance and
A number of other drugs have been tested and shown spread to other
Shigellosis
to be effective, including ceftriaxone, azithromycin, bacteria
pivmecillinam, and some fifth-generation quinolones.
While infections caused by non-dysenteriae Shigella in Source: WHO Library Cataloguing-in-Publication Data: Guidelines
for the control of shigellosis, including epidemics due to Shigella
immunocompetent individuals are routinely treated dysenteriae type 1 (www.searo. who.int/LinkFiles/CAH_Publications_
with a 3-day course of antibiotics, it is recommended shigella.pdf).
that S. dysenteriae type 1 infections be treated for 5 days
and that Shigella infections in immunocompromised
patients be treated for 7–10 days.
Treatment for shigellosis must be adapted to the clin-
ical context, with the recognition that the most fragile
more aggressive measures, possibly including resuscita-
patients are children <5 years old, who represent two-
tion, are often required.
thirds of all cases worldwide. There are few data on the
use of quinolones in children, but Shigella-induced dys- Rehydration and Nutrition Shigella
entery is a well-recognized indication for their use. The infection rarely causes significant dehydration. Cases
half-life of ciprofloxacin is longer in infants than in older requiring aggressive rehydration (particularly in indus-
individuals. The ciprofloxacin dose generally recom- trialized countries) are uncommon. In developing coun-
mended for children is 30 mg/kg per d in two divided tries, malnutrition remains the primary indicator for
doses. Adults living in areas with high standards of diarrhea-related death, highlighting the importance of
hygiene are likely to develop milder, shorter-duration nutrition in early management. Rehydration should be
disease, whereas infants in endemic areas can develop oral unless the patient is comatose or presents in shock.
severe, sometimes fatal dysentery. In the former set- Because of the improved effectiveness of reduced-
ting, treatment will remain minimal and bacteriologic osmolarity oral rehydration solution (especially for chil-
proof of infection will often come after symptoms have dren with acute noncholera diarrhea), the WHO and
resolved; in the latter setting, antibiotic treatment and UNICEF now recommend a standard solution of
284
245 mOsm/L (sodium, 75 mmol/L; chloride, 65 mmol/L; perforation, either isolated or complicating toxic mega-
glucose (anhydrous), 75 mmol/L; potassium, 20 mmol/L; colon, requires surgical treatment and intensive medical
citrate, 10 mmol/L). In shigellosis, the coupled transport support.
of sodium to glucose may be variably affected, but oral Rectal prolapse must be treated as soon as possible.
rehydration therapy remains the easiest and most effi- With the health care provider using surgical gloves or a
cient form of rehydration, especially in severe cases. soft warm wet cloth and the patient in the knee-chest
Nutrition should be started as soon as possible after position, the prolapsed rectum is gently pushed back
completion of initial rehydration. Early refeeding is safe, into place. If edema of the rectal mucosa is evident
well tolerated, and clinically beneficial. Because breast- (rendering reintegration difficult), it can be osmotically
feeding reduces diarrheal losses and the need for oral reduced by applying gauze impregnated with a warm
rehydration in infants, it should be maintained in the solution of saturated magnesium sulfate. Rectal pro-
absence of contraindications (e.g., maternal HIV infection). lapse often relapses but usually resolves along with the
resolution of dysentery.
Nonspecific, Symptom-Based Therapy
HUS must be treated by water restriction, includ-
Antimotility agents have been implicated in prolonged
ing discontinuation of oral rehydration solution and
fever in volunteers with shigellosis. These agents are
potassium-rich alimentation. Hemofiltration is usually
suspected of increasing the risk of toxic megacolon and
required.
are thought to have been responsible for HUS in chil-
dren infected by EHEC strains. For safety reasons, it is
better to avoid antimotility agents in bloody diarrhea.
Prevention
Treatment of Complications There is
no consensus regarding the best treatment for toxic Hand washing after defecation or handling of children’s
megacolon. The patient should be assessed frequently feces and before handling of food is recommended. Stool
by both medical and surgical teams. Anemia, dehydra- decontamination (e.g., with sodium hypochlorite), together
with a cleaning protocol for medical staff as well as for
SECTION IV
tion persists. However, some physicians recommend enteral vaccine candidates have been produced and are
continuation of medical therapy for up to 7 days if the undergoing clinical trials, no vaccine against shigellosis
patient seems to be improving clinically despite per- is currently available. Especially given the rapid pro-
sistent megacolon without free perforation. Intestinal gression of antibiotic resistance in Shigella, a vaccine is
urgently needed.
CHAPTER 29
Martin J. Blaser
285
286 Table 29-1
Clinical Features Associated With Infection Due to “Atypical” Campylobacter and Related
Species Implicated as Causes of Human Illness
Common Clinical Less Common
Species Features Clinical Features Additional Information
a
Campylobacter coli Fever, diarrhea, abdominal Bacteremia Clinically indistinguishable from C. jejuni
pain
Campylobacter fetus Bacteremia,a sepsis, Diarrhea, relapsing Not usually isolated from media containing
meningitis, vascular fevers cephalothin or incubated at 42°C
infections
Campylobacter Watery diarrhea, low-grade Bacteremia, Difficult to isolate because of cephalothin
upsaliensis fever, abdominal pain abscesses susceptibility
Campylobacter lari Abdominal pain, diarrhea Colitis, appendicitis Seagulls frequently colonized; organism
often transmitted to humans via
contaminated water
Campylobacter Watery or bloody diarrhea, Bacteremia Causes proliferative enteritis in swine
hyointestinalis vomiting, abdominal pain
Helicobacter Chronic mild diarrhea, Bacteremiaa Best treated with fluoroquinolones
fennelliae abdominal cramps, proctitis
Helicobacter Chronic mild diarrhea, Bacteremiaa Best treated with fluoroquinolones; identified
cinaedi abdominal cramps, proctitis in healthy hamsters
Campylobacter jejuni Diarrhea Chronic gastritis, Uncertain role as human pathogen
subspecies doylei bacteremiab
Arcobacter Diarrhea Bacteremia Cultured under aerobic conditions
SECTION IV
cryaerophilus
Arcobacter Fever, diarrhea, abdominal Bacteremia, Cultured under aerobic conditions; enzootic
butzleri pain, nausea appendicitis in nonhuman primates
Campylobacter Pulmonary, perianal, groin, Bacteremia Three clinically relevant biovars: sputorum,
sputorum and axillary abscesses; fecalis, and paraureolyticus
diarrhea
Infections of the Alimentary Tract
a
In immunocompromised hosts, especially HIV-infected persons.
b
In children.
Source: Adapted from BM Allos, MJ Blaser: Clin Infect Dis 20:1092, 1995.
during summer and early autumn. Persons of all ages are Pathology and Pathogenesis
affected; however, attack rates for C. jejuni are highest
among young children and young adults, while those C. jejuni infections may be subclinical, espe-
for C. fetus are highest at the extremes of age. Systemic cially in hosts in developing countries who
infections due to C. fetus (and to other Campylobacter have had multiple prior infections and thus are
and related species) are most common among com- partially immune. Symptomatic infections mostly
promised hosts. Persons at increased risk include those occur within 2–4 days (range, 1–7 days) of exposure to
with AIDS, hypogammaglobulinemia, neoplasia, liver the organism in food or water. The sites of tissue
disease, diabetes mellitus, and generalized atherosclero- injury include the jejunum, ileum, and colon. Biopsies
sis as well as neonates and pregnant women. However, show an acute nonspecific inflammatory reaction, with
apparently healthy nonpregnant persons occasionally neutrophils, monocytes, and eosinophils in the lamina
develop transient Campylobacter bacteremia as part of a propria, as well as damage to the epithelium, including
gastrointestinal illness. loss of mucus, glandular degeneration, and crypt
In contrast, in many developing countries, abscesses. Biopsy findings may be consistent with Crohn’s
C. jejuni infections are hyperendemic, with the disease or ulcerative colitis, but these “idiopathic”
highest rates among children <2 years old. Infec- chronic inflammatory diseases should not be diagnosed
tion rates fall with age, as does the illness-to-infection unless infectious colitis, specifically including that due to
ratio. These observations suggest that frequent exposure infection with Campylobacter species and related organ-
to C. jejuni leads to the acquisition of immunity. isms, has been ruled out.
The high frequency of C. jejuni infections and their C. fetus may cause a diarrheal illness similar to that 287
severity and recurrence among hypogammaglobulin- due to C. jejuni, especially in normal hosts. This organ-
emic patients suggest that antibodies are important in ism also may cause either intermittent diarrhea or
protective immunity. The pathogenesis of infection is nonspecific abdominal pain without localizing signs.
uncertain. Both the motility of the strain and its capac- Sequelae are uncommon, and the outcome is benign.
ity to adhere to host tissues appear to favor disease, but C. fetus may also cause a prolonged relapsing systemic
classic enterotoxins and cytotoxins (although described illness (with fever, chills, and myalgias) that has no
and including cytolethal distending toxin, or CDT) obvious primary source; this manifestation is especially
appear not to play substantial roles in tissue injury or common among compromised hosts. Secondary seed-
disease production. The organisms have been visualized ing of an organ (e.g., meninges, brain, bone, urinary
within the epithelium, albeit in low numbers. The doc- tract, or soft tissue) complicates the course, which may
umentation of a significant tissue response and occasion- be fulminant. C. fetus infections have a tropism for vas-
ally of C. jejuni bacteremia further suggests that tissue cular sites: endocarditis, mycotic aneurysm, and septic
invasion is clinically significant, and in vitro studies are thrombophlebitis may all occur. Infection during preg-
consistent with this pathogenetic feature. nancy often leads to fetal death. A variety of Campylo-
The pathogenesis of C. fetus infections is better bacter species and H. cinaedi can cause recurrent celluli-
defined. Virtually all clinical isolates of C. fetus possess tis with fever and bacteremia in immunocompromised
a proteinaceous capsule-like structure (an S-layer) that hosts.
renders the organisms resistant to complement-mediated
killing and opsonization. As a result, C. fetus can cause
bacteremia and can seed sites beyond the intestinal Complications
tract. The ability of the organism to switch the S-layer
proteins expressed—a phenomenon that results in anti- Except in infection with C. fetus, bacteremia is uncom-
genic variability—may contribute to the chronicity and mon, developing most often in immunocompromised
high rate of recurrence of C. fetus infections in com- hosts and at the extremes of age. Three patterns of
CHAPTER 29
promised hosts. extraintestinal infection have been noted: (1) tran-
sient bacteremia in a normal host with enteritis (benign
course, no specific treatment needed); (2) sustained bac-
teremia or focal infection in a normal host (bacteremia
Clinical Manifestations
originating from enteritis, with patients responding well
The clinical features of infections due to Campylobacter to antimicrobial therapy); and (3) sustained bacteremia
examination of stools with Gram’s staining or to use patients presenting for medical attention with
phase-contrast or dark-field microscopy to identify the Campylobacter enteritis, not all clearly benefit from
organisms′ characteristic “darting” motility. Confirma- specific antimicrobial therapy. Indications for therapy
tion of the diagnosis of Campylobacter infection is based include high fever, bloody diarrhea, severe diarrhea,
on identification of an isolate from cultures of stool, persistence for >1 week, and worsening of symptoms. A
blood, or another site. Campylobacter-specific media 5- to 7-day course of erythromycin (250 mg orally four
Infections of the Alimentary Tract
should be used to culture stools from all patients with times daily or—for children—30–50 mg/kg per day, in
inflammatory or bloody diarrhea. Since all Campy- divided doses) is the regimen of choice. Both clinical
lobacter species are fastidious, they will not be isolated trials and in vitro susceptibility testing indicate that
unless selective media or other selective techniques are other macrolides, including azithromycin (a 1- or 3-day
used. Not all media are equally useful for isolation of regimen), also are useful therapeutic agents. An alterna-
the broad array of campylobacters; therefore, failure to tive regimen for adults is ciprofloxacin (500 mg orally
isolate campylobacters from stool does not entirely rule twice daily) or another fluoroquinolone for 5–7 days,
out their presence. The detection of the organisms in but resistance to this class of agents as well as to tetra-
stool almost always implies infection; there is a brief cyclines has been increasing. Patients infected with anti-
period of postconvalescent fecal carriage and no obvi- biotic-resistant strains are at increased risk of adverse
ous commensalism in humans. In contrast, C. sputo- outcomes. Use of antimotility agents, which may
rum and related organisms found in the oral cavity are prolong the duration of symptoms and have been asso-
commensals that only rarely have pathogenic signifi- ciated with toxic megacolon and with death, is not rec-
cance. Because of the low levels of metabolic activity of ommended.
Campylobacter species in standard blood culture media, For systemic infections, treatment with gentamicin
Campylobacter bacteremia may be difficult to detect (1.7 mg/kg IV every 8 h after a loading dose of 2 mg/kg),
unless laboratorians check for low-positive results in imipenem (500 mg IV every 6 h), or chloramphenicol
quantitative assays. (50 mg/kg IV each day in three or four divided doses)
should be started empirically, but susceptibility testing
should then be performed. Ciprofloxacin and amoxicillin/
Differential Diagnosis clavulanate are alternative agents for susceptible
strains. In the absence of immunocompromise or endo-
The symptoms of Campylobacter enteritis are not suffi- vascular infections, therapy should be administered
ciently unusual to distinguish this illness from that due for 14 days. For immunocompromised patients with
to Salmonella, Shigella, Yersinia, and other pathogens.
therapy. Volume depletion probably contributes to the 289
systemic infections due to C. fetus and for patients with few deaths that are reported. As stated above, occasional
endovascular infections, prolonged therapy (for up to patients develop reactive arthritis or Guillain-Barré
4 weeks) is usually necessary. For recurrent infections in syndrome or its variants. Systemic infection with
immunocompromised hosts, lifelong therapy/prophy- C. fetus is much more often fatal than that due to
laxis is sometimes necessary. related species; this higher mortality rate reflects in
part the population affected. Prognosis depends on the
rapidity with which appropriate therapy is begun. Oth-
erwise-healthy hosts usually survive C. fetus infections
Prognosis
without sequelae. Compromised hosts often have recur-
Nearly all patients recover fully from Campylobacter rent and/or life-threatening infections due to a variety
enteritis, either spontaneously or after antimicrobial of Campylobacter species.
CHAPTER 29
Infections Due to Campylobacter and Related Organisms
chApter 30
Members of the genus Vibrio cause a number of impor- their lipopolysaccharide (LPS) O antigens. Although
tant infectious syndromes. Classic among them is cholera, some non-O1 V. cholerae serogroups (strains that do not
a devastating diarrheal disease caused by V. cholerae that agglutinate in antisera to the O1 group antigen) have
has been responsible for seven global pandemics and occasionally caused sporadic outbreaks of diarrhea, sero-
much suffering over the past two centuries. Epidemic group O1 was, until the emergence of serogroup O139
cholera remains a significant public health concern in in 1992, the exclusive cause of epidemic cholera. Two
the developing world today. Other vibrioses caused by biotypes of V. cholerae O1, classical and El Tor, are dis-
other Vibrio species include syndromes of diarrhea, soft tinguished. Each biotype is further subdivided into two
tissue infection, or primary sepsis. All Vibrio species are serotypes, termed Inaba and Ogawa.
highly motile, facultatively anaerobic, curved gram- The natural habitat of V. cholerae is coastal salt water
negative rods with one or more flagella. In nature, vib- and brackish estuaries, where the organism lives in close
rios most commonly reside in tidal rivers and bays under relation to plankton. Humans become infected inciden-
conditions of moderate salinity. They proliferate in tally but, once infected, can act as vehicles for spread.
the summer months when water temperatures exceed Ingestion of water contaminated by human feces is the
20°C. As might be expected, the illnesses they cause also most common means of acquisition of V. cholerae. Con-
increase in frequency during the warm months. sumption of contaminated food also can contribute to
spread. There is no known animal reservoir. While the
infectious dose is relatively high, it is markedly reduced
in hypochlorhydric persons, in those using antacids, and
chOLerA when gastric acidity is buffered by a meal. Cholera is
predominantly a pediatric disease in endemic areas, but
DefinitiOn it affects adults and children equally when newly intro-
Cholera is an acute diarrheal disease that can, in a mat- duced into a population. In endemic areas, the burden
ter of hours, result in profound, rapidly progressive of disease is often greatest during “cholera seasons” asso-
dehydration and death. Accordingly, cholera gravis ciated with high temperatures, heavy rainfall, and flood-
(the severe form of cholera) is a much-feared disease, ing, but cholera can occur year-round. For unexplained
particularly in its epidemic presentation. Fortunately, reasons, susceptibility to cholera is significantly influ-
prompt aggressive fluid repletion and supportive care enced by ABO blood group status; persons with type
can obviate the high mortality that cholera has histori- O blood are at greatest risk of severe disease if infected,
cally wrought. While the term cholera has occasionally while those with type AB are at least risk.
been applied to any severely dehydrating secretory diar- Cholera is native to the Ganges delta in the
rheal illness, whether infectious in etiology or not, it Indian subcontinent. Since 1817, seven global
now refers to disease caused by V. cholerae serogroup O1 pandemics have occurred. The current (seventh)
or O139—i.e., the serogroups with epidemic potential. pandemic—the first due to the El Tor biotype—began
in Indonesia in 1961 and spread throughout Asia as
V. cholerae El Tor displaced the endemic classical biotype.
MiCROBiOlOgy AnD ePiDeMiOlOgy
In the early 1970s, El Tor cholera erupted in Africa,
The species V. cholerae is classified into more than 200 causing major epidemics before becoming a persistent
serogroups based on the carbohydrate determinants of endemic problem. Currently, >90% of cholera cases
290
291
Figure 30-1
World distribution of cholera in 2009. (Adapted from WHO: Wkly Epidemiol Rec 84:309, 2009.)
CHAPTER 30
reported annually to the World Health Organization in inland fresh waters rather than in its classic niche of
(WHO) are from Africa (Fig. 30-1), but the true bur- coastal salt waters. In 2010, cholera reappeared in Haiti
den in Africa as well as in Asia is unknown since diag- after a century-long absence.
nosis is often syndromic and since many countries with In October 1992, a large-scale outbreak of clinical
endemic cholera do not report cholera to the WHO. It cholera caused by a new serogroup, O139, occurred in
is possible that >3 million cases of cholera occur yearly
(of which only ∼200,000 are reported to the WHO),
CHAPTER 30
discerned by immobilization with specific antiserum.
Laboratory isolation of the organism requires the use of
a selective medium such as taurocholate-tellurite-gelatin
(TTG) agar or thiosulfate–citrate–bile salts–sucrose
(TCBS) agar. If a delay in sample processing is expected,
Carey-Blair transport medium and/or alkaline-peptone
Treatment Cholera
None or mild, Thirst in some cases; <5% loss of total None or Mild, but Diarrheab
but diarrhea body weight <2 years 1/4–1/2 cup (50–100 mL) of
Moderate Thirst, postural hypotension, weakness, ORS, to a maximum of 0.5 L/d
tachycardia, decreased skin turgor, dry 2–9 years 1/2–1 cup (100–200 mL) of
mouth/tongue, no tears; 5–10% loss ORS, to a maximum of 1 L/d
of total body weight ≥10 years As much ORS as desired, to
Severe Unconsciousness, lethargy, or a maximum of 2 L/d
“floppiness”; weak or absent pulse; Moderateb,c
inability to drink; sunken eyes (and, in <4 months (<5 kg) 200–400 mL of ORS
infants, sunken fontanelles); 4–11 months (5–<8 kg) 400–600 mL of ORS
>10% loss of total body weight
12–23 months (8–<11 kg) 600–800 mL of ORS
2–4 years (11–<16 kg) 800–1200 mL of ORS
5–14 years (16–<30 kg) 1200–2200 mL of ORS
≥15 years (≥30 kg) 2200–4000 mL of ORS
together with an actively transported molecule such Severeb
as glucose (or galactose). Cl− and water follow. This All ages and weights IV fluid replacement with
transport mechanism remains intact even when chol- Ringer’s lactate (or, if not
era toxin is active. ORS may be made by adding safe available, normal saline):
water to prepackaged sachets containing salts and 100 mL/kg in first 3-h period
sugar or by adding 0.5 teaspoon of table salt (NaCl; (or first 6-h period for
SECTION IV
CHAPTER 30
three divided doses for 3 days), or azithromycin (a single ing in proximity to vaccinated individuals. The WHO
1-g dose) may be a clinically effective substitute. Preg- now recommends that vaccination against cholera be
nant women and children are usually treated with eryth- part of a larger response plan for populations at risk for
romycin or azithromycin (10 mg/kg in children). epidemic cholera. The oral killed vaccines are available
in Europe and Asia but (like other cholera vaccines) are
not available in the United States.
a
Especially with liver disease or hemochromatosis.
Source: Table 161-3 in Harrisons Principles of Internal Medicine, 14th edition.
filter-feeding mollusks. As a result, human infection Serotypes O3:K6, O4:K68, and O1:K-untypable, which
commonly follows the ingestion of seawater or of raw are genetically related to one another, account for this
or undercooked shellfish (Table 30-5). Most nonchol- increase. The enteropathogenicity of V. parahaemolyticus
era vibrios can be cultured on blood or MacConkey is linked to its ability to cause hemolysis on Wagatsuma
agar, which contains enough salt to support the growth agar (i.e., the Kanagawa phenomenon). Although the mech-
of these halophilic species. In the microbiology labora- anism by which the organism causes diarrhea remains
SECTION IV
tory, the species of noncholera vibrios are distin- unclear, the genome sequence of V. parahaemolyticus
guished by standard biochemical tests. The most contains two type III secretion systems, which
important of these organisms are V. parahaemolyticus directly inject toxic bacterial proteins into host cells.
and V. vulnificus. V. parahaemolyticus should be considered a possible
The two major types of syndromes for which these etiologic agent in all cases of diarrhea that can be
species are responsible are gastrointestinal illness (due to linked epidemiologically to seafood consumption or to
Infections of the Alimentary Tract
CHAPTER 30
Diarrhea can result in severe dehydration. Many cases Cutaneous manifestations develop in most cases (usually
include abdominal cramps, nausea, vomiting, and fever. within 36 h of onset) and characteristically involve the
Like those with cholera, patients who are seriously extremities (the lower more often than the upper). In a
dehydrated should receive oral or IV fluids; the value of common sequence, erythematous patches are followed
antibiotics is not clear. by ecchymoses, vesicles, and bullae. In fact, sepsis and
Extraintestinal infections due to non-O1/O139 hemorrhagic bullous skin lesions suggest the diagnosis
V. cholerae commonly follow occupational or recre-
VIRAL GASTROENTERITIS
Acute infectious gastroenteritis is a common onset of vomiting and/or diarrhea, which may be
illness that affects persons of all ages worldwide. accompanied by fever, nausea, abdominal cramps,
It is a leading cause of mortality among children anorexia, and malaise. As shown in Table 31-2, sev-
in developing countries, accounting for an estimated eral features can help distinguish gastroenteritis caused
1.8 million deaths each year, and is responsible for up to by viruses from that caused by bacterial agents. How-
10–12% of all hospitalizations among children in indus- ever, the distinction based on clinical and epidemiologic
trialized countries, including the United States. Elderly parameters alone is often difficult, and laboratory tests
persons, especially those with debilitating health condi- may be required to confirm the diagnosis.
tions, are also at risk of severe complications and death
from acute gastroenteritis. Among healthy young adults,
acute gastroenteritis is rarely fatal but incurs substantial huMan CaliCiViruses
medical and social costs, including those of time lost
Etiologic agent
from work.
Several enteric viruses have been recognized as The Norwalk virus is the prototype strain of a group
important etiologic agents of acute infectious gastroen- of nonenveloped, small (27–40 nm), round, icosahedral
teritis (Table 31-1, Fig. 31-1). Although most viral viruses with relatively amorphous surface features on
gastroenteritis is caused by RNA viruses, the DNA visualization by electron microscopy. These viruses have
viruses that are occasionally involved (e.g., adenovirus been difficult to classify because they have not been
types 40 and 41) are included in this chapter. Illness adapted to cell culture, they often are shed in low titers
caused by these viruses is characterized by the acute for only a few days, and no animal models are available.
Table 31-1
Viral Causes of Gastroenteritis aMonG huMans
PriMary aGe CliniCal
Virus faMily GenoMe GrouP at risK seVerity deteCtion assays
Group A rotavirus Reoviridae Double-strand Children <5 years +++ EM, EIA
segmented RNA (commercial),
PAGE, RT-PCR
Norovirus Caliciviridae Positive-sense All ages ++ EM, EIA, RT-PCR
single-strand RNA
Sapovirus Caliciviridae Positive-sense Children <5 years + EM, EIA, RT-PCR
single-strand RNA
Astrovirus Astroviridae Positive-sense Children <5 years + EM, EIA, RT-PCR
single-strand RNA
Adenovirus Adenoviridae Double-strand DNA Children <5 years +/+ + EM, EIA
(types 40 and 41) (commercial), PCR
Abbreviations: EIA, enzyme immunoassay; EM, electron microscopy; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain
reaction; RT-PCR, reverse-transcription PCR.
299
300
Figure 31-1
Viral agents of gastroenteritis. NV, norovirus; SV, sapovirus.
Table 31-2
Characteristics of Gastroenteritis Caused by Viral and Bacterial Agents
Feature Viral Gastroenteritis Bacterial Gastroenteritis
SECTION IV
Setting Incidence similar in developing and More common in settings with poor hygiene and sanitation
developed countries
Infectious Low (10–100 viral particles) for most agents High (>105 bacteria) for Escherichia coli, Salmonella, Vibrio;
dose medium (102–105 bacteria) for Campylobacter jejuni; low
(10–100 bacteria) for Shigella
Seasonality In temperate climates, winter seasonality More common in summer or rainy months, particularly in
Infections of the Alimentary Tract
for most agents; year-round occurrence in developing countries with a high disease burden
tropical areas
Incubation 1–3 days for most agents; can be shorter for 1–7 days for common agents (e.g., Campylobacter, E. coli,
period norovirus Shigella, Salmonella); a few hours for bacteria producing
preformed toxins (e.g., Staphylococcus aureus, Bacillus cereus)
Reservoir Primarily humans Depending on species, human (e.g., Shigella, Salmonella),
animal (e.g., Campylobacter, Salmonella, E. coli), and water
(e.g., Vibrio) reservoirs exist.
Fever Common with rotavirus and norovirus; Common with agents causing inflammatory diarrhea (e.g.,
uncommon with other agents Salmonella, Shigella?)
Vomiting Prominent and can be the only presenting Common with bacteria producing preformed toxins; less
feature, especially in children prominent in diarrhea due to other agents
Diarrhea Common; nonbloody in almost all cases Prominent and frequently bloody with agents causing
inflammatory diarrhea
Duration 1–3 days for norovirus and sapovirus; 1–2 days for bacteria producing preformed toxins; 2–8 days for
2–8 days for other viruses most other bacteria
Diagnosis This is often a diagnosis of exclusion in Fecal examination for leukocytes and blood is helpful in
clinical practice. Commercial enzyme differential diagnosis. Culture of stool specimens, sometimes
immunoassays are available for detection of on special media, can identify several pathogens. Molecular
rotavirus and adenovirus, but identification techniques are useful epidemiologic tools but are not routinely
of other agents is limited to research and used in most laboratories.
public health laboratories.
Treatment Supportive therapy to maintain Supportive hydration therapy is adequate for most patients.
adequate hydration and nutrition should be Antibiotics are recommended for patients with dysentery
given. Antibiotics and antimotility agents caused by Shigella or Vibrio cholerae and for some patients
are contraindicated. with Clostridium difficile colitis.
Molecular cloning and characterization have demon- group antigens and are present on the gastroduode- 301
strated that the viruses have a single, positive-strand nal epithelium of individuals with the secretor phe-
RNA genome ∼7.5 kb in length and that they possess a notype may serve as ligands for the attachment of
single virion-associated protein—similar to that of typi- Norwalk virus. Additional studies must more fully elu-
cal caliciviruses—with a molecular mass of 60 kDa. On cidate norovirus-carbohydrate interactions, including
the basis of these molecular characteristics, these viruses potential strain-specific variations. After the infection
are presently classified in two genera belonging to the of volunteers, reversible lesions are noted in the upper
family Caliciviridae: the noroviruses and the sapoviruses jejunum, with broadening and blunting of the villi,
(previously called Norwalk-like viruses and Sapporo- shortening of the microvilli, vacuolization of the lin-
like viruses, respectively). ing epithelium, crypt hyperplasia, and infiltration of
the lamina propria by polymorphonuclear neutrophils
Epidemiology and lymphocytes. The lesions persist for at least 4 days
after the resolution of symptoms and are associated with
Infections with the Norwalk and related human malabsorption of carbohydrates and fats and a decreased
caliciviruses are common worldwide, and most level of brush-border enzymes. Adenylate cyclase activ-
adults have antibodies to these viruses. Antibody ity is not altered. No histopathologic changes are seen
is acquired at an earlier age in developing countries—a in the stomach or colon, but gastric motor function is
pattern consistent with the presumed fecal-oral mode of delayed, and this alteration is believed to contribute to
transmission. Infections occur year-round, although, in the nausea and vomiting that are typical of this illness.
temperate climates, a distinct increase has been noted in
cold-weather months. Noroviruses may be the most
Clinical manifestations
common infectious agents of mild gastroenteritis in the
community and affect all age groups, whereas sapovi- Gastroenteritis caused by Norwalk and related human
ruses primarily cause gastroenteritis in children. Norovi- caliciviruses has a sudden onset, following an average
ruses also cause traveler’s diarrhea, and outbreaks have incubation period of 24 h (range, 12–72 h). The ill-
CHAPTER 31
occurred among military personnel deployed to various ness generally lasts 12–60 h and is characterized by one
parts of the world. The limited data available indicate or more of the following symptoms: nausea, vomit-
that norovirus may be the second most common viral ing, abdominal cramps, and diarrhea. Vomiting is more
agent (after rotavirus) among young children and the prevalent among children, whereas a greater proportion
most common agent among older children and adults. of adults develop diarrhea. Constitutional symptoms are
For example, in a comprehensive evaluation of eight common, including headache, fever, chills, and myalgias.
Viral Gastroenteritis
enteric pathogens in patients with gastroenteritis in The stools are characteristically loose and watery, with-
England, three-fourths of patients had at least one out blood, mucus, or leukocytes. White cell counts are
pathogen detected in fecal specimens, and noroviruses generally normal; rarely, leukocytosis with relative lym-
were the most prevalent, detected in 36% of patients phopenia may be observed. Death is a rare outcome and
and 18% of healthy controls. Noroviruses are also rec- usually results from severe dehydration in vulnerable
ognized as the major cause of epidemics of gastroenteri- persons (e.g., elderly patients with debilitating health
tis worldwide. In the United States, >90% of outbreaks conditions).
of nonbacterial gastroenteritis are caused by noroviruses.
Virus is transmitted predominantly by the fecal-oral
route but is also present in vomitus. Because an inoculum Immunity
with very few viruses can be infectious, transmission can Approximately 50% of persons challenged with
occur by aerosolization, by contact with contaminated Norwalk virus become ill and acquire short-term
fomites, and by person-to-person contact. Viral shed- immunity against the infecting strain. Immunity to
ding and infectivity are greatest during the acute illness, Norwalk virus appears to correlate inversely with level
but challenge studies with Norwalk virus in volunteers of antibody; i.e., persons with higher levels of preexist-
indicate that viral antigen may be shed by asymptom- ing antibody to Norwalk virus are more susceptible to
atically infected persons and also by symptomatic per- illness. This observation suggests that some individuals
sons before the onset of symptoms and for several weeks have a genetic predisposition to illness. Specific ABO,
after the resolution of illness. Lewis, and secretor blood group phenotypes may influ-
ence susceptibility to norovirus infection.
Pathogenesis
Diagnosis
The exact sites and cellular receptors for attachment of
viral particles have not been determined. Data suggest Cloning and sequencing of the genomes of Norwalk
that carbohydrates that are similar to human histo-blood and several other human caliciviruses have allowed
302 the development of assays based on polymerase chain major groups of rotavirus (A through G); human illness
reaction (PCR) for detection of virus in stool and is caused primarily by group A and, to a much lesser
vomitus. Virus-like particles produced by expression extent, by groups B and C. Two outer-capsid proteins,
of capsid proteins in a recombinant baculovirus vec- VP7 (G-protein) and VP4 (P-protein), determine sero-
tor have been used to develop enzyme immunoassays type specificity, induce neutralizing antibodies, and
(EIAs) for detection of virus in stool or a serologic form the basis for binary classification of rotaviruses
response to a specific viral antigen. These newer diag- (G and P types). The segmented genome of rotavirus
nostic techniques are considerably more sensitive than allows genetic reassortment (i.e., exchange of genome
previous detection methods, such as electron micros- segments between viruses) during co-infection—a
copy, immune electron microscopy, and EIAs based on property that may play a role in viral evolution and has
reagents derived from humans. However, no currently been utilized in the development of reassortant animal-
available single assay can detect all human caliciviruses human rotavirus–based vaccines.
because of their great genetic and antigenic diversity. In
addition, the assays are still cumbersome and are avail- Epidemiology
able primarily in research laboratories, although they
are increasingly being adopted by public health labo- Worldwide, nearly all children are infected with
ratories for routine screening of fecal specimens from rotavirus by 3–5 years of age. Neonatal infections
patients affected by outbreaks of gastroenteritis. Com- are common but are often asymptomatic or mild,
mercial EIA kits, which are available in some European presumably because of protection from maternal anti-
countries and in Japan but not yet in the United States, body or breast-feeding. First infections after 3 months of
have limited sensitivity and usefulness in clinical practice age are likely to be symptomatic, and the incidence of
and are of greatest utility in outbreaks, in which many disease peaks among children 4–23 months of age.
specimens are tested and only a few need be positive to Reinfections are common, but the severity of disease
identify norovirus as the cause. decreases with each repeat infection. Therefore, severe
rotavirus infections are relatively uncommon among
SECTION IV
fluid therapy is indicated. No specific antiviral therapy is round, with less pronounced seasonal peaks than in
available. temperate settings, where rotavirus disease occurs pre-
dominantly during the cooler fall and winter months.
Before the introduction of rotavirus vaccine in the
Prevention United States, the rotavirus season each year began
in the Southwest during the autumn and early winter
Epidemic prevention relies on situation-specific mea-
(October through December) and migrated across the
sures, such as control of contamination of food and
continent, peaking in the Northeast during late winter
water, exclusion of ill food handlers, and reduction of
and spring (March through May). The reasons for this
person-to-person spread through good personal hygiene
characteristic pattern are not clear, but a recent study
and disinfection of contaminated fomites. The role
suggested a correlation with state-specific differences in
of immunoprophylaxis is not clear, given the lack of
birth rates, which could influence the rate of accumu-
long-term immunity from natural disease, but efforts to
lation of susceptible infants after each rotavirus season.
develop norovirus vaccines are ongoing.
After the implementation of routine vaccination of
U.S. infants against rotavirus in 2006, the onset of
Rotavirus the 2007–2008 and 2008–2009 rotavirus seasons was
delayed by 11 weeks and 6 weeks, respectively, and the
Etiologic agent seasons were shorter, lasting 14 and 17 weeks, respec-
Rotaviruses are members of the family Reoviridae. The tively, in comparison with a median of 26 weeks in
viral genome consists of 11 segments of double-strand 2000–2006 (Fig. 31-2). These changes in seasonal pat-
RNA that are enclosed in a triple-layered, nonen- terns of rotavirus activity were accompanied by declines
veloped, icosahedral capsid 75 nm in diameter. Viral in the number of detections of rotavirus by 64% and
protein 6 (VP6), the major structural protein, is the 60% in 2007–2008 and 2008–2009, respectively, from
target of commercial immunoassays and determines the figures for 2000–2006, as collected by a national
the group specificity of rotaviruses. There are seven network of sentinel laboratories.
70
2000–2006 Maximum
303
2000–2006 Median
60
2000–2006 Minimum
2007–2008 Season
40
30
20
10
0
27 29 31 33 35 37 39 41 43 45 47 49 51 1 3 5 7 9 11 13 15 17 19 21 23 25
Week of year
Figure 31-2
The maximal or minimal percentage of rotavirus-positive two consecutive weeks during which the percentage of stool
tests for 2000–2006 may have occurred during any of the six specimens testing positive for rotavirus was ≥10%. At the
baseline seasons. The onset of rotavirus season was defined top right, the dots bracket the rotavirus season from onset to
as the first of two consecutive weeks during which the per- end, and the diamond indicates the peak week during each
centage of stool specimens testing positive for rotavirus was period. (Adapted from Centers for Disease Control and
≥10%, and the end of the season was defined as the last of Prevention, 2009.)
CHAPTER 31
During episodes of rotavirus-associated diarrhea, small intestine. The loss of absorptive villous epi-
virus is shed in large quantities in stool (107–1012/g). thelium, coupled with the proliferation of secretory
Viral shedding detectable by EIA usually subsides within crypt cells, results in secretory diarrhea. Brush-border
1 week but may persist for >30 days in immunocom- enzymes characteristic of differentiated cells are
Viral Gastroenteritis
promised individuals. Viral shedding may be detected reduced, and this change leads to the accumulation of
for longer periods by sensitive molecular assays, such as unmetabolized disaccharides and consequent osmotic
PCR. The virus is transmitted predominantly through diarrhea. Studies in mice indicate that a nonstructural
the fecal-oral route. Spread through respiratory secre- rotavirus protein, NSP4, functions as an enterotoxin
tions, person-to-person contact, or contaminated envi- and contributes to secretory diarrhea by altering epithe-
ronmental surfaces has also been postulated to explain lial cell function and permeability. In addition, rotavi-
the rapid acquisition of antibody in the first 3 years of rus may evoke fluid secretion through activation of the
life, regardless of sanitary conditions. enteric nervous system in the intestinal wall. Recent
At least 10 different G serotypes of group A rotavirus data indicate that rotavirus antigenemia and viremia are
have been identified in humans, but only five types common among children with acute rotavirus infection,
(G1 through G4 and G9) are common. While human although the antigen and RNA levels in serum are sub-
rotavirus strains that possess a high degree of genetic stantially lower than those in stool.
homology with animal strains have been identified,
animal-to-human transmission appears to be uncommon. Clinical manifestations
Group B rotaviruses have been associated with
several large epidemics of severe gastroenteritis The clinical spectrum of rotavirus infection ranges
among adults in China since 1982 and have also from subclinical infection to severe gastroenteritis lead-
been identified in India. Group C rotaviruses have been ing to life-threatening dehydration. After an incuba-
associated with a small proportion of pediatric gastroen- tion period of 1–3 days, the illness has an abrupt onset,
teritis cases in several countries worldwide. with vomiting frequently preceding the onset of
diarrhea. Up to one-third of patients may have a tem-
perature of >39°C. The stools are characteristically
Pathogenesis
loose and watery and only infrequently contain red or
Rotaviruses infect and ultimately destroy mature white cells. Gastrointestinal symptoms generally resolve
enterocytes in the villous epithelium of the proximal in 3–7 days.
304 Respiratory and neurologic features in children with
rotavirus infection have been reported, but causal asso- children with chronic symptomatic rotavirus disease,
ciations have not been proven. Moreover, rotavirus orally administered immunoglobulins or colostrum may
infection has been associated with a variety of other result in the resolution of symptoms, but the best choices
clinical conditions (e.g., sudden infant death syndrome, regarding agents and their doses have not been well
necrotizing enterocolitis, intussusception, Kawasaki’s studied, and treatment decisions are often empirical.
disease, and type 1 diabetes), but no causal relationship
has been confirmed with any of these syndromes.
Prevention
Rotavirus does not appear to be a major oppor-
tunistic pathogen in children with HIV infection. In Efforts to develop rotavirus vaccines were pursued
severely immunodeficient children, rotavirus can cause because it was apparent—given the similar rates in less-
protracted diarrhea with prolonged viral excretion and, developed and industrialized nations—that improve-
in rare instances, can disseminate systemically. Persons ments in hygiene and sanitation were unlikely to reduce
who are immunosuppressed for bone marrow transplan- disease incidence. The first rotavirus vaccine licensed in
tation are also at risk for severe or even fatal rotavirus the United States in 1998 was withdrawn from the market
disease. within 1 year because it was linked with intussuscep-
tion, a severe bowel obstruction.
In 2006, promising safety and efficacy results for
Immunity two new rotavirus vaccines were reported from
Protection against rotavirus disease is correlated with large clinical trials conducted in North America,
the presence of virus-specific secretory IgA antibodies Europe, and Latin America. Both vaccines are now rec-
in the intestine and, to some extent, the serum. Because ommended for routine immunization of all U.S. infants,
virus-specific IgA production at the intestinal surface is and their use has rapidly led to a decline in rotavirus
short lived, complete protection against disease is only hospitalizations and emergency department visits at
temporary. However, each infection and subsequent hospitals across the United States. In Mexico, a decline
SECTION IV
reinfection confers progressively greater immunity; thus in deaths from childhood diarrhea following introduc-
severe disease is most common among young children tion of rotavirus vaccines has been documented. Fur-
with first or second infections. Immunologic memory is thermore, postmarketing surveillance information has
believed to be important in the attenuation of disease not revealed an association of these vaccines with any
severity upon reinfection. serious adverse events (including intussusception),
although a risk of low magnitude cannot be excluded
Infections of the Alimentary Tract
Figure 31-3
Rotavirus mortality rates by country, per 100,000 children <5 years of age. (Reproduced with permission from UD Parashar
et al: J Infect Dis 200:S9, 2009.)
of rotavirus vaccines was moderate (50–75%) in these methods to confirm and characterize strains will permit
settings when compared with that in industrialized more comprehensive assessment of the etiologic role of
countries. Nevertheless, even a moderately efficacious these agents.
Toroviruses are 100- to 140-nm, enveloped, positive-
CHAPTER 31
rotavirus vaccine would be likely to have substantial
public health benefits in these areas with a high disease strand RNA viruses that are recognized as causes of
burden. Given these considerations, in April 2009 the gastroenteritis in horses (Berne virus) and cattle (Breda
World Health Organization recommended the use of virus). Their role as a cause of diarrhea in humans is still
rotavirus vaccines in all countries worldwide. unclear, but studies from Canada have demonstrated
associations between torovirus excretion and both nos-
ocomial gastroenteritis and necrotizing enterocolitis in
Viral Gastroenteritis
Other Viral Agents of neonates. These associations require further evaluation.
Gastroenteritis Picobirnaviruses are small, bisegmented, double-strand
Enteric adenoviruses of serotypes 40 and 41 belonging RNA viruses that cause gastroenteritis in a variety of
to subgroup F are 70- to 80-nm viruses with double- animals. Their role as primary causes of gastroenteritis in
strand DNA that cause ∼2–12% of all diarrhea episodes humans remains unclear, but several studies have found
in young children. Unlike adenoviruses that cause an association between picobirnaviruses and gastro
respiratory illness, enteric adenoviruses are difficult to enteritis in HIV-infected adults.
cultivate in cell lines, but they can be detected with Several other viruses (e.g., enteroviruses, reoviruses,
commercially available EIAs. pestiviruses, and parvovirus B) have been identified in
Astroviruses, 28- to 30-nm viruses with a character- the feces of patients with diarrhea, but their etiologic
istic icosahedral structure, contain a positive-sense, role in gastroenteritis has not been proven. Diarrhea
single-strand RNA. At least seven serotypes have has also been noted as a manifestation of infection with
been identified, of which serotype 1 is most common. recently recognized viruses that primarily cause severe
Astroviruses are primarily pediatric pathogens, caus- respiratory illness: the severe acute respiratory syn-
ing ∼2–10% of cases of mild to moderate gastroenteri- drome–associated coronavirus (SARS-CoV), influenza
tis in children. The availability of simple immunoas- A/H5N1 virus, and the current pandemic strain of
says to detect virus in fecal specimens and of molecular influenza A/H1N1 virus.
chAPter 32
AmebIAsIs
definition
Amebiasis is infection with the parasitic intestinal pro-
tozoan Entamoeba histolytica (the “tissue-lysing ameba”).
Most infections are probably asymptomatic, but
E. histolytica can cause disease ranging from dysentery to
extraintestinal infections, including liver abscesses.
CHAPTER 32
serum from men than by serum from women has been cysteine proteinase activity, via either direct gene
reported. targeting or chemical inhibitors, significantly reduces
E. histolytica infections are most common in disease. The ultimate effect of all these amebic virulence
areas of the world where poor sanitation and factors on the human colon is the production of small
crowding compromise the barriers to contami- ulcers that have heaped borders and contain focal areas
nation of food and drinking water with human feces. of epithelial cell loss, a modest inflammatory response,
needs further clarification. Studies of children in a the liver. Most individuals with amebic liver abscess
highly endemic area have suggested that prior E. his- do not have concurrent signs or symptoms of coli-
tolytica intestinal infection may stimulate mucosal IgA tis, and most do not have E. histolytica trophozoites in
antibodies to amebic antigens, thereby reducing the their stools. The exceptions are individuals with fulmi-
likelihood of subsequent infections; this protection is nant amebic colitis, in which concurrent amebic liver
relatively short lived. In contrast, among individuals in abscess is not uncommon. Disease can arise from months
an area of Vietnam with a high prevalence of amebic to years after travel to or residence in an endemic area;
liver abscess, a prior episode of disease did not reduce therefore, a careful travel history is key in making the
the risk of a second case, despite the presence of serum diagnosis. The classic presentations of amebic liver
antibodies. Studies of animal models suggest that cell- abscess are right-upper-quadrant pain, fever, and hepatic
mediated immunity may play a role in host defense, tenderness. The pace of disease is usually acute, with
and glucocorticoid use has been associated with worse symptoms lasting <10 days. However, a more chronic
outcomes in patients with amebic colitis. However, presentation, with weight loss and anorexia as prominent
individuals with HIV/AIDS do not appear to be at accompanying features, does occur. Jaundice is unusual,
increased risk for infection with E. histolytica, and there but dullness and rales at the right lung base (secondary to
is no evidence that they develop more severe disease pleural effusion) are common. The most common labo-
than do immunocompetent hosts. ratory findings are leukocytosis (without eosinophilia),
an elevated alkaline phosphatase level, mild anemia, and
an elevated erythrocyte sedimentation rate.
Clinical Syndromes
Intestinal amebiasis Other extraintestinal complications
of amebiasis
Most patients harboring Entamoeba species are asymp-
tomatic, but individuals with E. histolytica infection can Right-sided pleural effusions and atelectasis are com-
develop disease. Symptoms of amebic colitis generally mon in cases of amebic liver abscess and generally
require no treatment. However, the abscess ruptures this method still is not feasible for clinical diagnosis in 309
through the diaphragm in ∼10% of patients, causing most endemic areas. Commercially available tests that
pleuropulmonary amebiasis. Suggestive symptoms are use enzyme-linked immunosorbent assays (ELISAs)
sudden-onset cough, pleuritic chest pain, and short- or immunochromatographic techniques to detect
ness of breath. In some patients, pleuropulmonary Entamoeba antigens are less expensive and more easily
amebiasis is the presenting manifestation of amebic performed and are being used with increasing frequency.
liver abscess and may be confused with bacterial pneu- Greater sensitivity than microscopy and the ability to
monia and empyema. A dramatic complication is the detect E. histolytica specifically are claimed by some of
development of a hepatobronchial fistula, in which the leading kits, representing significant advantages over
patients can cough up the contents of the liver abscess— microscopy. Unfortunately, not all clinical studies have
copious amounts of brown sputum that may contain supported these claims, concerns have been raised about
E. histolytica trophozoites. In ∼1–3% of cases, the amebic the specificity of the tests in nonendemic areas, and the
liver abscess ruptures into the peritoneum, and perito- ELISAs are less sensitive and specific than are PCR-
neal signs and shock develop. Even rarer is rupture of an based diagnostics. At this point, antigen detection–based
amebic liver abscess into the pericardium; the signs and ELISAs that can specifically identify E. histolytica in stool
symptoms are those commonly seen with pericarditis probably represent the best choice in endemic areas;
(chest pain, pericardial rub, dyspnea, tachypnea, or car- however, the results of any of these diagnostic tests need
diac tamponade), and nearly 30% of cases end in death. to be interpreted in light of clinical presentation, and a
Cerebral abscesses complicate <0.1% of cases of amebic second confirmatory test (e.g., microscopy and/or ame-
liver abscess and are associated with the sudden onset of bic serology) may be prudent. In instances in which
headache, vomiting, seizures, and mental status changes amebiasis is suspected on clinical grounds in a patient
and a high mortality rate. Cutaneous amebiasis (which with acute colitis but initial stool samples are negative,
usually involves the anal and perianal regions), genital colonoscopy with examination of brushings or mucosal
disease (including rectovaginal fistulas), and urinary tract biopsies for E. histolytica trophozoites may be helpful in
lesions are rare but reported complications of amebiasis. making the diagnosis or in identifying other diseases,
CHAPTER 32
such as inflammatory bowel disease or pseudomembra-
nous colitis.
Diagnostic Tests The diagnosis of amebic liver abscess is based on the
detection (generally by ultrasound or CT; Fig. 32-4)
The diagnosis of amebic colitis has traditionally been of one or more space-occupying lesions in the liver and
based on the demonstration of E. histolytica trophozo- a positive serologic test for antibodies to E. histolytica
bic serology help differentiate amebic colitis from these was significantly different for patients who underwent
other entities. Amebomas may be confused with colonic percutaneous radiography-guided aspiration of the
carcinoma; several case reports describe instances in abscess accompanied by medical therapy than for those
which amebomas and associated liver abscesses were ini- who received medical therapy alone. Aspiration should
tially considered to be colon cancer with liver metas- be reserved for individuals in whom pyogenic abscess
tases. Amebic liver abscess must be distinguished from or a bacterial superinfection is suspected but whose
Infections of the Alimentary Tract
pyogenic liver abscess, echinococcal cysts, and primary diagnosis is uncertain, for patients failing to respond to
or metastatic liver tumors. It is difficult to differentiate tinidazole or metronidazole (i.e., those who have persis
pyogenic from amebic liver abscesses on purely clinical tent fever or abdominal pain after 4 days of treatment),
grounds, but amebic serology is usually the key test in for individuals with large liver abscesses in the left lobe
excluding or diagnosing amebic liver abscess. Abscesses (because of the risk of rupture into the pericardium),
that rupture into the pleural space may be accompanied and for patients whose large abscesses and accelerated
by cough, sputum production, and dyspnea and may clinical course raise concerns about imminent rupture.
initially be diagnosed as bronchopneumonia. In contrast, aspiration and/or percutaneous catheter
drainage improves outcomes in patients with pleuro
pulmonary amebiasis and empyema (where amebic
Treatment Amebiasis liver abscesses have ruptured into the pleural space),
and percutaneous catheter or surgical drainage is abso
The nitroimidazole compounds tinidazole and metro lutely indicated for cases of amebic pericarditis. Rupture
nidazole are the drugs of choice for the treatment of of an amebic liver abscess into the peritoneum is gener
amebic colitis and amebic liver abscess (Table 32-1). ally managed conservatively, with medical therapy and
To date, E. histolytica has not demonstrated resistance to percutaneous catheter drainage of fluid collections as
any of the commonly used agents—a situation that greatly needed.
simplifies treatment. Tinidazole appears to be better Neither metronidazole nor tinidazole reaches high
tolerated and slightly more effective than metronidazole levels in the gut lumen; therefore, patients with amebic
for amebic colitis and amebic liver abscess. Metronida colitis or amebic liver abscess should also receive treat
zole is available as a parenteral formulation for patients ment with a luminal agent (paromomycin or iodoquinol)
who cannot take oral medications. Whenever possible, to ensure eradication of the infection (Table 32-1).
fulminant amebic colitis is managed conservatively, Paromomycin is the preferred agent. Asymptomatic
even in the presence of perforation, with the addition individuals with documented E. histolytica infection
311
should be treated because of the risks of developing
amebic colitis or amebic liver abscess in the future and
of transmitting the infection to others. Paromomycin
or iodoquinol in the doses listed in the table should be
used in these cases.
Nitazoxanide, a broad-spectrum antiparasitic drug,
is efficacious against E. histolytica trophozoites in both
tissue and gut lumen and may become an important
addition to the therapeutic repertoire. However, clini
cal experience with nitazoxanide for the treatment of
E. histolytica infection remains limited at this point.
CHAPTER 32
of increased intracranial pressure, scant purulent material
Infection with Free-Living Amebas that may contain a few amebas, and marked leptomen-
ingitis (Fig. 32-5).
In contrast to the trophozoites of the parasitic The diagnosis of PAM is based on the finding of
E. histolytica, which can survive only in humans motile Naegleria trophozoites in wet mounts of freshly
and some other primate hosts, free-living amebas obtained cerebrospinal fluid (CSF). Laboratory findings
of the genera Naegleria, Acanthamoeba, and Balamuthia in the CSF resemble those in bacterial meningitis, with
death. Pathologic findings in the brain include cerebral involves topical administration of a cationic antiseptic
edema and multiple areas of necrosis and hemorrhage. agent such as a biguanide or chlorhexidine, with or
Amebic trophozoites and cysts are scattered through- without a diamidine agent. The persistence of the cyst
out the tissue and are often located near blood vessels form of Acanthamoeba complicates treatment, and long
(Fig. 32-6). Multinucleated giant cells forming granu- durations of therapy (6 months to 1 year) are required.
lomas give the syndrome its name but are seen less In severe cases, particularly when vision is threatened
Infections of the Alimentary Tract
often in highly immunocompromised patients. The or already diminished, penetrating keratoplasty may be
diagnosis is usually made by detection of Acanthamoeba indicated.
trophozoites or cysts in biopsy specimens; a fluores-
cein-labeled antiserum is available from the Centers for
Balamuthia Infections
Disease Control and Prevention (CDC) to help identify
Acanthamoeba in microscopic sections. Acanthamoeba tro- Balamuthia mandrillaris is a free-living ameba that causes
phozoites and cysts are occasionally seen in CSF, but meningoencephalitis in both immunosuppressed and
samples from most patients with granulomatous ame- immunocompetent hosts, particularly children and the
bic encephalitis show mild lymphocyte-predominant elderly. The disease presents similarly to granulomatous
pleocytosis, slightly elevated protein levels, and nor- amebic encephalitis caused by Acanthamoeba, and essen-
mal or slightly depressed glucose concentrations with- tially all of the points made above with regard to the lat-
out the presence of amebas. CT findings vary, with ter organism—in terms of clinical presentation, pathologic
hypodense lesions that resemble infarcts in some patients findings, and lack of proven therapies—apply to
and multiple enhancing lesions that resemble toxoplas- Balamuthia infections as well. Most cases are identified post
mosis in others. Unfortunately, there are no therapies mortem; the few cases identified before death have been
with proven efficacy against this disease, and almost all found during histologic examination of brain biopsy speci-
cases have ended in death. There have been case reports mens. A specific antiserum is available from the CDC to
of survivors treated with multidrug combinations aid in identifying B. mandrillaris in clinical specimens.
chaPTEr 33
Peter F. Weller
ProToZoaL inFEcTions
giarDiasis
Giardia intestinalis (also known as G. lamblia or
G. duodenalis) is a cosmopolitan protozoal para- Excystation follows
site that inhabits the small intestines of humans exposure to stomach acid
and intestinal proteases,
and other mammals. Giardiasis is one of the most com- releasing trophozoite forms
that multiply by binary
mon parasitic diseases in both developed and developing fission and reside in the
Causes: Asymptomatic infection,
acute diarrhea, or chronic diarrhea
countries worldwide, causing both endemic and epi- upper small bowel adherent and malabsorption. Small bowel may
to enterocytes. demonstrate villous blunting, crypt
demic intestinal disease and diarrhea. hypertrophy, and mucosal inflammation.
fecally derived Giardia cysts; outmoded water systems isolates may contribute to different courses of infection.
are subject to cross-contamination from leaking sewer
lines. The efficacy of water as a means of transmission is Clinical manifestations
enhanced by the small infectious inoculum of Giardia,
the prolonged survival of cysts in cold water, and the Disease manifestations of giardiasis range from asymp-
resistance of cysts to killing by routine chlorination tomatic carriage to fulminant diarrhea and malabsorption.
Infections of the Alimentary Tract
methods that are adequate for controlling bacteria. Most infected persons are asymptomatic, but in epidem-
Viable cysts can be eradicated from water by either ics the proportion of symptomatic cases may be higher.
boiling or filtration. In the United States, Giardia (like Symptoms may develop suddenly or gradually. In per-
Cryptosporidium; see below) is a common cause of sons with acute giardiasis, symptoms develop after an
waterborne epidemics of gastroenteritis. incubation period that lasts at least 5–6 days and usually
Giardia is common in developing countries, and 1–3 weeks. Prominent early symptoms include diarrhea,
infections may be acquired by travelers. abdominal pain, bloating, belching, flatus, nausea, and
Giardia parasites genotypically similar to those in vomiting. Although diarrhea is common, upper intes-
humans are found in many mammals, including beavers tinal manifestations such as nausea, vomiting, bloating,
from reservoirs implicated in epidemics. The impor- and abdominal pain may predominate. The duration
tance of dogs and cats as sources of infection for humans of acute giardiasis is usually >1 week, although diar-
is unclear. rhea often subsides. Individuals with chronic giardiasis
Giardiasis, like cryptosporidiosis, creates a significant may present with or without having experienced an
economic burden because of the costs incurred in the antecedent acute symptomatic episode. Diarrhea is not
installation of water filtration systems required to pre- necessarily prominent, but increased flatus, loose stools,
vent waterborne epidemics, in the management of sulfurous belching, and (in some instances) weight loss
epidemics that involve large communities, and in the occur. Symptoms may be continual or episodic and can
evaluation and treatment of endemic infections. persist for years. Some persons who have relatively mild
symptoms for long periods recognize the extent of their
discomfort only in retrospect. Fever, the presence of
Pathophysiology blood and/or mucus in the stools, and other signs and
The reasons that some, but not all, infected patients symptoms of colitis are uncommon and suggest a differ-
develop clinical manifestations and the mechanisms by ent diagnosis or a concomitant illness. Symptoms tend
which Giardia causes alterations in small-bowel function to be intermittent yet recurring and gradually debilitat-
are largely unknown. Although trophozoites adhere to ing, in contrast with the acute disabling symptoms asso-
the epithelium, they do not cause invasive or locally ciated with many enteric bacterial infections. Because
Table 33-1 315
Diagnosis of Intestinal Protozoal Infections
Fecal Acid-Fast Stool Antigen
Parasite Stool O+Pa Stain Immunoassays Other
Giardia + +
Cryptosporidium – + +
Isospora – +
Cyclospora – +
Microsporidia – Special fecal stains, tissue
biopsies
a
O+P, ova and parasites.
CHAPTER 33
tinal diseases, such as that occurring in cystic fibrosis. toms probably reflect delayed regeneration of intestinal
In patients with AIDS, Giardia can cause enteric illness brush-border enzymes. Continued infection should be
that is refractory to treatment. documented by stool examinations before treatment is
repeated. Patients who remain infected after repeated
treatments should be evaluated for reinfection through
Diagnosis family members, close personal contacts, and environ-
distribution of infection can be spotty within the prin- papillotomy or T-tube placement. Prevention requires
cipal site of infection, the small bowel. Cryptosporidia minimizing exposure to infectious oocysts in human or
are found in the pharynx, stomach, and large bowel of animal feces. Use of submicron water filters may mini-
some patients and at times in the respiratory tract. Espe- mize acquisition of infection from drinking water.
cially in patients with AIDS, involvement of the biliary
tract can cause papillary stenosis, sclerosing cholangitis,
Infections of the Alimentary Tract
or cholecystitis. Isosporiasis
The coccidian parasite Isospora belli causes human intes-
Clinical manifestations tinal disease. Infection is acquired by the consumption
Asymptomatic infections can occur in both immunocom- of oocysts, after which the parasite invades intestinal
petent and immunocompromised hosts. In immunocom- epithelial cells and undergoes both sexual and asexual
petent persons, symptoms develop after an incubation cycles of development. Oocysts excreted in stool are
period of ∼1 week and consist principally of watery non- not immediately infectious but must undergo further
bloody diarrhea, sometimes in conjunction with abdomi- maturation.
nal pain, nausea, anorexia, fever, and/or weight loss. In Although I. belli infects many animals, little is
these hosts, the illness usually subsides after 1–2 weeks. In known about the epidemiology or prevalence of
contrast, in immunocompromised hosts (especially those this parasite in humans. It appears to be most
with AIDS and CD4+ T cell counts <100/μL), diarrhea common in tropical and subtropical countries. Acute
can be chronic, persistent, and remarkably profuse, caus- infections can begin abruptly with fever, abdominal
ing clinically significant fluid and electrolyte depletion. pain, and watery nonbloody diarrhea and can last for
Stool volumes may range from 1 to 25 L/d. Weight loss, weeks or months. In patients who have AIDS or are
wasting, and abdominal pain may be severe. Biliary tract immunocompromised for other reasons, infections
involvement can manifest as midepigastric or right-upper- often are not self-limited but rather resemble crypto-
quadrant pain. sporidiosis, with chronic, profuse watery diarrhea.
Eosinophilia, which is not found in other enteric proto-
zoan infections, may be detectable. The diagnosis
Diagnosis
(Table 33-1) is usually made by detection of the large
(Table 33-1) Evaluation starts with fecal examina- (∼25-μm) oocysts in stool by modified acid-fast stain-
tion for small oocysts, which are smaller (4–5 μm in ing. Oocyst excretion may be low-level and intermit-
diameter) than the fecal stages of most other parasites. tent; if repeated stool examinations are unrevealing,
sampling of duodenal contents by aspiration or small- Microsporidiosis 317
bowel biopsy (often with electron-microscopic exami-
nation) may be necessary. Microsporidia are obligate intracellular spore-forming
protozoa that infect many animals and cause disease
in humans, especially as opportunistic pathogens in
Treatment Isosporiasis AIDS. Microsporidia are members of a distinct phylum,
Microspora, which contains dozens of genera and hun-
Trimethoprim-sulfamethoxazole (TMP-SMX, 160/800 mg dreds of species. The various microsporidia are differen-
four times daily for 10 days; and for HIV-infected tiated by their developmental life cycles, ultrastructural
patients, then three times daily for 3 weeks) is effective. features, and molecular taxonomy based on ribosomal
For patients intolerant of sulfonamides, pyrimethamine RNA. The complex life cycles of the organisms result
(50–75 mg/d) can be used. Relapses can occur in per- in the production of infectious spores (Fig. 33-3).
sons with AIDS and necessitate maintenance therapy Currently, eight genera of microsporidia—Encephalitozoon,
with TMP-SMX (160/800 mg three times per week). Pleistophora, Nosema, Vittaforma, Trachipleistophora,
Brachiola, Microsporidium, and Enterocytozoon—are rec-
ognized as causes of human disease. Although some
Cyclosporiasis microsporidia are probably prevalent causes of self-
Cyclospora cayetanensis, a cause of diarrheal illness, is glob- limited or asymptomatic infections in immunocompetent
ally distributed: illness due to C. cayetanensis has been patients, little is known about how microsporidiosis is
reported in the United States, Asia, Africa, Latin America, acquired.
and Europe. The epidemiology of this parasite has not Microsporidiosis is most common among patients
yet been fully defined, but waterborne transmission and with AIDS, less common among patients with other
food-borne transmission by basil and imported raspber- types of immunocompromise, and rare among immu-
ries have been recognized. The full spectrum of illness nocompetent hosts. In patients with AIDS, intestinal
attributable to Cyclospora has not been delineated. Some infections with Enterocytozoon bieneusi and Encepha-
CHAPTER 33
patients may harbor the infection without symptoms, litozoon (formerly Septata) intestinalis are recognized
but many have diarrhea, flulike symptoms, and flatu- to contribute to chronic diarrhea and wasting; these
lence and belching. The illness can be self-limited, can infections are found in 10–40% of patients with
wax and wane, or in many cases can involve prolonged chronic diarrhea. Both organisms have been found
diarrhea, anorexia, and upper gastrointestinal symptoms, in the biliary tracts of patients with cholecystitis.
with sustained fatigue and weight loss in some instances. E. intestinalis may also disseminate to cause fever,
diarrhea, sinusitis, cholangitis, and bronchiolitis. In
Intracellular
multiplication
via merogony and
Encephalitozoon intestinalis
sporogony
in epithelial cells, endothelial
cells, or macrophages
While E. bieneusi is
Presumed primarily in the gastrointestinal tract,
ingestion or other species may invade the lung
respiratory or eye or disseminate to cause: Spore-laden
aquisition of host epithelial
Chronic diarrhea
spores cells sloughed
Cholangitis
Sinusitis into lumina of
Bronchitis gastrointestinal,
Nephritis respiratory, or
Cystitis/prostatitis genitourinary tract
Keratoconjunctivitis
Encephalitis
SECTION IV
Person-to-person,
zoonotic,
water-borne, or
food-borne
transmission? Sloughed cells
degenerate;
spores shed in
bodily fluids
Infections of the Alimentary Tract
Figure 33-3
Life cycle of microsporidia. (Reprinted from RL Guerrant et al: Tropical Infectious Disease: Principles, Pathogens and Practice,
2nd ed, 2006, p 1128, with permission from Elsevier Science.)
Other Intestinal Protozoa diarrhea, and a few develop more fulminant dysen-
tery. In symptomatic individuals, the pathology in the
Balantidiasis
bowel—both gross and microscopic—is similar to that
Balantidium coli is a large ciliated protozoal parasite seen in amebiasis, with varying degrees of mucosal inva-
that can produce a spectrum of large-intestinal sion, focal necrosis, and ulceration. Balantidiasis, unlike
disease analogous to amebiasis. The parasite is amebiasis, does not spread hematogenously to other
widely distributed in the world. Since it infects pigs, organs. The diagnosis is made by detection of the
cases in humans are more common where pigs are raised. trophozoite stage in stool or sampled colonic tissue.
Infective cysts can be transmitted from person to person Tetracycline (500 mg four times daily for 10 days) is an
and through water, but many cases are due to the inges- effective therapeutic agent.
tion of cysts derived from porcine feces in association
with slaughtering, with use of pig feces for fertilizer, or
Blastocystis hominis infection
with contamination of water supplies by pig feces.
Ingested cysts liberate trophozoites, which reside B. hominis, while believed by some to be a protozoan
and replicate in the large bowel. Many patients remain capable of causing intestinal disease, remains an organ-
asymptomatic, but some have persisting intermittent ism of uncertain pathogenicity. Some patients who pass
B. hominis in their stools are asymptomatic, whereas among those with other sexually transmitted diseases 319
others have diarrhea and associated intestinal symptoms. (Chap. 130).
Diligent evaluation reveals other potential bacterial,
viral, or protozoal causes of diarrhea in some but not all
patients with symptoms. Because the pathogenicity of Clinical manifestations
B. hominis is uncertain and because therapy for Blastocys- Many men infected with T. vaginalis are asymptomatic,
tis infection is neither specific nor uniformly effective, although some develop urethritis and a few have epi-
patients with prominent intestinal symptoms should be didymitis or prostatitis. In contrast, infection in women,
fully evaluated for other infectious causes of diarrhea. which has an incubation period of 5–28 days, is usu-
If diarrheal symptoms associated with Blastocystis are ally symptomatic and manifests with malodorous vaginal
prominent, either metronidazole (750 mg thrice daily discharge (often yellow), vulvar erythema and itching,
for 10 days) or TMP-SMX (160 mg/800 mg twice dysuria or urinary frequency (in 30–50% of patients),
daily for 7 days) can be used. and dyspareunia. These manifestations, however, do not
clearly distinguish trichomoniasis from other types of
Dientamoeba fragilis infection infectious vaginitis.
D. fragilis is unique among intestinal protozoa in that it
has a trophozoite stage but not a cyst stage. How Diagnosis
trophozoites survive to transmit infection is not known. Detection of motile trichomonads by microscopic
When symptoms develop in patients with D. fragilis examination of wet mounts of vaginal or prostatic
infection, they are generally mild and include intermit- secretions has been the conventional means of diag-
tent diarrhea, abdominal pain, and anorexia. The diag- nosis. Although this approach provides an immediate
nosis is made by the detection of trophozoites in stool; diagnosis, its sensitivity for the detection of T. vaginalis
the lability of these forms accounts for the greater yield is only ∼50–60% in routine evaluations of vaginal secre-
when fecal samples are preserved immediately after tions. Direct immunofluorescent antibody staining is
CHAPTER 33
collection. Since fecal excretion rates vary, examination more sensitive (70–90%) than wet-mount examinations.
of several samples obtained on alternate days increases T. vaginalis can be recovered from the urethra of both
the rate of detection. Iodoquinol (650 mg three times males and females and is detectable in males after pros-
daily for 20 days), paromomycin (25–35 mg/kg per day tatic massage. Culture of the parasite is the most sensi-
in three doses for 7 days), metronidazole (500–750 mg tive means of detection; however, facilities for culture
three times daily for 10 days), or tetracycline (500 mg are not generally available, and detection of the organ-
More than a billion persons worldwide are infected immune evasion and host immune responses to these
with one or more species of intestinal nematodes. infections have not been elucidated in detail.
Table 34-1 summarizes biologic and clinical features of
infections due to the major intestinal parasitic nematodes.
These parasites are most common in regions with poor
fecal sanitation, particularly in resource-poor countries aScariaSiS
in the tropics and subtropics, but they have also been A. lumbricoides is the largest intestinal nematode para-
seen with increasing frequency among immigrants and site of humans, reaching up to 40 cm in length. Most
refugees to resource-rich countries. Although nema- infected individuals have low worm burdens and are
tode infections are not usually fatal, they contribute to asymptomatic. Clinical disease arises from larval migra-
malnutrition and diminished work capacity. It is inter- tion in the lungs or effects of the adult worms in the
esting that these helminth infections may protect some intestines.
individuals from allergic disease. Humans may on occa-
sion be infected with nematode parasites that ordinar-
ily infect animals; these zoonotic infections produce dis- life cycle
eases such as trichostrongyliasis, anisakiasis, capillariasis, Adult worms live in the lumen of the small intestine.
and abdominal angiostrongyliasis. Mature female Ascaris worms are extraordinarily fecund,
Intestinal nematodes are roundworms; they range in each producing up to 240,000 eggs a day, which pass
length from 1 mm to many centimeters when mature with the feces. Ascarid eggs, which are remarkably resis-
(Table 34-1). Their life cycles are complex and highly tant to environmental stresses, become infective after
varied; some species, including Strongyloides stercoralis several weeks of maturation in the soil and can remain
and Enterobius vermicularis, can be transmitted directly infective for years. After infective eggs are swallowed,
from person to person, while others, such as Ascaris larvae hatched in the intestine invade the mucosa,
lumbricoides, Necator americanus, and Ancylostoma duodenale, migrate through the circulation to the lungs, break into
require a soil phase for development. Because most hel- the alveoli, ascend the bronchial tree, and return—
minth parasites do not self-replicate, the acquisition of through swallowing—to the small intestine, where they
a heavy burden of adult worms requires repeated expo- develop into adult worms. Between 2 and 3 months
sure to the parasite in its infectious stage, whether larval elapse between initial infection and egg production.
or egg. Hence, clinical disease, as opposed to asymp- Adult worms live for 1–2 years.
tomatic infection, generally develops only with pro-
longed residence in an endemic area and is typically
epidemiology
related to infection intensity. In persons with marginal
nutrition, intestinal helminth infections may impair Ascaris is widely distributed in tropical and sub-
growth and development. Eosinophilia and elevated tropical regions as well as in other humid areas,
serum IgE levels are features of many helminth infec- including the rural southeastern United States.
tions and, when unexplained, should always prompt Transmission typically occurs through fecally contami-
a search for intestinal helminths. Significant protec- nated soil and is due either to a lack of sanitary facilities
tive immunity to intestinal nematodes appears not to or to the use of human feces as fertilizer. With their
develop in humans, although mechanisms of parasite propensity for hand-to-mouth fecal carriage, younger
320
Table 34-1 321
Major Human Intestinal Parasitic Nematodes
Parasitic Nematode
Necator
americanus,
Ascaris Ancylostoma Trichuris Enterobius
lumbricoides duodenale Strongyloides trichiura vermicularis
Feature (Roundworm) (Hookworm) stercoralis (Whipworm) (Pinworm)
CHAPTER 34
worm) 4000–10,000
A. duodenale:
10,000–25,000
Principal symptoms Rarely Iron-deficiency Gastrointestinal Gastrointestinal Perianal
gastrointesti- anemia in heavy symptoms; symptoms, pruritus
nal or biliary infection malabsorption anemia
obstruction or sepsis in
a
Time from infection to egg production by mature female worm.
children are most affected. Infection outside endemic that is aggravated by coughing or deep inspiration.
areas, though uncommon, can occur when eggs on Dyspnea and blood-tinged sputum are less common.
transported vegetables are ingested. Fever is usually reported. Eosinophilia develops during
this symptomatic phase and subsides slowly over weeks.
Chest x-rays may reveal evidence of eosinophilic pneu-
Clinical features
monitis (Löffler’s syndrome), with rounded infiltrates
During the lung phase of larval migration, ∼9–12 days a few millimeters to several centimeters in size. These
after egg ingestion, patients may develop an irritating infiltrates may be transient and intermittent, clearing
nonproductive cough and burning substernal discomfort after several weeks. Where there is seasonal transmission
322 of the parasite, seasonal pneumonitis with eosinophilia
may develop in previously infected and sensitized hosts.
Hookworm
In established infections, adult worms in the small Two hookworm species (A. duodenale and N. americanus)
intestine usually cause no symptoms. In heavy infec- are responsible for human infections. Most infected indi-
tions, particularly in children, a large bolus of entangled viduals are asymptomatic. Hookworm disease develops
worms can cause pain and small-bowel obstruction, from a combination of factors—a heavy worm burden, a
sometimes complicated by perforation, intussusception, prolonged duration of infection, and an inadequate iron
or volvulus. Single worms may cause disease when they intake—and results in iron-deficiency anemia and, on
migrate into aberrant sites. A large worm can enter and occasion, hypoproteinemia.
occlude the biliary tree, causing biliary colic, cholecys-
titis, cholangitis, pancreatitis, or (rarely) intrahepatic
abscesses. Migration of an adult worm up the esophagus Life cycle
can provoke coughing and oral expulsion of the worm. Adult hookworms, which are ∼1 cm long, use buccal
In highly endemic areas, intestinal and biliary ascariasis teeth (Ancylostoma) or cutting plates (Necator) to attach to
can rival acute appendicitis and gallstones as causes of the small-bowel mucosa and suck blood (0.2 mL/d per
surgical acute abdomen. Ancylostoma adult) and interstitial fluid. The adult hook-
worms produce thousands of eggs daily. The eggs are
Laboratory findings deposited with feces in soil, where rhabditiform larvae
hatch and develop over a 1-week period into infectious
Most cases of ascariasis can be diagnosed by micro-
filariform larvae. Infective larvae penetrate the skin and
scopic detection of characteristic Ascaris eggs (65 by
reach the lungs by way of the bloodstream. There they
45 μm) in fecal samples. Occasionally, patients present
invade alveoli and ascend the airways before being swal-
after passing an adult worm—identifiable by its large
lowed and reaching the small intestine. The prepatent
size and smooth cream-colored surface—in the stool
period from skin invasion to appearance of eggs in the
or through the mouth or nose. During the early trans-
feces is ∼6–8 weeks, but it may be longer with A. duodenale.
SECTION IV
Life cycle
Laboratory findings
In addition to a parasitic cycle of development,
The diagnosis is established by the finding of character- Strongyloides can undergo a free-living cycle of development
istic 40- by 60-μm oval hookworm eggs in the feces. in the soil (Fig. 34-1). This adaptability facilitates the
Stool-concentration procedures may be required to parasite’s survival in the absence of mammalian hosts.
detect light infections. Eggs of the two species are indis- Rhabditiform larvae passed in feces can transform into
tinguishable by light microscopy. In a stool sample that infectious filariform larvae either directly or after a free-
is not fresh, the eggs may have hatched to release rhab- living phase of development. Humans acquire strongy-
ditiform larvae, which need to be differentiated from loidiasis when filariform larvae in fecally contaminated
those of S. stercoralis. Hypochromic microcytic anemia, soil penetrate the skin or mucous membranes. The larvae
occasionally with eosinophilia or hypoalbuminemia, is then travel through the bloodstream to the lungs,
characteristic of hookworm disease. where they break into the alveolar spaces, ascend the
bronchial tree, are swallowed, and thereby reach the
small intestine. There the larvae mature into adult
Treatment Hookworm Infection worms that penetrate the mucosa of the proximal small
bowel. The minute (2-mm-long) parasitic adult female
Hookworm infection can be eradicated with several worms reproduce by parthenogenesis; adult males do
CHAPTER 34
safe and highly effective antihelminthic drugs, includ- not exist. Eggs hatch in the intestinal mucosa, releas-
ing albendazole (400 mg once), mebendazole (500 mg ing rhabditiform larvae that migrate to the lumen and
once), and pyrantel pamoate (11 mg/kg for 3 days). Mild pass with the feces into soil. Alternatively, rhabditiform
iron-deficiency anemia can often be treated with oral larvae in the bowel can develop directly into filariform
iron alone. Severe hookworm disease with protein loss larvae that penetrate the colonic wall or perianal skin
and malabsorption necessitates nutritional support and and enter the circulation to repeat the migration that
oral iron replacement along with deworming. There is establishes ongoing internal reinfection. This autoinfec-
Hyperinfection:
With immunosuppression, larger Larvae shed in stool
numbers of filariform larvae develop,
penetrate bowel, and disseminate,
causing:
Colitis, polymicrobial sepsis,
pneumonitis, or meningitis
Free-living
1-mm adults
in soil
Direct development
SECTION IV
Rhabditiform larvae
in soil Eggs in soil
Indirect development
(heterogonic)
(can multiply outside host
for several generations) in soil
Figure 34-1
Life cycle of Strongyloides stercoralis. (Adapted from Guerrant RL et al (eds): Tropical Infectious Diseases: Principles, Pathogens
Infections of the Alimentary Tract
and Practice, 2nd ed, p 1276. © 2006, with permission from Elsevier Science.)
aggravated by food ingestion. Nausea, diarrhea, gastro- course. Eosinophilia is often absent in severely infected
intestinal bleeding, mild chronic colitis, and weight loss patients. Disseminated strongyloidiasis, particularly in
can occur. Small-bowel obstruction may develop with patients with unsuspected infection who are given glu-
early, heavy infection. Pulmonary symptoms are rare in cocorticoids, can be fatal. Strongyloidiasis is a frequent
uncomplicated strongyloidiasis. Eosinophilia is common, complication of infection with human T cell lympho-
with levels fluctuating over time. tropic virus type I, but disseminated strongyloidiasis is
The ongoing autoinfection cycle of strongyloidiasis is not common among patients infected with HIV-1.
normally constrained by unknown factors of the host’s
immune system. Abrogation of host immunity, espe-
Diagnosis
cially with glucocorticoid therapy and much less com-
monly with other immunosuppressive medications, leads In uncomplicated strongyloidiasis, the finding of
to hyperinfection, with the generation of large num- rhabditiform larvae in feces is diagnostic. Rhabditiform
bers of filariform larvae. Colitis, enteritis, or malab- larvae are ∼250 μm long, with a short buccal cav-
sorption may develop. In disseminated strongyloidiasis, ity that distinguishes them from hookworm larvae. In
larvae may invade not only gastrointestinal tissues and the uncomplicated infections, few larvae are passed and
lungs but also the central nervous system, peritoneum, single stool examinations detect only about one-third
liver, and kidneys. Moreover, bacteremia may develop of cases. Serial examinations and the use of the agar
because of the passage of enteric flora through disrupted plate detection method improve the sensitivity of stool
mucosal barriers. Gram-negative sepsis, pneumonia, diagnosis. In uncomplicated strongyloidiasis (but not in
or meningitis may complicate or dominate the clinical hyperinfection), stool examinations may be repeatedly
negative. Strongyloides larvae may also be found by sam- malnourishment and other diarrheal illnesses. Moder- 325
pling of the duodenojejunal contents by aspiration or ately heavy Trichuris burdens also contribute to growth
biopsy. An enzyme-linked immunosorbent assay for retardation.
serum antibodies to antigens of Strongyloides is a sensi-
tive method of diagnosing uncomplicated infections. Diagnosis and treatment
Such serologic testing should be performed for patients
whose geographic histories indicate potential exposure, The characteristic 50- by 20-μm lemon-shaped Trichu-
especially those who exhibit eosinophilia and/or ris eggs are readily detected on stool examination. Adult
are candidates for glucocorticoid treatment of other worms, which are 3–5 cm long, are occasionally seen on
conditions. In disseminated strongyloidiasis, filariform proctoscopy. Mebendazole (500 mg once) or albendazole
larvae should be sought in stool as well as in samples (400 mg daily for 3 doses) is safe and moderately effec-
obtained from sites of potential larval migration, includ- tive for treatment, with cure rates of 70–90%. Ivermec-
ing sputum, bronchoalveolar lavage fluid, or surgical tin (200 mg/kg daily for 3 doses) is also safe but is not
drainage fluid. quite as efficacious as the benzimidazoles.
CHAPTER 34
Enterobius adult worms are ∼1 cm long and dwell in the
cecum. Gravid female worms migrate nocturnally into
Trichuriasis the perianal region and release up to 10,000 immature
eggs each. The eggs become infective within hours
Most infections with Trichuris trichiura are asymp- and are transmitted by hand-to-mouth passage. From
tomatic, but heavy infections may cause gastroin- ingested eggs, larvae hatch and mature into adults.
CHAPTER 34
Intestinal Nematode Infections
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SECTION V
Evaluation of the
Patient with Liver
Disease
chapter 35
A diagnosis of liver disease usually can be made accu- with portal areas at the periphery and central veins in
rately by a careful history, physical examination, and the center of each lobule. However, from a functional
application of a few laboratory tests. In some circum- point of view, the liver is organized into acini, with
stances, radiologic examinations are helpful or, indeed, both hepatic arterial and portal venous blood entering
diagnostic. Liver biopsy is considered the criterion stan- the acinus from the portal areas (zone 1) and then flow-
dard in evaluation of liver disease but is now needed ing through the sinusoids to the terminal hepatic veins
less for diagnosis than for grading and staging of (zone 3); the intervening hepatocytes constituting zone 2.
disease. This chapter provides an introduction to diag- The advantage of viewing the acinus as the physiologic
nosis and management of liver disease, briefly reviewing unit of the liver is that it helps to explain the morpho-
the structure and function of the liver; the major clini- logic patterns and zonality of many vascular and biliary
cal manifestations of liver disease; and the use of clinical diseases not explained by the lobular arrangement.
history, physical examination, laboratory tests, imaging Portal areas of the liver consist of small veins, arteries,
studies, and liver biopsy. bile ducts, and lymphatics organized in a loose stroma of
supporting matrix and small amounts of collagen. Blood
flowing into the portal areas is distributed through the
LIVEr STruCTurE aND fuNCTION
sinusoids, passing from zone 1 to zone 3 of the acinus and
The liver is the largest organ of the body, weighing draining into the terminal hepatic veins (“central veins”).
1–1.5 kg and representing 1.5–2.5% of the lean body Secreted bile flows in the opposite direction, in a coun-
mass. The size and shape of the liver vary and gener- tercurrent pattern from zone 3 to zone 1. The sinusoids
ally match the general body shape—long and lean or are lined by unique endothelial cells that have prominent
squat and square. The liver is located in the right upper fenestrae of variable size, allowing the free flow of plasma
quadrant of the abdomen under the right lower rib cage but not cellular elements. The plasma is thus in direct con-
against the diaphragm and projects for a variable extent tact with hepatocytes in the subendothelial space of Disse.
into the left upper quadrant. The liver is held in place Hepatocytes have distinct polarity. The basolateral
by ligamentous attachments to the diaphragm, perito- side of the hepatocyte lines the space of Disse and is
neum, great vessels, and upper gastrointestinal organs. It richly lined with microvilli; it demonstrates endocytotic
receives a dual blood supply; ∼20% of the blood flow and pinocytotic activity, with passive and active uptake
is oxygen-rich blood from the hepatic artery, and 80% of nutrients, proteins, and other molecules. The apical
is nutrient-rich blood from the portal vein arising from pole of the hepatocyte forms the canalicular membranes
the stomach, intestines, pancreas, and spleen. through which bile components are secreted. The cana-
The majority of cells in the liver are hepatocytes, liculi of hepatocytes form a fine network, which fuses
which constitute two-thirds of the mass of the liver. into the bile ductular elements near the portal areas.
The remaining cell types are Kupffer cells (members Kupffer cells usually lie within the sinusoidal vascu-
of the reticuloendothelial system), stellate (Ito or fat- lar space and represent the largest group of fixed mac-
storing) cells, endothelial cells and blood vessels, bile rophages in the body. The stellate cells are located in
ductular cells, and supporting structures. Viewed by light the space of Disse but are not usually prominent unless
microscopy, the liver appears to be organized in lobules, activated, when they produce collagen and matrix. Red
330
blood cells stay in the sinusoidal space as blood flows most commonly used liver “function” tests are measure- 331
through the lobules, but white blood cells can migrate ments of serum bilirubin, albumin, and prothrombin
through or around endothelial cells into the space of time. The serum bilirubin level is a measure of hepatic
CHAPTER 35
Disse and from there to portal areas, where they can conjugation and excretion, and the serum albumin level
return to the circulation through lymphatics. and prothrombin time are measures of protein synthesis.
Hepatocytes perform numerous and vital roles in Abnormalities of bilirubin, albumin, and prothrombin
maintaining homeostasis and health. These functions time are typical of hepatic dysfunction. Frank liver fail-
include the synthesis of most essential serum proteins ure is incompatible with life, and the functions of the
(albumin, carrier proteins, coagulation factors, many liver are too complex and diverse to be subserved by a
hormonal and growth factors), the production of bile and mechanical pump; dialysis membrane; or concoction of
Table 35-1
Liver Diseases
Inherited hyperbilirubinemia Liver involvement in systemic diseases
Gilbert’s syndrome Sarcoidosis
Crigler-Najjar syndrome, types I and II Amyloidosis
Dubin-Johnson syndrome Glycogen storage diseases
Rotor syndrome Celiac disease
Viral hepatitis Tuberculosis
Hepatitis A Mycobacterium avium intracellulare
Hepatitis B Cholestatic syndromes
Hepatitis C Benign postoperative cholestasis
Hepatitis D Jaundice of sepsis
Hepatitis E Total parenteral nutrition (TPN)-induced jaundice
Others (mononucleosis, herpes, adenovirus hepatitis) Cholestasis of pregnancy
Cryptogenic hepatitis Cholangitis and cholecystitis
Immune and autoimmune liver diseases Extrahepatic biliary obstruction (stone, stricture, cancer)
Primary biliary cirrhosis Biliary atresia
Autoimmune hepatitis Caroli’s disease
Sclerosing cholangitis Cryptosporidiosis
Overlap syndromes Drug-induced liver disease
Graft-versus-host disease Hepatocellular patterns (isoniazid, acetaminophen)
Allograft rejection Cholestatic patterns (methyltestosterone)
Genetic liver diseases Mixed patterns (sulfonamides, phenytoin)
α1 Antitrypsin deficiency Micro- and macrovesicular steatosis (methotrexate, fialuridine)
Hemochromatosis Vascular injury
Wilson’s disease Venoocclusive disease
Benign recurrent intrahepatic cholestasis (BRIC) Budd-Chiari syndrome
Progressive familial intrahepatic cholestasis (PFIC), types I-III Ischemic hepatitis
Others (galactosemia, tyrosinemia, cystic fibrosis, Passive congestion
Newman-Pick disease, Gaucher’s disease) Portal vein thrombosis
Alcoholic liver disease Nodular regenerative hyperplasia
Acute fatty liver Mass lesions
Acute alcoholic hepatitis Hepatocellular carcinoma
Laënnec’s cirrhosis Cholangiocarcinoma
Nonalcoholic fatty liver Adenoma
Steatosis Focal nodular hyperplasia
Steatohepatitis Metastatic tumors
Abscess
Acute fatty liver of pregnancy
Cysts
Hemangioma
332 few distinct patterns, usually classified as hepatocellular, Generally, the constellation of symptoms and their pat-
cholestatic (obstructive), or mixed. In hepatocellular dis- terns of onset rather than a specific symptom points to
eases (such as viral hepatitis or alcoholic liver disease), an etiology.
features of liver injury, inflammation, and necrosis pre- Fatigue is the most common and most characteris-
SECTION V
dominate. In cholestatic diseases (such as gallstone or tic symptom of liver disease. It is variously described as
malignant obstruction, primary biliary cirrhosis, some lethargy, weakness, listlessness, malaise, increased need
drug-induced liver diseases), features of inhibition of for sleep, lack of stamina, and poor energy. The fatigue
bile flow predominate. In a mixed pattern, features of of liver disease typically arises after activity or exercise
both hepatocellular and cholestatic injury are present and is rarely present or severe in the morning after ade-
(such as in cholestatic forms of viral hepatitis and many quate rest (afternoon versus morning fatigue). Fatigue in
Evaluation of the Patient with Liver Disease
drug-induced liver diseases). The pattern of onset and liver disease is often intermittent and variable in severity
prominence of symptoms can rapidly suggest a diagnosis, from hour to hour and day to day. In some patients, it
particularly if major risk factors are considered such as may not be clear whether fatigue is due to the liver dis-
the age and sex of the patient and a history of exposure ease or to other problems such as stress, anxiety, sleep
or risk behaviors. disturbance, or a concurrent illness.
Typical presenting symptoms of liver disease include Nausea occurs with more severe liver disease and
jaundice, fatigue, itching, right upper quadrant pain, may accompany fatigue or be provoked by odors of
nausea, poor appetite, abdominal distention, and intes- food or eating fatty foods. Vomiting can occur but is
tinal bleeding. At present, however, many patients are rarely persistent or prominent. Poor appetite with
diagnosed with liver disease who have no symptoms weight loss occurs commonly in acute liver diseases
and who have been found to have abnormalities in bio- but is rare in chronic disease, except when cirrhosis is
chemical liver tests as a part of a routine physical exami- present and advanced. Diarrhea is uncommon in liver
nation or screening for blood donation or for insurance disease, except with severe jaundice, where lack of bile
or employment. The wide availability of batteries of acids reaching the intestine can lead to steatorrhea.
liver tests makes it relatively simple to demonstrate the Right upper quadrant discomfort or ache (“liver
presence of liver injury as well as to rule it out in some- pain”) occurs in many liver diseases and is usually
one suspected of liver disease. marked by tenderness over the liver area. The pain
Evaluation of patients with liver disease should be arises from stretching or irritation of Glisson’s capsule,
directed at (1) establishing the etiologic diagnosis, which surrounds the liver and is rich in nerve endings.
(2) estimating the disease severity (grading), and (3) Severe pain is most typical of gallbladder disease, liver
establishing the disease stage (staging). Diagnosis should abscess, and severe venoocclusive disease but is an occa-
focus on the category of disease such as hepatocellular, sional accompaniment of acute hepatitis.
cholestatic, or mixed injury, as well as on the specific Itching occurs with acute liver disease, appearing
etiologic diagnosis. Grading refers to assessing the sever- early in obstructive jaundice (from biliary obstruction or
ity or activity of disease—active or inactive, and mild, drug-induced cholestasis) and somewhat later in hepa-
moderate, or severe. Staging refers to estimating the tocellular disease (acute hepatitis). Itching also occurs
place in the course of the natural history of the disease, in chronic liver diseases, typically the cholestatic forms
whether acute or chronic; early or late; precirrhotic, such as primary biliary cirrhosis and sclerosing cholan-
cirrhotic, or end-stage. gitis where it is often the presenting symptom, occur-
The goal of this chapter is to introduce general, ring before the onset of jaundice. However, itching can
salient concepts in the evaluation of patients with liver occur in any liver disease, particularly once cirrhosis is
disease that help lead to the diagnoses discussed in sub- present.
sequent chapters. Jaundice is the hallmark symptom of liver disease and
perhaps the most reliable marker of severity. Patients
usually report darkening of the urine before they notice
Clinical History
scleral icterus. Jaundice is rarely detectable with a biliru-
The clinical history should focus on the symptoms bin level <43 μmol/L (2.5 mg/dL). With severe cho-
of liver disease—their nature, patterns of onset, and lestasis there will also be lightening of the color of the
progression—and on potential risk factors for liver dis- stools and steatorrhea. Jaundice without dark urine usually
ease. The symptoms of liver disease include consti- indicates indirect (unconjugated) hyperbilirubinemia
tutional symptoms such as fatigue, weakness, nausea, and is typical of hemolytic anemia and the genetic
poor appetite, and malaise and the more liver-specific disorders of bilirubin conjugation, the common and
symptoms of jaundice, dark urine, light stools, itching, benign form being Gilbert’s syndrome and the rare and
abdominal pain, and bloating. Symptoms can also sug- severe form being Crigler-Najjar syndrome. Gilbert’s
gest the presence of cirrhosis, end-stage liver disease, or syndrome affects up to 5% of the population; the jaundice
complications of cirrhosis such as portal hypertension. is more noticeable after fasting and with stress.
Major risk factors for liver disease that should be an increased rate of alcoholic liver disease is probably 333
sought in the clinical history include details of alcohol more than two drinks (22–30 g) per day in women and
use, medications (including herbal compounds, birth three drinks (33–45 g) in men. Most patients with alco-
CHAPTER 35
control pills, and over-the-counter medications), per- holic cirrhosis have a much higher daily intake and have
sonal habits, sexual activity, travel, exposure to jaundiced drunk excessively for ≥10 years before onset of liver
or other high-risk persons, injection drug use, recent disease. In assessing alcohol intake, the history should
surgery, remote or recent transfusion with blood and also focus on whether alcohol abuse or dependence is
blood products, occupation, accidental exposure to present. Alcoholism is usually defined by the behavioral
blood or needlestick, and familial history of liver disease. patterns and consequences of alcohol intake, not on the
For assessing the risk of viral hepatitis, a careful his- basis of the amount of alcohol intake. Abuse is defined
other diagnostic approaches. In many patients, the phys- Signs of advanced liver disease include muscle-wasting
ical examination is normal unless the disease is acute or and weight loss as well as hepatomegaly, bruising, ascites,
severe and advanced. Nevertheless, the physical exami- and edema. Ascites is best appreciated by attempts to
nation is important in that it can be the first evidence detect shifting dullness by careful percussion. US exami-
for the presence of hepatic failure, portal hyperten- nation will confirm the finding of ascites in equivocal
sion, and liver decompensation. In addition, the physi- cases. Peripheral edema can occur with or without asci-
cal examination can reveal signs that point to a specific tes. In patients with advanced liver disease, other factors
diagnosis, either in risk factors or in associated diseases frequently contribute to edema formation, including
or findings. hypoalbuminemia, venous insufficiency, heart failure,
Typical physical findings in liver disease are icterus, and medications.
hepatomegaly, hepatic tenderness, splenomegaly, spider Hepatic failure is defined as the occurrence of signs
angiomata, palmar erythema, and excoriations. Signs of or symptoms of hepatic encephalopathy in a person with
advanced disease include muscle wasting, ascites, edema, severe acute or chronic liver disease. The first signs of
dilated abdominal veins, hepatic fetor, asterixis, mental hepatic encephalopathy can be subtle and nonspecific—
confusion, stupor, and coma. In males with cirrhosis, change in sleep patterns, change in personality, irrita-
particularly when related to alcohol, signs of hyperes- bility, and mental dullness. Thereafter, confusion, dis-
trogenemia such as gynecomastia, testicular atrophy, and orientation, stupor, and eventually coma supervene. In
loss of male-pattern hair distribution may be found. acute liver failure, excitability and mania may be pres-
Icterus is best appreciated by inspecting the sclera ent. Physical findings include asterixis and flapping
under natural light. In fair-skinned individuals, a yellow tremors of the body and tongue. Fetor hepaticus refers
color of the skin may be obvious. In dark-skinned indi- to the slightly sweet, ammoniacal odor that can occur
viduals, the mucous membranes below the tongue can in patients with liver failure, particularly if there is portal-
demonstrate jaundice. Jaundice is rarely detectable if the venous shunting of blood around the liver. Other causes
serum bilirubin level is <43 μmol/L (2.5 mg/dL) but of coma and disorientation should be excluded, mainly
may remain detectable below this level during recovery electrolyte imbalances, sedative use, and renal or respi-
from jaundice (because of protein and tissue binding of ratory failure. The appearance of hepatic encepha-
conjugated bilirubin). lopathy during acute hepatitis is the major criterion for
Spider angiomata and palmar erythema occur in both diagnosis of fulminant hepatitis and indicates a poor
acute and chronic liver disease and may be especially prognosis. In chronic liver disease, encephalopathy is
prominent in persons with cirrhosis, but they can occur usually triggered by a medical complication such as gas-
in normal individuals and are frequently present dur- trointestinal bleeding, over-diuresis, uremia, dehydra-
ing pregnancy. Spider angiomata are superficial, tortu- tion, electrolyte imbalance, infection, constipation, or
ous arterioles and, unlike simple telangiectases, typically use of narcotic analgesics.
fill from the center outward. Spider angiomata occur A helpful measure of hepatic encephalopathy is a
only on the arms, face, and upper torso; they can be careful mental status examination and use of the trail-
pulsatile and may be difficult to detect in dark-skinned making test, which consists of a series of 25 numbered
individuals. circles that the patient is asked to connect as rapidly
Hepatomegaly is not a very reliable sign of liver dis- as possible using a pencil. The normal range for the
ease, because of the variability of the size and shape of connect-the-dot test is 15–30 seconds; it is consider-
the liver and the physical impediments to assessing liver ably delayed in patients with early hepatic encepha-
size by percussion and palpation. Marked hepatomegaly lopathy. Other tests include drawing abstract objects
is typical of cirrhosis, venoocclusive disease, infiltrative or comparison of a signature to previous examples.
disorders such as amyloidosis, metastatic or primary cancers More sophisticated testing such as with electroen-
of the liver, and alcoholic hepatitis. Careful assess- cephalography and visual evoked potentials can detect
ment of the liver edge may also demonstrate unusual mild forms of encephalopathy, but are rarely clinically
firmness, irregularity of the surface, or frank nodules. useful.
Other signs of advanced liver disease include umbili- present. Based on these results, further testing over 335
cal hernia from ascites, hydrothorax, prominent veins time may be necessary. Other laboratory tests may be
over the abdomen, and caput medusa, which consists of helpful, such as γ-glutamyl transpeptidase (gGT) to
CHAPTER 35
collateral veins seen radiating from the umbilicus and define whether alkaline phosphatase elevations are due
resulting from the recanulation of the umbilical vein. to liver disease; hepatitis serology to define the type of
Widened pulse pressure and signs of a hyperdynamic viral hepatitis; and autoimmune markers to diagnose
circulation can occur in patients with cirrhosis as a result primary biliary cirrhosis (antimitochondrial antibody;
of fluid and sodium retention, increased cardiac output, AMA), sclerosing cholangitis (peripheral antineutrophil
and reduced peripheral resistance. Patients with long- cytoplasmic antibody; P-ANCA), and autoimmune
standing cirrhosis and portal hypertension are prone to hepatitis (antinuclear, smooth-muscle, and liver-kidney
CHAPTER 35
Abnormal liver tests
Acute Chronic
< 6 months > 6 months
Liver biopsy in acute liver disease: Liver biopsy in chronic liver disease:
Reserved for patients in whom the diagnosis Often valuable for diagnosis as well as
remains unclear despite medical evaluation staging and grading liver disease
Figure 35-1
Algorithm for evaluation of abnormal liver tests. For is largely applicable to patients without immune deficiency.
patients with suspected liver disease, an appropriate In patients with HIV infection or after bone marrow or solid
approach to evaluation is initial testing for routine liver tests organ transplantation, diagnostic evaluation should also
such as bilirubin, albumin, alanine aminotransferase (ALT), include evaluation of opportunistic infections (adenovirus,
aspartate aminotransferase (AST), and alkaline phosphatase cytomegalovirus, coccidioidomycosis, etc.) as well as vas-
(AlkP). These results (sometimes complemented by testing cular and immunologic conditions (venoocclusive disease,
of γ-glutamyl transpeptidase; gGT) will establish whether the graft-versus-host disease). HAV, HCV: hepatitis A or C virus;
pattern of abnormalities is hepatic, cholestatic, or mixed. HBsAg, hepatitis B surface antigen; anti-HBc, antibody
In addition, the duration of symptoms or abnormalities will to hepatitis B core (antigen); ANA, antinuclear antibodies;
show whether the disease is acute or chronic. If the disease SMA, smooth-muscle antibody; MRCP, magnetic resonance
is acute and if history, laboratory tests, and imaging studies cholangiopancreatography; ERCP, endoscopic retrograde
do not reveal a diagnosis, liver biopsy is appropriate to help cholangiopancreatography; α1AT, α1 antitrypsin; AMA; anti-
establish the diagnosis. If the disease is chronic, liver biopsy mitochondrial antibody; P-ANCA, peripheral antineutrophil
can be helpful not only for diagnosis but also to grade the cytoplasmic antibody.
activity and stage the progression of disease. This approach
particularly in chronic liver disease. Serum amino- e antigen and hepatitis B virus DNA can help resolve
transferase levels are used as convenient and noninvasive these different patterns, but these markers can also fluc-
means to follow disease activity, but aminotransfer- tuate and change over time. Similarly, in chronic hepa-
ase levels are not always reliable in reflecting disease titis C, serum aminotransferase levels can be normal
severity. Thus, normal serum aminotransferase levels despite moderate activity of disease. Finally, in both
in patients with hepatitis B surface antigen (HBsAg) in alcoholic and nonalcoholic steatohepatitis, aminotrans-
serum may indicate the inactive HBsAg carrier state or ferase levels are quite unreliable in reflecting severity.
may reflect mild chronic hepatitis B or hepatitis B with In these conditions, liver biopsy is helpful in guiding
fluctuating disease activity. Serum testing for hepatitis B management and recommending therapy, particularly
338 if therapy is difficult, prolonged, and expensive as is Table 35-4
often the case in chronic viral hepatitis. There are sev- Child-Pugh Classification of Cirrhosis
eral well-verified numerical scales for grading activity in
Factor Units 1 2 3
chronic liver disease, the most common being the his-
SECTION V
tology activity index and the Ishak histology scale. Serum μmol/L <34 34-51 >51
Liver biopsy is also the most accurate means of assess- bilirubin mg/dL <2.0 2.0-3.0 >3.0
ing stage of disease as early or advanced, precirrhotic, Serum g/L >35 30-35 <30
and cirrhotic. Staging of disease pertains largely to albumin g/dL >3.5 3.0-3.5 <3.0
chronic liver diseases in which progression to cirrhosis Prothrombin seconds 0-4 4-6 >6
and end-stage liver disease can occur, but which may time prolonged <1.7 1.7-2.3 >2.3
Evaluation of the Patient with Liver Disease
CHAPTER 35
from alcohol should be encouraged for all patients with ation should be given to surveillance for complications
alcohol-related liver disease and in patients with cir- of chronic liver disease such as variceal hemorrhage and
rhosis and those receiving interferon-based therapy for hepatocellular carcinoma. Patients with cirrhosis war-
hepatitis B or C. Regarding vaccinations, all patients rant upper endoscopy to assess the presence of varices
with liver disease should receive hepatitis A vaccine and and should be given chronic therapy with beta blockers
those with risk factors should receive hepatitis B vac- or offered endoscopic obliteration if large varices are
cination as well. Influenza and pneumococcal vacci- found. Patients with cirrhosis also warrant screening and
Several biochemical tests are useful in the evalu- TesTs BAseD on DeToXiFicATion AnD
ation and management of patients with hepatic eXcreTory FuncTions
dysfunction. These tests can be used to (1) detect the
Serum bilirubin
presence of liver disease, (2) distinguish among dif-
ferent types of liver disorders, (3) gauge the extent of (See also Chap. 42) Bilirubin, a breakdown product
known liver damage, and (4) follow the response to of the porphyrin ring of heme-containing proteins, is
treatment. found in the blood in two fractions—conjugated and
Liver tests have shortcomings. They can be normal unconjugated. The unconjugated fraction, also termed
in patients with serious liver disease and abnormal in the indirect fraction, is insoluble in water and is bound
patients with diseases that do not affect the liver. Liver to albumin in the blood. The conjugated (direct) bili-
tests rarely suggest a specific diagnosis; rather, they sug- rubin fraction is water soluble and can therefore be
gest a general category of liver disease, such as hepato- excreted by the kidney. When measured by modifica-
cellular or cholestatic, which then further directs the tions of the original van den Bergh method, normal
evaluation. values of total serum bilirubin are reported between
The liver carries out thousands of biochemical func- 1 and 1.5 mg/dL with 95% of a normal population
tions, most of which cannot be easily measured by falling between 0.2 and 0.9 mg/dL. If the direct-acting
blood tests. Laboratory tests measure only a limited fraction is less than 15% of the total, the bilirubin can
number of these functions. In fact, many tests, such as be considered to all be indirect. The most frequently
the aminotransferases or alkaline phosphatase, do not reported upper limit of normal for conjugated biliru-
measure liver function at all. Rather, they detect liver bin is 0.3 mg/dL.
cell damage or interference with bile flow. Thus, no one Elevation of the unconjugated fraction of biliru-
test enables the clinician to accurately assess the liver’s bin is rarely due to liver disease. An isolated elevation
total functional capacity. of unconjugated bilirubin is seen primarily in hemolytic
To increase both the sensitivity and the specificity disorders and in a number of genetic conditions such
of laboratory tests in the detection of liver disease, it is as Crigler-Najjar and Gilbert’s syndromes (Chap. 42).
best to use them as a battery. Tests usually employed in Isolated unconjugated hyperbilirubinemia (bilirubin
clinical practice include the bilirubin, aminotransferases, elevated but <15% direct) should prompt a workup for
alkaline phosphatase, albumin, and prothrombin time hemolysis (Fig. 36-1). In the absence of hemolysis,
tests. When more than one of these tests provide abnor- an isolated, unconjugated hyperbilirubinemia in an
mal findings or the findings are persistently abnormal on otherwise healthy patient can be attributed to Gilbert’s
serial determinations, the probability of liver disease is syndrome, and no further evaluation is required.
high. When all test results are normal, the probability of In contrast, conjugated hyperbilirubinemia almost
missing occult liver disease is low. always implies liver or biliary tract disease. The rate-
When evaluating patients with liver disorders, it limiting step in bilirubin metabolism is not conjuga-
is helpful to group these tests into general categories. tion of bilirubin, but rather the transport of conju-
The classification we have found most useful is given gated bilirubin into the bile canaliculi. Thus, elevation
below. of the conjugated fraction may be seen in any type of
340
EVALUATION OF CHRONICALLY ABNORMAL LIVER TESTS 341
Liver Tests
CHAPTER 36
Isolated elevation Cholestatic pattern
of the bilirubin (see Table 302-1) Isolated elevation
of the alkaline
phosphatase
Review drugs
Ultrasound
Fractionate
bilirubin Ducts not Dilated ducts
dilated
Figure 36-1
Algorithm for the evaluation of chronically abnormal liver antibody; ANA, antinuclear antibody; SPEP, serum
tests. ERCP, endoscopic retrograde cholangiopancreatog- protein electrophoresis; TIBC, total iron-binding capacity;
raphy; CT, computed tomography; AMA, antimitochondrial GGT, α glutamyl transpeptidase; W/U, work up.
Patients with advanced liver disease typically have sig- level of the aminotransferases. Thus, the absolute eleva-
nificant muscle wasting, which likely contributes to tion of the aminotransferases is of no prognostic signifi-
hyperammonemia in these patients. Some physicians cance in acute hepatocellular disorders.
use the blood ammonia for detecting encephalopathy or The normal range for aminotransferases varies widely
for monitoring hepatic synthetic function, although its among laboratories, but generally ranges from 10-40 U/L.
use for either of these indications has problems. There The inter-laboratory variation in normal range is due to
Evaluation of the Patient with Liver Disease
is very poor correlation between either the presence or technical reasons; no reference standards exist to estab-
the severity of acute encephalopathy and elevation of lish upper limits of normal for ALT and AST. Some
blood ammonia; it can be occasionally useful for iden- have recommended revisions of normal limits of the
tifying occult liver disease in patients with mental status aminotransferases adjustments for sex and BMI, but oth-
changes. There is also a poor correlation of the blood ers have noted the potential costs and unclear benefits of
serum ammonia and hepatic function. The ammonia implementing this change.
can be elevated in patients with severe portal hyperten- Any type of liver cell injury can cause modest ele-
sion and portal blood shunting around the liver even in vations in the serum aminotransferases. Levels of up to
the presence of normal or near-normal hepatic function. 300 U/L are nonspecific and may be found in any type
Elevated arterial ammonia levels have been shown to of liver disorder. Minimal ALT elevations in asymp-
correlate with outcome in fulminant hepatic failure. tomatic blood donors rarely indicate severe liver disease;
studies have shown that fatty liver disease is the most
likely explanation. Striking elevations—i.e., aminotrans-
Serum enzymes ferases >1000 U/L—occur almost exclusively in disor-
The liver contains thousands of enzymes, some of ders associated with extensive hepatocellular injury such
which are also present in the serum in very low con- as (1) viral hepatitis, (2) ischemic liver injury (prolonged
centrations. These enzymes have no known function in hypotension or acute heart failure), or (3) toxin- or
the serum and behave like other serum proteins. They drug-induced liver injury.
are distributed in the plasma and in interstitial fluid and The pattern of the aminotransferase elevation can be
have characteristic half-lives, which are usually mea- helpful diagnostically. In most acute hepatocellular dis-
sured in days. Very little is known about the catabolism orders, the ALT is higher than or equal to the AST.
of serum enzymes, although they are probably cleared While the AST:ALT ratio is typically less than 1 in
by cells in the reticuloendothelial system. The elevation patients with chronic viral hepatitis and non-alcoholic
of a given enzyme activity in the serum is thought to fatty liver disease, a number of groups have noted that
primarily reflect its increased rate of entrance into serum as cirrhosis develops this ratio rises to greater than 1. An
from damaged liver cells. AST:ALT ratio >2:1 is suggestive, while a ratio >3:1
Serum enzyme tests can be grouped into three is highly suggestive of alcoholic liver disease. The AST
categories: (1) enzymes whose elevation in serum in alcoholic liver disease is rarely >300 U/L, and the
reflects damage to hepatocytes, (2) enzymes whose ele- ALT is often normal. A low level of ALT in the serum
vation in serum reflects cholestasis, and (3) enzyme tests is due to an alcohol-induced deficiency of pyridoxal
that do not fit precisely into either pattern. phosphate.
The aminotransferases are usually not greatly elevated
Enzymes that reflect damage to hepatocytes in obstructive jaundice. One notable exception occurs
The aminotransferases (transaminases) are sensitive indi- during the acute phase of biliary obstruction caused by
cators of liver cell injury and are most helpful in rec- the passage of a gallstone into the common bile duct. In
ognizing acute hepatocellular diseases such as hepatitis. this setting, the aminotransferases can briefly be in the
They include the aspartate aminotransferase (AST) and 1000–2000 U/L range. However, aminotransferase lev-
the alanine aminotransferase (ALT). AST is found in els decrease quickly, and the liver-function tests rapidly
the liver, cardiac muscle, skeletal muscle, kidneys, brain, evolve into one typical of cholestasis.
pancreas, lungs, leukocytes, and erythrocytes in decreas-
ing order of concentration. ALT is found primarily in Enzymes that reflect cholestasis
the liver and is therefore a more specific indicator of The activities of three enzymes—alkaline phosphatase,
liver injury. The aminotransferases are normally present 5′-nucleotidase, and γ-glutamyl transpeptidase (GGT)—
in the serum in low concentrations. These enzymes are are usually elevated in cholestasis. Alkaline phospha-
released into the blood in greater amounts when there is tase and 5′-nucleotidase are found in or near the bile
canalicular membrane of hepatocytes, while GGT is In the absence of jaundice or elevated aminotrans- 343
located in the endoplasmic reticulum and in bile duct ferases, an elevated alkaline phosphatase of liver origin
epithelial cells. Reflecting its more diffuse localization often, but not always, suggests early cholestasis and, less
CHAPTER 36
in the liver, GGT elevation in serum is less specific for often, hepatic infiltration by tumor or granulomata.
cholestasis than are elevations of alkaline phosphatase or Other conditions that cause isolated elevations of the
5′-nucleotidase. Some have advocated the use of GGT alkaline phosphatase include Hodgkin’s disease, diabe-
to identify patients with occult alcohol use. Its lack of tes, hyperthyroidism, congestive heart failure, amyloi-
specificity makes its use in this setting questionable. dosis, and inflammatory bowel disease.
The normal serum alkaline phosphatase consists The level of serum alkaline phosphatase elevation is
of many distinct isoenzymes found in the liver; bone; not helpful in distinguishing between intrahepatic and
occurs because the cirrhotic liver fails to clear bacte- ancillary tests are reviewed here.
rial antigens that normally reach the liver through the
hepatic circulation. Percutaneous liver biopsy
Increases in the concentration of specific isotypes of
γ globulins are often helpful in the recognition of cer- Percutaneous biopsy of the liver is a safe procedure
tain chronic liver diseases. Diffuse polyclonal increases that can be easily performed at the bedside with local
in IgG levels are common in autoimmune hepatitis; anesthesia and ultrasound guidance. Liver biopsy is of
increases >100% should alert the clinician to this proven value in the following situations: (1) hepatocel-
possibility. Increases in the IgM levels are common in lular disease of uncertain cause, (2) prolonged hepatitis
primary biliary cirrhosis, while increases in the IgA lev- with the possibility of chronic active hepatitis, (3) unex-
els occur in alcoholic liver disease. plained hepatomegaly, (4) unexplained splenomegaly,
(5) hepatic filling defects by radiologic imaging,
(6) fever of unknown origin, (7) staging of malignant
Coagulation Factors lymphoma. Liver biopsy is most accurate in disorders
With the exception of factor VIII, which is produced causing diffuse changes throughout the liver and is
by vascular endothelial cells, the blood clotting factors subject to sampling error in focal infiltrative disorders
are made exclusively in hepatocytes. Their serum half- such as hepatic metastases. Liver biopsy should not be
lives are much shorter than albumin, ranging from 6 h the initial procedure in the diagnosis of cholestasis. The
for factor VII to 5 days for fibrinogen. Because of their biliary tree should first be assessed for signs of obstruc-
rapid turnover, measurement of the clotting factors is tion. Contraindications to performing a percutaneous
the single best acute measure of hepatic synthetic func- liver biopsy include significant ascites and prolonged
tion and helpful in both the diagnosis and assessing the INR. Under these circumstances, the biopsy can be
prognosis of acute parenchymal liver disease. Useful for performed via the transjugular approach.
this purpose is the serum prothrombin time, which collec-
tively measures factors II, V, VII, and X. Biosynthesis of Ultrasonography
factors II, VII, IX, and X depends on vitamin K. The
international normalized ratio (INR) is used to express Ultrasonography is the first diagnostic test to use in
the degree of anticoagulation on warfarin therapy. patients whose liver tests suggest cholestasis, to look
The INR standardizes prothrombin time measurement for the presence of a dilated intrahepatic or extrahe-
according to the characteristics of the thromboplastin patic biliary tree or to identify gallstones. In addition,
reagent used in a particular lab which is expressed as an it shows space-occupying lesions within the liver,
International Sensitivity Index (ISI); the ISI is then used enables the clinician to distinguish between cystic and
in calculating the INR. Because the ISI is validated only solid masses, and helps direct percutaneous biopsies.
for patients on vitamin K antagonists, there has been Ultrasound with Doppler imaging can detect the
concern regarding the validity of using it for patients patency of the portal vein, hepatic artery, and hepatic
with chronic liver disease. veins and determine the direction of blood flow. This
The prothrombin time may be elevated in hepatitis is the first test ordered in patients suspected of having
and cirrhosis as well as in disorders that lead to vitamin K Budd-Chiari syndrome.
deficiency such as obstructive jaundice or fat malab-
sorption of any kind. Marked prolongation of the pro-
Use of Liver Tests
thrombin time, >5 s above control and not corrected
by parenteral vitamin K administration, is a poor prog- As previously noted, the best way to increase the sen-
nostic sign in acute viral hepatitis and other acute and sitivity and specificity of laboratory tests in the detec-
chronic liver diseases. The INR, along with the total tion of liver disease is to employ a battery of tests that
serum bilirubin and creatinine, are components of the includes the aminotransferases, alkaline phosphatase,
Table 36-1 345
Liver Test Patterns in Hepatobiliary Disorders
CHAPTER 36
Alkaline
Type of Disorder Bilirubin Aminotransferases Phosphatase Albumin Prothrombin Time
bilirubin, albumin, and prothrombin time along with remember that no single set of liver tests will necessarily
the judicious use of the other tests described in this provide a diagnosis. It is often necessary to repeat these
chapter. Table 36-1 shows how patterns of liver tests tests on several occasions over days to weeks for a diag-
can lead the clinician to a category of disease that will nostic pattern to emerge. Figure 36-1 is an algorithm
direct further evaluation. However, it is important to for the evaluation of chronically abnormal liver tests.
This page intentionally left blank
SECTION VI
Disorders of
the Liver and
Biliary Tree
cHapter 37
THE HYPERBILIRUBINEMIAS
allan W. Wolkoff
~286 AA ~245 AA
A(TA)6TAA
CHAPTER 37
TATA Box
Figure 37-2
Structural organization of the human UGT1 gene 245 carboxyl-terminal amino acids common to all of the
complex. This large complex on chromosome 2 contains at isoforms. mRNAs for specific isoforms are assembled by
least 13 substrate-specific first exons (A1, A2, etc.). Since splicing a particular first exon such as the bilirubin-specific
four of these are pseudogenes, nine UGT1 isoforms with exon A1 to exons 2 to 5. The resulting message encodes
The Hyperbilirubinemias
differing substrate specificities are expressed. Each exon a complete enzyme, in this particular case bilirubin-UDP-
1 has its own promoter and encodes the amino-terminal glucuronosyltransferase (UGT1A1). Mutations in a first exon
substrate-specific ∼286 amino acids of the various UGT1- affect only a single isoform. Those in exons 2–5 affect all
encoded isoforms, and common exons 2–5 that encode the enzymes encoded by the UGT1 complex.
domain. Exon A1 and the four common exons, col- syndrome, type I (CN-I)]. Unconjugated bilirubin that
lectively designated the UGT1A1 gene (Fig. 37-2), reaches the gut is partly reabsorbed, amplifying any
encode the physiologically critical enzyme bilirubin- underlying hyperbilirubinemia. Recent reports suggest
UDP-glucuronosyltransferase (UGT1A1). A func- that oral administration of calcium phosphate with or
tional corollary of the organization of the UGT1 without the lipase inhibitor orlistat may be an efficient
gene is that a mutation in one of the first exons means to interrupt bilirubin enterohepatic cycling to
will affect only a single enzyme isoform. By con- reduce serum bilirubin levels in this situation. Although
trast, a mutation in exons 2–5 will alter all isoforms orlistat administration for 4–6 weeks to 16 patients with
encoded by the UGT1 gene complex. Crigler-Najjar syndrome was associated with a 10-20%
4. Biliary excretion: Bilirubin mono- and diglucuronides decrease in serum bilirubin in 7 patients, the cost and
are excreted across the canalicular plasma membrane side effects (i.e., diarrhea) may obviate the small benefit
into the bile canaliculus by an ATP-dependent achievable with this treatment.
transport process mediated by a canalicular mem-
brane protein called multidrug resistance–associated Renal excretion of bilirubin conjugates
protein 2 (MRP2). Mutations of MRP2 result in the
Dubin-Johnson syndrome (see below). Unconjugated bilirubin is not excreted in urine, as it is
too tightly bound to albumin for effective glomerular
filtration and there is no tubular mechanism for its renal
Extrahepatic Aspects of secretion. In contrast, the bilirubin conjugates are read-
Bilirubin Disposition ily filtered at the glomerulus and can appear in urine in
disorders characterized by increased bilirubin conjugates
Bilirubin in the gut in the circulation.
Following secretion into bile, conjugated bilirubin
reaches the duodenum and passes down the gastro-
intestinal tract without reabsorption by the intestinal Disorders of Bilirubin Metabolism
mucosa. An appreciable fraction is converted by bacte- Leading to Unconjugated
rial metabolism in the gut to the water-soluble color- Hyperbilirubinemia
less compound urobilinogen. Urobilinogen undergoes
enterohepatic cycling. Urobilinogen not taken up by Increased Bilirubin Production
the liver reaches the systemic circulation, from which
Hemolysis
some is cleared by the kidneys. Unconjugated bilirubin
ordinarily does not reach the gut except in neonates or, by Increased destruction of erythrocytes leads to increased
ill-defined alternative pathways, in the presence of severe bilirubin turnover and unconjugated hyperbilirubi-
unconjugated hyperbilirubinemia [e.g., Crigler-Najjar nemia; the hyperbilirubinemia is usually modest in
350 the presence of normal liver function. In particular, drugs, including flavaspidic acid, novobiocin, and
the bone marrow is only capable of a sustained eight- rifampin, as well as various cholecystographic contrast
fold increase in erythrocyte production in response to agents, have been reported to inhibit bilirubin uptake.
a hemolytic stress. Therefore, hemolysis alone cannot The resulting unconjugated hyperbilirubinemia resolves
result in a sustained hyperbilirubinemia of more than with cessation of the medication.
∼68 μmol/L (4 mg/dL). Higher values imply concom-
itant hepatic dysfunction. When hemolysis is the only
abnormality in an otherwise healthy individual, the Impaired conjugation
result is a purely unconjugated hyperbilirubinemia, with Physiologic neonatal jaundice
SECTION VI
the direct-reacting fraction as measured in a typical clin- Bilirubin produced by the fetus is cleared by the pla-
ical laboratory being ≤15% of the total serum bilirubin. centa and eliminated by the maternal liver. Immediately
In the presence of systemic disease, which may include after birth, the neonatal liver must assume responsibility
a degree of hepatic dysfunction, hemolysis may produce a for bilirubin clearance and excretion. However, many
component of conjugated hyperbilirubinemia in addition hepatic physiologic processes are incompletely devel-
to an elevated unconjugated bilirubin concentration. oped at birth. Levels of UGT1A1 are low, and alterna-
Prolonged hemolysis may lead to the precipitation
Disorders of the Liver and Biliary Tree
CHAPTER 37
nated very slowly by alternative pathways that include
Hereditary Defects in Bilirubin direct passage into the bile and small intestine. These
Conjugation account for the small amounts of urobilinogen found in
Three familial disorders characterized by differing feces. No bilirubin is found in the urine. First described
degrees of unconjugated hyperbilirubinemia have long in 1952, the disorder is rare (estimated prevalence,
been recognized. The defining clinical features of each 0.6–1.0 per million). Many patients are from geographically
are described below (Table 37-1). While these disor- or socially isolated communities in which consanguinity
The Hyperbilirubinemias
ders have been recognized for decades to reflect dif- is common, and pedigree analyses show an autosomal
fering degrees of deficiency in the ability to conjugate recessive pattern of inheritance. The majority of patients
bilirubin, recent advances in the molecular biology of (type IA) exhibit defects in the glucuronide conjuga-
the UGT1 gene complex have elucidated their inter tion of a spectrum of substrates in addition to bilirubin,
relationships and clarified previously puzzling features. including various drugs and other xenobiotics. These
individuals have mutations in one of the common exons
(2–5) of the UGT1 gene (Fig. 37-2). In a smaller subset
Crigler-Najjar syndrome, type I
(type IB), the defect is limited largely to bilirubin con-
CN-I is characterized by striking unconjugated hyper- jugation, and the causative mutation is in the bilirubin-
bilirubinemia of about 340–765 μmol/L (20–45 mg/dL) specific exon A1. Estrogen glucuronidation is mediated
that appears in the neonatal period and persists for life. by UGT1A1 and is defective in all CN-I patients. More
Other conventional hepatic biochemical tests such as than 30 different genetic lesions of UGT1A1 respon-
serum aminotransferases and alkaline phosphatase are sible for CN-I have been identified, including dele-
normal, and there is no evidence of hemolysis. Hepatic tions, insertions, alterations in intron splice donor and
Table 37-1
Principal Differential Characteristics of Gilbert’s and Crigler-Najjar Syndromes
Crigler-Najjar Syndrome
Total serum bilirubin, 310–755 (usually >345) 100–430 (usually ≤345) Typically ≤70 μmol/L (≤4 mg/dL) in
μmol/L (mg/dL) [18–45 (usually >20)] [6–25 (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- Typically absent; traces Markedly reduced: 0–10% of Reduced: typically 10–33% of
glucuronosyltransferase in some patients normal normal
activity
Inheritance (all autosomal) Recessive Predominantly recessive Promoter mutation: recessive
Missense mutations: 7 of 8 dominant;
1 reportedly recessive
352 acceptor sites, exon skipping, and point mutations that therapy is widely recommended, a single bedtime dose
introduce premature stop codons or alter critical amino often sufficing to maintain clinically safe plasma biliru-
acids. Their common feature is that they all encode bin concentrations.
proteins with absent or, at most, traces of bilirubin- Over 77 different mutations in the UGT1 gene have
UDP-glucuronosyltransferase enzymatic activity. been identified as causing CN-I or CN-II. It was found
Prior to the availability of phototherapy, most that missense mutations are more common in CN-II
patients with CN-I died of bilirubin encephalopathy patients, as would be expected in this less severe phe-
(kernicterus) in infancy or early childhood. A few lived notype. Their common feature is that they encode for a
as long as early adult life without overt neurologic bilirubin-UDP-glucuronosyltransferase with markedly
SECTION VI
damage, although more subtle testing usually indicated reduced, but detectable, enzymatic activity. The spectrum
mild but progressive brain damage. In the absence of of residual enzyme activity explains the spectrum of
liver transplantation, death eventually supervened from phenotypic severity of the resulting hyperbilirubinemia.
late-onset bilirubin encephalopathy, which often fol- Molecular analysis has established that a large majority
lowed a nonspecific febrile illness. Although isolated of CN-II patients are either homozygotes or compound
hepatocyte transplantation has been used in a small heterozygotes for CN-II mutations and that individu-
number of cases of CN-I, early liver transplantation als carrying one mutated and one entirely normal allele
Disorders of the Liver and Biliary Tree
(Chap. 310) remains the best hope to prevent brain have normal bilirubin concentrations.
injury and death.
Gilbert’s syndrome
Crigler-Najjar syndrome, type II (CN-II)
This syndrome is characterized by mild unconju-
This condition was recognized as a distinct entity in gated hyperbilirubinemia, normal values for standard
1962 and is characterized by marked unconjugated hepatic biochemical tests, and normal hepatic histol-
hyperbilirubinemia in the absence of abnormalities of ogy other than a modest increase of lipofuscin pigment
other conventional hepatic biochemical tests, hepatic in some patients. Serum bilirubin concentrations are
histology, or hemolysis. It differs from CN-I in several most often <51 μmol/L (<3 mg/dL), although both
specific ways (Table 37-1): (1) Although there is con- higher and lower values are frequent. The clinical spec-
siderable overlap, average bilirubin concentrations are trum of hyperbilirubinemia fades into that of CN-II
lower in CN-II; (2) accordingly, CN-II is only infre- at serum bilirubin concentrations of 86–136 μmol/L
quently associated with kernicterus; (3) bile is deeply (5–8 mg/dL). At the other end of the scale, the dis-
colored, and bilirubin glucuronides are present, with tinction between mild cases of GS and a normal state
a striking, characteristic increase in the proportion of is often blurred. Bilirubin concentrations may fluctuate
monoglucuronides; (4) UGT1A1 in liver is usually pres- substantially in any given individual, and at least 25%
ent at reduced levels (typically ≤10% of normal) but of patients will exhibit temporarily normal values dur-
may be undetectable by older, less sensitive assays; ing prolonged follow-up. More elevated values are asso-
(5) while typically detected in infancy, hyperbilirubinemia ciated with stress, fatigue, alcohol use, reduced caloric
was not recognized in some cases until later in life and, intake, and intercurrent illness, while increased caloric
in one instance, at age 34. As with CN-I, most CN-II intake or administration of enzyme-inducing agents
cases exhibit abnormalities in the conjugation of other produces lower bilirubin levels. GS is most often diag-
compounds, such as salicylamide and menthol, but in nosed at or shortly after puberty or in adult life during
some instances the defect appears limited to bilirubin. routine examinations that include multichannel bio-
Reduction of serum bilirubin concentrations by >25% chemical analyses. UGT1A1 activity is typically reduced
in response to enzyme inducers such as phenobarbital to 10–35% of normal, and bile pigments exhibit a char-
distinguishes CN-II from CN-I, although this response acteristic increase in bilirubin monoglucuronides. Studies
may not be elicited in early infancy and often is of radiobilirubin kinetics indicate that hepatic biliru-
not accompanied by measurable UGT1A1 induction. bin clearance is reduced to an average of one-third of
Bilirubin concentrations during phenobarbital adminis- normal. Administration of phenobarbital normalizes
tration do not return to normal but are typically in the both the serum bilirubin concentration and hepatic bili-
range of 51–86 μmol/L (3–5 mg/dL). Although the rubin clearance; however, failure of UGT1A1 activity
incidence of kernicterus in CN-II is low, instances have to improve in many such instances suggests the pos-
occurred, not only in infants but also in adolescents and sible coexistence of an additional defect. Compartmen-
adults, often in the setting of an intercurrent illness, fast- tal analysis of bilirubin kinetic data suggests that GS
ing, or another factor that temporarily raises the serum patients have a defect in bilirubin uptake as well as in
bilirubin concentration above baseline and reduces conjugation. Defect(s) in the hepatic uptake of other
serum albumin levels. For this reason, phenobarbital organic anions that at least partially share an uptake
mechanism with bilirubin, such as sulfobromophtha- for the phenotypic picture and several different pat- 353
lein and indocyanine green (ICG), are observed in a terns of inheritance. Studies in Europe and the United
minority of patients. The metabolism and transport of States found that nearly all patients had normal cod-
bile acids that do not utilize the bilirubin uptake mech- ing regions for UGT1A1 but were homozygous for
anism, are normal. The magnitude of changes in the the insertion of an extra TA (i.e., A[TA]7TAA rather
plasma bilirubin concentration induced by provocation than A[TA]6TAA) in the promoter region of the first
tests such as 48 hours of fasting or the IV administration exon. This appeared to be necessary, but not suffi-
of nicotinic acid have been reported to be of help in cient, for clinically expressed GS, since 15% of normal
separating GS patients from normal individuals. Other controls were also homozygous for this variant. While
CHAPTER 37
studies dispute this assertion. Moreover, on theoreti- normal by standard criteria, these individuals had some-
cal grounds, the results of such studies should provide what higher bilirubin concentrations than the rest of
no more information than simple measurements of the the controls studied. Heterozygotes for this abnormality
baseline plasma bilirubin concentration. Family studies had bilirubin concentrations identical to those homozy-
indicate that GS and hereditary hemolytic anemias such gous for the normal A[TA]6TAA allele. The prevalence
as hereditary spherocytosis, glucose-6-phosphate dehy- of the A[TA]7TAA allele in a general Western popula-
drogenase deficiency, and β-thalassemia trait sort inde- tion is 30%, in which case 9% would be homozygotes.
The Hyperbilirubinemias
pendently. Reports of hemolysis in up to 50% of GS This is slightly higher than the prevalence of GS based
patients are believed to reflect better case finding, since on purely phenotypic parameters. It was suggested that
patients with both GS and hemolysis have higher biliru- additional variables, such as mild hemolysis or a defect
bin concentrations, and are more likely to be jaundiced, in bilirubin uptake, might be among the factors enhanc-
than patients with either defect alone. ing phenotypic expression of the defect.
GS is common, with many series placing its preva- Phenotypic expression of GS due solely to the
lence at ≥8%. Males predominate over females by A[TA]7TAA promoter abnormality is inherited as an
reported ratios ranging from 1.5:1 to >7:1. However, autosomal recessive trait. A number of CN-II kindreds
these ratios may have a large artifactual component have been identified in whom there is also an allele
since normal males have higher mean bilirubin levels containing a normal coding region but the A[TA]7TAA
than normal females, but the diagnosis of GS is often promoter abnormality. CN-II heterozygotes who have
based on comparison to normal ranges established in the A[TA]6TAA promoter are phenotypically normal,
men. The high prevalence of GS in the general popula- whereas those with the A[TA]7TAA promoter express
tion may explain the reported frequency of mild uncon- the phenotypic picture of GS. GS in such kindreds may
jugated hyperbilirubinemia in liver transplant recipients. also result from homozygosity for the A[TA]7TAA pro-
The disposition of most xenobiotics metabolized by moter abnormality. Seven different missense mutations
glucuronidation appears to be normal in GS, as is oxida- in the UGT1 gene that reportedly cause GS with domi-
tive drug metabolism in the majority of reported stud- nant inheritance have been found in Japanese individu-
ies. The principal exception is the metabolism of the als. Another Japanese patient with mild unconjugated
antitumor agent irinotecan (CPT-11), whose active hyperbilirubinemia was homozygous for a missense
metabolite (SN-38) is glucuronidated specifically by mutation in exon 5. GS in her family appeared to be
bilirubin-UDP-glucuronosyltransferase. Administration of recessive. Missense mutations causing GS have not been
CPT-11 to patients with GS has resulted in several tox- reported outside of certain Asian populations.
icities, including intractable diarrhea and myelosup-
pression. Some reports also suggest abnormal disposition
of menthol, estradiol benzoate, acetaminophen, tolbuta- Disorders of Bilirubin
mide, and rifamycin SV. Although some of these studies Metabolism Leading to Mixed
have been disputed, and there have been no reports of or Predominantly Conjugated
clinical complications from use of these agents in GS, Hyperbilirubinemia
prudence should be exercised in prescribing them, or
any agents metabolized primarily by glucuronidation, In hyperbilirubinemia due to acquired liver disease
in this condition. It should also be noted that the HIV (e.g., acute hepatitis, common bile duct stone), there
protease inhibitors indinavir and atazanavir (Chap. 189) are usually elevations in the serum concentrations of
can inhibit UGT1A1, resulting in hyperbilirubinemia both conjugated and unconjugated bilirubin. Although
that is most pronounced in patients with preexisting GS. biliary tract obstruction or hepatocellular cholestatic
Most older pedigree studies of GS were consistent injury may present on occasion with a predominantly
with autosomal dominant inheritance with variable conjugated hyperbilirubinemia, it is generally not pos-
expressivity. However, studies of the UGT1 gene in sible to differentiate intrahepatic from extrahepatic
GS have indicated a variety of molecular genetic bases causes of jaundice based on the serum levels or relative
354 proportions of unconjugated and conjugated bilirubin. often unnecessary diagnostic examinations for unex-
The major reason for determining the amounts of con- plained jaundice and have high levels of anxiety. In
jugated and unconjugated bilirubin in the serum is for women, the condition may be subclinical until the
the initial differentiation of hepatic parenchymal and patient becomes pregnant or receives oral contra-
obstructive disorders (mixed conjugated and uncon- ceptives, at which time chemical hyperbilirubinemia
jugated hyperbilirubinemia) from the inheritable and becomes frank jaundice. Even in these situations, other
hemolytic disorders discussed above that are associated routine liver function tests, including serum alkaline
with unconjugated hyperbilirubinemia. phosphatase and transaminase activities, are normal.
A cardinal feature of DJS is the accumulation in the
SECTION VI
(Table 37-2). Total bilirubin concentrations are typi- Biliary excretion of a number of anionic compounds
cally between 34 and 85 μmol/L (2 and 5 mg/dL) but is compromised in DJS. These include various cho-
on occasion can be in the normal range or as high as lecystographic agents, as well as sulfobromophthalein
340–430 μmol/L (20–25 mg/dL) and can fluctuate (Bromsulphalein, BSP), a synthetic dye formerly used in
widely in any given patient. The degree of hyperbili- a test of liver function. In this test, the rate of disap-
rubinemia may be increased by intercurrent illness, oral pearance of BSP from plasma was determined following
contraceptive use, and pregnancy. As the hyperbilirubi- bolus IV administration. BSP is conjugated with gluta-
nemia is due to a predominant rise in conjugated biliru- thione in the hepatocyte; the resulting conjugate is nor-
bin, bilirubinuria is characteristically present. Aside from mally excreted rapidly into the bile canaliculus. Patients
elevated serum bilirubin levels, other routine laboratory with DJS exhibit characteristic rises in plasma concen-
tests are normal. Physical examination is usually normal trations at 90 minutes after injection, due to reflux of
except for jaundice, although an occasional patient may conjugated BSP into the circulation from the hepato-
have hepatosplenomegaly. cyte. Dyes such as ICG that are taken up by hepatocytes
Patients with DJS are usually asymptomatic, although but are not further metabolized prior to biliary excre-
some may have vague constitutional symptoms. These tion do not show this reflux phenomenon. Continuous
latter patients have usually undergone extensive and BSP infusion studies suggest a reduction in the tmax for
Table 37-2
Principal Differential Characteristics of Inheritable Disorders of Bile Canalicular Function
DJS Rotor PFIC1 BRIC1 PFIC2 BRIC2 PFIC3
Abbreviations: BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt excretory protein; DJS, Dubin-Johnson syndrome;
γ-GT, γ-glutamyltransferase; MRP2, multidrug resistance–associated protein 2; PFIC, progressive familial intrahepatic cholestasis; ↑↑, increased.
biliary excretion. Bile acid disposition, including hepa- as seen in DJS. Kinetic analysis of plasma BSP infusion 355
tocellular uptake and biliary excretion, is normal in DJS. studies suggests the presence of a defect in intrahepato-
These patients have normal serum and biliary bile acid cellular storage of this compound. This has never been
concentrations and do not have pruritus. demonstrated directly, and the molecular basis of Rotor
By analogy with findings in several mutant rat strains, syndrome remains unknown.
the selective defect in biliary excretion of bilirubin con-
jugates and certain other classes of organic compounds, Benign recurrent intrahepatic
but not of bile acids, that characterizes DJS in humans cholestasis (BRIC)
was found to reflect defective expression of MRP2,
This rare disorder is characterized by recurrent attacks of
CHAPTER 37
an ATP-dependent canalicular membrane transporter.
Several different mutations in the MRP2 gene produce pruritus and jaundice. The typical episode begins with
the Dubin-Johnson phenotype, which has an autoso- mild malaise and elevations in serum aminotransferase
mal recessive pattern of inheritance. Although MRP2 levels, followed rapidly by rises in alkaline phospha-
is undoubtedly important in the biliary excretion of tase and conjugated bilirubin and onset of jaundice and
conjugated bilirubin, the fact that this pigment is still itching. The first one or two episodes may be misdiag-
excreted in the absence of MRP2 suggests that other, nosed as acute viral hepatitis. The cholestatic episodes,
The Hyperbilirubinemias
as yet uncharacterized, transport proteins may serve in a which may begin in childhood or adulthood, can vary
secondary role in this process. in duration from several weeks to months, followed by
Patients with DJS also have a diagnostic abnormal- a complete clinical and biochemical resolution. Intervals
ity in urinary coproporphyrin excretion. There are two between attacks may vary from several months to years.
naturally occurring coproporphyrin isomers, I and III. Between episodes, physical examination is normal, as are
Normally, ∼75% of the coproporphyrin in urine is serum levels of bile acids, bilirubin, transaminases, and
isomer III. In urine from DJS patients, total copro- alkaline phosphatase. The disorder is familial and has
porphyrin content is normal, but >80% is isomer I. an autosomal recessive pattern of inheritance. BRIC is
Heterozygotes for the syndrome show an intermediate considered a benign disorder in that it does not lead to
pattern. The molecular basis for this phenomenon cirrhosis or end-stage liver disease. However, the epi-
remains unclear. sodes of jaundice and pruritus can be prolonged and
debilitating, and some patients have undergone liver
transplantation to relieve the intractable and disabling
Rotor syndrome symptoms. Treatment during the cholestatic episodes is
This benign, autosomal recessive disorder is clinically symptomatic; there is no specific treatment to prevent
similar to DJS (Table 37-2), although it is seen even less or shorten the occurrence of episodes.
frequently. A major phenotypic difference is that the A gene termed FIC1 was recently identified
liver in patients with Rotor syndrome has no increased and found to be mutated in patients with BRIC.
pigmentation and appears totally normal. The only Curiously, this gene is expressed strongly in the small
abnormality in routine laboratory tests is an elevation of intestine but only weakly in the liver. The protein
total serum bilirubin, due to a predominant rise in con- encoded by FIC1 shows little similarity to those that
jugated bilirubin. This is accompanied by bilirubinuria. have been shown to play a role in bile canalicular
Several additional features differentiate Rotor syndrome excretion of various compounds. Rather, it appears to
from DJS. In Rotor syndrome, the gallbladder is usu- be a member of a P-type ATPase family that transports
ally visualized on oral cholecystography, in contrast to aminophospholipids from the outer to the inner leaflet
the nonvisualization that is typical of DJS. The pat- of a variety of cell membranes. Its relationship to the
tern of urinary coproporphyrin excretion also differs. pathobiology of this disorder remains unclear. A sec-
The pattern in Rotor syndrome resembles that of many ond phenotypically identical form of BRIC, termed
acquired disorders of hepatobiliary function, in which BRIC type 2, has been described resulting from muta-
coproporphyrin I, the major coproporphyrin isomer in tions in the bile salt excretory protein (BSEP), the
bile, refluxes from the hepatocyte back into the circula- protein that is defective in progressive familial intra-
tion and is excreted in urine. Thus, total urinary copro- hepatic cholestasis type 2 (Table 37-2). How some
porphyrin excretion is substantially increased in Rotor mutations in this protein result in the episodic BRIC
syndrome, in contrast to the normal levels seen in DJS. phenotype is unknown.
Although the fraction of coproporphyrin I in urine is
elevated, it is usually <70% of the total, compared with
≥80% in DJS. The disorders also can be distinguished by Progressive familial intrahepatic
cholestasis (FIC)
their patterns of BSP excretion. Although clearance of
BSP from plasma is delayed in Rotor syndrome, there This name is applied to three phenotypically related
is no reflux of conjugated BSP back into the circulation syndromes (Table 37-2). Progressive FIC type 1 (Byler
356 disease) presents in early infancy as cholestasis that may excretory protein. As noted above, some mutations of this
be initially episodic. However, in contrast to BRIC, protein are associated with BRIC type 2, rather than
Byler’s disease progresses to malnutrition, growth retar- the progressive FIC type 2 phenotype. Progressive FIC
dation, and end-stage liver disease during childhood. type 3 has been associated with a mutation of MDR3,
This disorder is also a consequence of an FIC1 muta- a protein that is essential for normal hepatocellular
tion. The functional relationship of the FIC1 protein excretion of phospholipids across the bile canaliculus.
to the pathogenesis of cholestasis in these disorders is Although all three types of progressive FIC have similar
unknown. Two other types of progressive FIC (types clinical phenotypes, only type 3 is associated with high
2 and 3) have been described. Progressive FIC type serum levels of γ-glutamyltransferase activity. In con-
SECTION VI
2 is associated with a mutation in the protein named trast, activity of this enzyme is normal or only mildly
sister of p-glycoprotein, which is the major bile canalicu- elevated in symptomatic BRIC and progressive FIC
lar exporter of bile acids and is also known as bile salt types 1 and 2.
Disorders of the Liver and Biliary Tree
CHAPTER 38
Jules L. Dienstag
Figure 38-1
electron micrographs of hepatitis A virus particles 22-nm particles of hepatitis B surface antigen. 132,000×.
and serum from a patient with hepatitis B. Left: 27-nm (Hepatitis D resembles 42-nm virions of hepatitis B but is
hepatitis A virus particles purified from stool of a patient with smaller, 35–37 nm; hepatitis E resembles hepatitis A virus but
acute hepatitis A and aggregated by antibody to hepatitis A is slightly larger, 32–34 nm; hepatitis C has been visualized as
virus. Right: Concentrated serum from a patient with hepatitis B, a 55-nm particle.)
demonstrating the 42-nm virions, tubular forms, and spherical
357
358 Jaundice Pre-S2
Pre-S1
ALT IgG Anti-HAV
IgM Anti-HAV
P
Fecal HAV S
C
SECTION VI
0 4 8 12 16 20 Pre-C
Weeks after exposure
Figure 38-2
Scheme of typical clinical and laboratory features of X
hepatitis A.
Figure 38-3
Disorders of the Liver and Biliary Tree
HAV 27 Icosahedral 7.5-kb RNA, Hepatovirus HAV Anti-HAV Early fecal shedding
nonenveloped linear, 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 circular, HBcAg Anti-HBc Acute diagnosis: HBsAg, IgM anti-HBc
and core) ss/ds HBeAg Anti-HBe Chronic diagnosis: IgG anti-HBc, HBsAg
spherical Markers of replication: HBeAg, HBV DNA
Liver, lymphocytes, other organs
27 Nucleocapsid HBcAg Anti-HBc Nucleocapsid contains DNA and DNA polymerase;
core HBeAg Anti-HBe 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 fluids,
represents hepatocyte cytoplasm; anti-HBs appears following
excess virus infection—protective antibody
coat material
359
HCV Approx. Enveloped 9.4-kb RNA, Hepacivirus HCV Anti-HCV Bloodborne agent, formerly labeled non-A, non-B
40–60 linear, ss, + C100-3 hepatitis
C33c Acute diagnosis: anti-HCV (C33c, C22-3, NS5), HCV RNA
C22-3 Chronic diagnosis: anti-HCV (C100-3, C33c, C22-3, NS5)
NS5 and HCV RNA; cytoplasmic location in hepatocytes
HDV 35–37 Enveloped 1.7-kb RNA, Resembles HBsAg Anti-HBs Defective RNA virus, requires helper function of HBV
hybrid circular, ss, − viroids and plant HDV antigen Anti-HDV (hepadnaviruses); HDV antigen present in hepatocyte
particle with satellite viruses nucleus
HBsAg coat Diagnosis: anti-HDV, HDV RNA; HBV/HDV coinfection—
and HDV core IgM anti-HBc and anti-HDV; HDV superinfection—IgG
anti-HBc and anti-HDV
HEV 32–34 Nonenveloped 7.6-kb RNA, Hepevirus HEV antigen Anti-HEV Agent of enterically transmitted hepatitis; rare in USA;
icosahedral linear, ss, + occurs in Asia, Mediterranean countries, Central America
Diagnosis: IgM/IgG anti-HEV (assays not routinely
available); virus in stool, bile, hepatocyte cytoplasm
spherical and tubular structures is referred to as hepatitis B the protein product is HBeAg, which has a signal pep-
surface antigen (HBsAg). The concentration of HBsAg tide that binds it to the smooth endoplasmic reticulum
and virus particles in the blood may reach 500 μg/mL and leads to its secretion into the circulation. If transla-
and 10 trillion particles per milliliter, respectively. The tion begins with the core region, HBcAg is the protein
envelope protein, HBsAg, is the product of the S gene product; it has no signal peptide, it is not secreted, but it
of HBV. assembles into nucleocapsid particles, which bind to and
A number of different HBsAg subdeterminants have incorporate RNA, and which, ultimately, contain HBV
Disorders of the Liver and Biliary Tree
been identified. There is a common group-reactive DNA. Also packaged within the nucleocapsid core is a
antigen, a, shared by all HBsAg isolates. In addition, DNA polymerase, which directs replication and repair
HBsAg may contain one of several subtype-specific of HBV DNA. When packaging within viral proteins
antigens—namely, d or y, w or r—as well as other more is complete, synthesis of the incomplete plus strand
recently characterized specificities. Hepatitis B isolates stops; this accounts for the single-strand gap and for dif-
fall into one of at least eight subtypes and eight geno- ferences in the size of the gap. HBcAg particles remain
types (A–H). Geographic distribution of genotypes and in the hepatocyte, where they are readily detectable by
subtypes varies; genotypes A (corresponding to subtype immunohistochemical staining, and are exported after
adw) and D (ayw) predominate in the United States and encapsidation by an envelope of HBsAg. Therefore,
Europe, while genotypes B (adw) and C (adr) predomi- naked core particles do not circulate in the serum. The
nate in Asia. Clinical course and outcome are indepen- secreted nucleocapsid protein, HBeAg, provides a con-
dent of subtype, but preliminary reports suggest that venient, readily detectable, qualitative marker of HBV
genotype B is associated with less rapidly progressive replication and relative infectivity.
liver disease and a lower likelihood, or delayed appear- HBsAg-positive serum containing HBeAg is more
ance, of hepatocellular carcinoma than genotype C. likely to be highly infectious and to be associated with
Patients with genotype A appear to be more likely to the presence of hepatitis B virions (and detectable HBV
clear circulating viremia and to achieve HBsAg sero- DNA, discussed later) than HBeAg-negative or anti-HBe-
conversion, both spontaneously and in response to positive serum. For example, HBsAg carrier mothers who
antiviral therapy. In addition, “precore” mutations are are HBeAg-positive almost invariably (>90%) transmit
favored by certain genotypes (discussed later). hepatitis B infection to their offspring, whereas HBsAg
Upstream of the S gene are the pre-S genes carrier mothers with anti-HBe rarely (10–15%) infect
(Fig. 38-3), which code for pre-S gene products, includ- their offspring.
ing receptors on the HBV surface for polymerized Early during the course of acute hepatitis B, HBeAg
human serum albumin and for hepatocyte mem- appears transiently; its disappearance may be a harbinger
brane proteins. The pre-S region actually consists of of clinical improvement and resolution of infection.
both pre-S1 and pre-S2. Depending on where transla- Persistence of HBeAg in serum beyond the first three
tion is initiated, three potential HBsAg gene products months of acute infection may be predictive of the
are synthesized. The protein product of the S gene is development of chronic infection, and the presence of
HBsAg (major protein), the product of the S region plus HBeAg during chronic hepatitis B is associated with
the adjacent pre-S2 region is the middle protein, and the ongoing viral replication, infectivity, and inflammatory
product of the pre-S1 plus pre-S2 plus S regions is the liver injury.
large protein. Compared with the smaller spherical and The third of the HBV genes is the largest, the P gene
tubular particles of HBV, complete 42-nm virions are (Fig. 38-3), which codes for the DNA polymerase; as
enriched in the large protein. Both pre-S proteins and noted earlier, this enzyme has both DNA-dependent
their respective antibodies can be detected during HBV DNA polymerase and RNA-dependent reverse tran-
infection, and the period of pre-S antigenemia appears scriptase activities. The fourth gene, X, codes for
to coincide with other markers of virus replication, as a small, nonparticulate protein, hepatitis B x antigen
detailed later. (HBxAg), that is capable of transactivating the tran-
The intact 42-nm virion contains a 27-nm nucleo- scription of both viral and cellular genes (Fig. 38-3). In
capsid core particle. Nucleocapsid proteins are coded the cytoplasm, HBxAg effects calcium release (possibly
from mitochondria), which activates signal-transduction weeks to months. Because variability exists in the time 361
pathways that lead to stimulation of HBV reverse tran- of appearance of anti-HBs after HBV infection, occa-
scription and HBV DNA replication. Such transactiva- sionally a gap of several weeks or longer may separate
tion may enhance the replication of HBV, leading to the disappearance of HBsAg and the appearance of anti-
the clinical association observed between the expression HBs. During this “gap” or “window” period, anti-HBc
of HBxAg and antibodies to it in patients with severe may represent the only serologic evidence of current
chronic hepatitis and hepatocellular carcinoma. The or recent HBV infection, and blood containing anti-
transactivating activity can enhance the transcription HBc in the absence of HBsAg and anti-HBs has been
and replication of other viruses besides HBV, such as implicated in the development of transfusion-associated
CHAPTER 38
HIV. Cellular processes transactivated by X include the hepatitis B. In part because the sensitivity of immuno-
human interferon γ gene and class I major histocompat- assays for HBsAg and anti-HBs has increased, however,
ibility genes; potentially, these effects could contribute this window period is rarely encountered. In some per-
to enhanced susceptibility of HBV-infected hepatocytes sons, years after HBV infection, anti-HBc may persist in
to cytolytic T cells. The expression of X can also induce the circulation longer than anti-HBs. Therefore, isolated
programmed cell death (apoptosis). anti-HBc does not necessarily indicate active virus rep-
lication; most instances of isolated anti-HBc represent
CHAPTER 38
pre-C gene at nucleotide 1896. This substitution results existence raises a concern that may complicate vaccina-
in the replacement of the TGG tryptophan codon by tion strategies and serologic diagnosis.
a stop codon (TAG), which prevents the translation Different types of mutations emerge during anti-
of HBeAg. Another mutation, in the core-promoter viral therapy of chronic hepatitis B with nucleoside
region, prevents transcription of the coding region for analogues; such “YMDD” and similar mutations
HBeAg and yields an HBeAg-negative phenotype. in the polymerase motif of HBV are described in
Patients with such mutations in the precore region and Chap. 40.
has been described; however, pathophysiologic and amino acids, which is cleaved after translation to yield
clinical consequences of this genetic diversity have not 10 viral proteins. The 5′ end of the genome consists of
been recognized. The clinical spectrum of hepatitis D an untranslated region (containing an internal ribosomal
is common to all seven genotypes identified, the pre- entry site) adjacent to the genes for four structural pro-
dominant of which is genotype 1. teins, the nucleocapsid core protein, C; two envelope
HDV can either infect a person simultaneously glycoproteins, E1 and E2; and a membrane protein p7.
with HBV (co-infection) or superinfect a person already The 5′ untranslated region and core gene are highly
infected with HBV (superinfection); when HDV infec- conserved among genotypes, but the envelope proteins
tion is transmitted from a donor with one HBsAg are coded for by the hypervariable region, which varies
subtype to an HBsAg-positive recipient with a differ- from isolate to isolate and may allow the virus to evade
ent subtype, the HDV agent assumes the HBsAg sub- host immunologic containment directed at accessible
type of the recipient, rather than the donor. Because virus-envelope proteins. The 3′ end of the genome also
HDV relies absolutely on HBV, the duration of HDV includes an untranslated region and contains the genes
infection is determined by the duration of (and cannot for six nonstructural (NS) proteins NS2, NS3, NS4A,
outlast) HBV infection. HDV antigen is expressed pri- NS4B, NS5A, and NS5B. The NS2 cysteine protease
marily in hepatocyte nuclei and is occasionally detect- cleaves NS3 from NS2, and the NS3-4A serine protease
able in serum. During acute HDV infection, anti-HDV cleaves all the downstream proteins from the polyprot-
of the IgM class predominates, and 30–40 days may ein. Important NS proteins involved in virus replication
elapse after symptoms appear before anti-HDV can be include the NS3 helicase, NS3-NS4A serine prote-
detected. In self-limited infection, anti-HDV is low- ase, and the NS5B RNA-dependent RNA polymerase
titer and transient, rarely remaining detectable beyond (Fig. 38-6). Because HCV does not replicate via a
p7 NS4A
Conserved Hypervariable
region region
Figure 38-6
Organization of the hepatitis C virus genome and its asso- the structural proteins is p7, a membrane protein that appears
ciated, 3000 amino-acid (AA) proteins. The three structural to function as an ion channel. At the 3′ end are six nonstructural
genes at the 5′ end are the core region, C, which codes for the (NS) regions, NS2, which codes for a cysteine protease; NS3,
nucleocapsid, and the envelope regions, E1 and E2, which code which codes for a serine protease and an RNA helicase; NS4 and
for envelope glycoproteins. The 5′ untranslated region and the NS4B; NS5A; and NS5B, which codes for an RNA-dependent
C region are highly conserved among isolates, while the enve- RNA polymerase. After translation of the entire polyprotein, indi-
lope domain E2 contains the hypervariable region. Adjacent to vidual proteins are cleaved by both host and viral proteases.
DNA intermediate, it does not integrate into the host 365
genome. Because HCV tends to circulate in relatively Anti-HCV
low titer, 103–107 virions/mL, visualization of virus par- HCV RNA
ticles, estimated to be 40–60 nm in diameter, remains
difficult. Still, the replication rate of HCV is very ALT
high, 1012 virions per day; its half-life is 2.7 h. The
chimpanzee is a helpful but cumbersome animal model.
Although a robust, reproducible, small animal model
is lacking, HCV replication has been documented in
CHAPTER 38
an immunodeficient mouse model containing explants 0 1 2 3 4 5 6 12 24 36 48 60 120
Months after exposure
of human liver and in transgenic mouse and rat models.
Although in vitro replication has been difficult, hepa- Figure 38-7
tocellular carcinoma–derived cell lines have been Scheme of typical laboratory features during acute
described (replicon systems) that support replication of hepatitis C progressing to chronicity. HCV RNA is the first
genetically manipulated, truncated, or full-length HCV detectable event, preceding alanine aminotransferase (ALT)
RNA (but not intact virions). Recently, complete rep-
been detected in stool, bile, and liver and is excreted from the cytoplasm and covalently closed circular viral
in the stool during the late incubation period; immune DNA from the nucleus of infected hepatocytes. Ulti-
responses to viral antigens occur very early during mately, HBV-HLA-specific cytolytic T cell responses of
the course of acute infection. Both IgM anti-HEV the adaptive immune system are felt to be responsible
and IgG anti-HEV can be detected, but both fall for recovery from HBV infection.
rapidly after acute infection, reaching low levels within Debate continues over the relative importance of viral
9–12 months. Currently, serologic testing for HEV and host factors in the pathogenesis of HBV-associated
Disorders of the Liver and Biliary Tree
infection is not available routinely. liver injury and its outcome. As noted earlier, precore
genetic mutants of HBV have been associated with the
more severe outcomes of HBV infection (severe chronic
Pathogenesis and fulminant hepatitis), suggesting that, under cer-
Under ordinary circumstances, none of the hepatitis tain circumstances, relative pathogenicity is a property
viruses is known to be directly cytopathic to hepatocytes. of the virus, not the host. The fact that concomitant
Evidence suggests that the clinical manifestations and HDV and HBV infections are associated with more
outcomes after acute liver injury associated with viral severe liver injury than HBV infection alone and the
hepatitis are determined by the immunologic responses fact that cells transfected in vitro with the gene for
of the host. Among the viral hepatitides, the immuno- HDV (delta) antigen express HDV antigen and then
pathogenesis of hepatitis B and C has been studied most become necrotic in the absence of any immunologic
extensively. influences are also consistent with a viral effect on
pathogenicity. Similarly, in patients who undergo liver
transplantation for end-stage chronic hepatitis B, occa-
Hepatitis B
sionally, rapidly progressive liver injury appears in the
For HBV, the existence of inactive hepatitis B carriers new liver. This clinical pattern is associated with an
with normal liver histology and function suggests unusual histologic pattern in the new liver, fibrosing
that the virus is not directly cytopathic. The fact that cholestatic hepatitis, which, ultrastructurally, appears to
patients with defects in cellular immune competence represent a choking of the cell with overwhelming
are more likely to remain chronically infected rather quantities of HBsAg. This observation suggests that,
than to clear HBV supports the role of cellular immune under the influence of the potent immunosuppressive
responses in the pathogenesis of hepatitis B–related liver agents required to prevent allograft rejection, HBV may
injury. The model that has the most experimental sup- have a direct cytopathic effect on liver cells, indepen-
port involves cytolytic T cells sensitized specifically to dent of the immune system.
recognize host and hepatitis B viral antigens on the liver Although the precise mechanism of liver injury in
cell surface. Nucleocapsid proteins (HBcAg and HBV infection remains elusive, studies of nucleocap-
possibly HBeAg), present on the cell membrane in sid proteins have shed light on the profound immuno-
minute quantities, are the viral target antigens that, with logic tolerance to HBV of babies born to mothers with
host antigens, invite cytolytic T cells to destroy HBV- highly replicative (HBeAg-positive), chronic HBV
infected hepatocytes. Differences in the robustness and infection. In HBeAg-expressing transgenic mice, in
broad polyclonality of CD8+ cytolytic T cell respon- utero exposure to HBeAg, which is sufficiently small to
siveness and in the elaboration of antiviral cytokines by traverse the placenta, induces T cell tolerance to both
T cells have been invoked to explain differences in out- nucleocapsid proteins. This, in turn, may explain why,
comes between those who recover after acute hepatitis, when infection occurs so early in life, immunologic
and those who progress to chronic hepatitis, or between clearance does not occur, and protracted, lifelong infec-
those with mild and those with severe (fulminant) acute tion ensues.
HBV infection. An important distinction should be drawn between
Although a robust cytolytic T cell response occurs HBV infection acquired at birth, common in endemic
and eliminates virus-infected liver cells during acute areas, such as the Far East, and infection acquired in
hepatitis B, >90% of HBV DNA has been found in adulthood, common in the West. Infection in the
neonatal period is associated with the acquisition of HCV-specific CD8 cytotoxic T cells. These responses 367
immunologic tolerance to HBV, absence of an acute appear to be more robust (higher in number, more
hepatitis illness, but the almost invariable establishment diverse in viral antigen specificity, more functionally
of chronic, often lifelong infection. Neonatally acquired effective, and more long lasting) in those who recover
HBV infection can culminate decades later in cirrho- from HCV than in those who have chronic infection.
sis and hepatocellular carcinoma (see “Complications Several HLA alleles have been linked with self-
and Sequelae”). In contrast, when HBV infection is limited hepatitis C, the most convincing of which is
acquired during adolescence or early adulthood, the the C/C haplotype of the IL28B gene. Although atten-
host immune response to HBV infected hepatocytes tion has focused on adaptive immunity, HCV proteins
CHAPTER 38
tends to be robust, an acute hepatitis-like illness is the have been shown to interfere with innate immunity
rule, and failure to recover is the exception. After adult- by resulting in blocking of type 1 interferon responses
hood acquired infection, chronicity is uncommon, and inhibition of interferon signaling and effector mol-
and the risk of hepatocellular carcinoma is very low. ecules in the interferon signaling cascade. Also shown to
Based on these observations, some authorities catego- contribute to limiting HCV infection are natural killer
rize HBV infection into an “immunotolerant” phase, an cells of the innate immune system that function when
“immunoreactive” phase, and an “inactive” phase. This HLA class 1 molecules required for successful adaptive
sis. Hepatic cell regeneration is present, as evidenced a biopsy can be done by the angiographically guided
by numerous mitotic figures, multinucleated cells, and transjugular route, which permits the performance
“rosette” or “pseudoacinar” formation. The mono- of this invasive procedure in the presence of severe
nuclear infiltration consists primarily of small lympho- coagulopathy.
cytes, although plasma cells and eosinophils occasionally Immunohistochemical and electron-microscopic stud-
are present. Liver cell damage consists of hepatic cell ies have localized HBsAg to the cytoplasm and plasma
degeneration and necrosis, cell dropout, ballooning membrane of infected liver cells. In contrast, HBcAg
of cells, and acidophilic degeneration of hepatocytes predominates in the nucleus, but, occasionally, scant
(forming so-called Councilman or apoptotic bodies). amounts are also seen in the cytoplasm and on the cell
Large hepatocytes with a ground-glass appearance of membrane. HDV antigen is localized to the hepato-
the cytoplasm may be seen in chronic but not in acute cyte nucleus, while HAV, HCV, and HEV antigens are
HBV infection; these cells contain HBsAg and can be localized to the cytoplasm.
identified histochemically with orcein or aldehyde
fuchsin. In uncomplicated viral hepatitis, the reticulin
framework is preserved.
In hepatitis C, the histologic lesion is often remark- Epidemiology and Global Features
able for a relative paucity of inflammation, a marked Before the availability of serologic tests for hepa-
increase in activation of sinusoidal lining cells, lymphoid titis viruses, all viral hepatitis cases were labeled
aggregates, the presence of fat (more frequent in geno- either as “infectious” or “serum” hepatitis.
type 3 and linked to increased fibrosis), and, occasion- Modes of transmission overlap, however, and a clear
ally, bile duct lesions in which biliary epithelial cells distinction among the different types of viral hepatitis cannot be
appear to be piled up without interruption of the base- made solely on the basis of clinical or epidemiologic features
ment membrane. Occasionally, microvesicular steatosis (Table 38-2). The most accurate means to distinguish
occurs in hepatitis D. In hepatitis E, a common histo- the various types of viral hepatitis involves specific sero-
logic feature is marked cholestasis. A cholestatic vari- logic testing.
ant of slowly resolving acute hepatitis A also has been
described.
Hepatitis A
A more severe histologic lesion, bridging hepatic necrosis,
also termed subacute or confluent necrosis or interface hepa- This agent is transmitted almost exclusively by the fecal-oral
titis, is observed occasionally in acute hepatitis. “Bridg- route. Person-to-person spread of HAV is enhanced by
ing” between lobules results from large areas of hepatic poor personal hygiene and overcrowding; large out-
cell dropout, with collapse of the reticulin framework. breaks as well as sporadic cases have been traced to
Characteristically, the bridge consists of condensed contaminated food, water, milk, frozen raspberries and
reticulum, inflammatory debris, and degenerating liver strawberries, green onions imported from Mexico, and
cells that span adjacent portal areas, portal to central shellfish. Intrafamily and intrainstitutional spread are also
veins, or central vein to central vein. This lesion had common. Early epidemiologic observations supported a
been thought to have prognostic significance; in many predilection for hepatitis A to occur in late fall and early
of the originally described patients with this lesion, winter. In temperate zones, epidemic waves have been
a subacute course terminated in death within sev- recorded every 5–20 years as new segments of nonim-
eral weeks to months, or severe chronic hepatitis and mune population appeared; however, in developed
Table 38-2 369
Clinical and Epidemiologic Features of Viral Hepatitis
Feature HAV HBV HCV HDV HEV
Incubation (days) 15–45, mean 30–180, mean 60–90 15–160, mean 50 30–180, mean 60–90 14–60,
30 mean 40
Onset Acute Insidious or acute Insidious Insidious or acute Acute
Age preference Children, Young adults (sexual Any age, but more Any age (similar to Young adults
young adults and percutaneous), common in adults HBV) (20–40 years)
babies, toddlers
CHAPTER 38
Transmission
Fecal-oral +++ − − − +++
Percutaneous Unusual +++ +++ +++ −
Perinatal − +++ ±a + −
Sexual ± ++ ±a ++ −
Clinical
a
Primarily with HIV co-infection and high-level viremia in index case; risk ∼5%.
b
Up 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.
d
In acute HBV/HDV co-infection, the frequency of chronicity is the same as that for HBV; in HDV superinfection, chronicity is invariable.
e
10–20% in pregnant women.
f
Common in Mediterranean countries, rare in North America and western Europe.
Abbreviation: HBIG, hepatitis B immunoglobulin.
countries, the incidence of hepatitis A has been declin- never recalled having had a symptomatic case of hepatitis.
ing, presumably as a function of improved sanitation, In subsequent decades, however, the prevalence of
and these cyclic patterns are no longer observed. No anti-HAV has been declining in the United States. In
HAV carrier state has been identified after acute hep- developing countries, exposure, infection, and sub-
atitis A; perpetuation of the virus in nature depends sequent immunity are almost universal in childhood.
presumably on nonepidemic, inapparent subclinical As the frequency of subclinical childhood infections
infection, ingestion of contaminated food or water in, declines in developed countries, a susceptible cohort of
or imported from, endemic areas, and/or contamination adults emerges. Hepatitis A tends to be more symptom-
linked to environmental reservoirs. atic in adults; therefore, paradoxically, as the frequency
In the general population, anti-HAV, a marker for of HAV infection declines, the likelihood of clinically
previous HAV infection, increases in prevalence as a apparent, even severe, HAV illnesses increases in the
function of increasing age and of decreasing socioeco- susceptible adult population. Travel to endemic areas
nomic status. In the 1970s, serologic evidence of prior is a common source of infection for adults from non-
hepatitis A infection occurred in ∼40% of urban pop- endemic areas. More recently recognized epidemio-
ulations in the United States, most of whose members logic foci of HAV infection include child-care centers,
370 neonatal intensive care units, promiscuous men who acute infection in the neonate is clinically asymptom-
have sex with men, and injection drug users. Although atic, but the child is very likely to remain chronically
hepatitis A is rarely bloodborne, several outbreaks infected.
have been recognized in recipients of clotting-factor The >350–400 million HBsAg carriers in the world
concentrates. In the United States, the introduction of constitute the main reservoir of hepatitis B in human
hepatitis A vaccination programs among children from beings. Whereas serum HBsAg is infrequent (0.1–0.5%) in
high-incidence states has resulted in a >70% reduction normal populations in the United States and western Europe,
in the annual incidence of new HAV infections and has a prevalence of up to 5–20% has been found in the Far East
shifted the burden of new infections from children to and in some tropical countries; in persons with Down’s
SECTION VI
label for the epidemiologic spectrum of HBV infec- blood; persons who require repeated transfusions espe-
tion recognized today. As detailed later, most of the cially with pooled blood-product concentrates (e.g.,
hepatitis transmitted by blood transfusion is not caused hemophiliacs); residents and staff of custodial institu-
by HBV; moreover, in approximately two-thirds of tions for the developmentally handicapped; prisoners;
patients with acute type B hepatitis, no history of an and, to a lesser extent, family members of chronically
identifiable percutaneous exposure can be elicited. We infected patients. In volunteer blood donors, the preva-
now recognize that many cases of hepatitis B result lence of anti-HBs, a reflection of previous HBV infec-
from less obvious modes of nonpercutaneous or covert tion, ranges from 5–10%, but the prevalence is higher
percutaneous transmission. HBsAg has been identi- in lower socioeconomic strata, older age groups, and
fied in almost every body fluid from infected persons, persons—including those mentioned earlier—exposed
and at least some of these body fluids—most notably to blood products. Because of highly sensitive virologic
semen and saliva—are infectious, albeit less so than screening of donor blood, the risk of acquiring HBV
serum, when administered percutaneously or non- infection from a blood transfusion is 1 in 230,000.
percutaneously to experimental animals. Among the Prevalence of infection, modes of transmission, and
nonpercutaneous modes of HBV transmission, oral human behavior conspire to mold geographically dif-
ingestion has been documented as a potential but inef- ferent epidemiologic patterns of HBV infection. In the
ficient route of exposure. By contrast, the two non- Far East and Africa, hepatitis B, a disease of the new-
percutaneous routes considered to have the greatest born and young children, is perpetuated by a cycle of
impact are intimate (especially sexual) contact and maternal-neonatal spread. In North America and west-
perinatal transmission. ern Europe, hepatitis B is primarily a disease of ado-
In sub-Saharan Africa, intimate contact among lescence and early adulthood, the time of life when
toddlers is considered instrumental in contributing to the intimate sexual contact as well as recreational and occu-
maintenance of the high frequency of hepatitis B in the pational percutaneous exposures tend to occur. To
population. Perinatal transmission occurs primarily in some degree, however, this dichotomy between high-
infants born to HBsAg carrier mothers or mothers with prevalence and low-prevalence geographic regions has
acute hepatitis B during the third trimester of pregnancy been minimized by immigration from high-prevalence
or during the early postpartum period. Perinatal trans- to low-prevalence areas. The introduction of hepatitis
mission is uncommon in North America and western B vaccine in the early 1980s and adoption of univer-
Europe but occurs with great frequency and is the most sal childhood vaccination policies in many countries
important mode of HBV perpetuation in the Far East resulted in a dramatic, ∼90%, decline in the incidence of
and developing countries. Although the precise mode of new HBV infections in those countries as well as in the
perinatal transmission is unknown, and although ∼10% dire consequences of chronic infection, including hepa-
of infections may be acquired in utero, epidemiologic tocellular carcinoma. Populations and groups for whom
evidence suggests that most infections occur approx- HBV-infection screening is recommended are listed in
imately at the time of delivery and are not related to Table 38-3.
breast-feeding. The likelihood of perinatal transmis-
sion of HBV correlates with the presence of HBeAg
Hepatitis D
and high-level viral replication; 90% of HBeAg-positive
mothers but only 10–15% of anti-HBe-positive mothers Infection with HDV has a worldwide distribution, but
transmit HBV infection to their offspring. In most cases, two epidemiologic patterns exist. In Mediterranean
Table 38-3 Hepatitis C 371
High-Risk Populations for Which
Routine screening of blood donors for HBsAg and the
HBV-Infection Screening Is Recommended
elimination of commercial blood sources in the early
Persons born in countries/regions with a high (>8%) and 1970s reduced the frequency of, but did not elimi-
intermediate (>2%) prevalence of HBV infection including
nate, transfusion-associated hepatitis. During the 1970s,
immigrants and adopted children and including persons
born in the United States who were not vaccinated as the likelihood of acquiring hepatitis after transfusion of
infants and whose parents immigrated from areas of high voluntarily donated, HBsAg-screened blood was ∼10%
HBV endemicity per patient (up to 0.9% per unit transfused); 90–95% of
Household and sexual contacts of persons with hepatitis B these cases were classified, based on serologic exclusion
CHAPTER 38
Persons who have used injection drugs of hepatitis A and B, as “non-A, non-B” hepatitis. For
Persons with multiple sexual contacts or a history of patients requiring transfusion of pooled products, such
sexually transmitted disease
as clotting factor concentrates, the risk was even higher,
Men who have sex with men
Inmates of correctional facilities
up to 20–30%.
Persons with elevated alanine or aspartate aminotransferase During the 1980s, voluntary self-exclusion of blood
levels donors with risk factors for AIDS and then the intro-
able risk factors; 0.5% of volunteer blood donors; and, in is rare between stable, monogamous sexual partners.
the most recent survey conducted in the United States Breast-feeding does not increase the risk of HCV infec-
between 1999 and 2000, 1.6% of the general population tion between an infected mother and her infant. Infec-
in the United States, which translates into 4.1 million tion of health workers is not dramatically higher than
persons (3.2 million with viremia). Comparable frequen- among the general population; however, health workers
cies of HCV infection occur in most countries around are more likely to acquire HCV infection through acci-
the world, with 170 million persons infected worldwide, dental needle punctures, the efficiency of which is ∼3%.
Disorders of the Liver and Biliary Tree
but extraordinarily high prevalences of HCV infection Infection of household contacts is rare as well.
occur in certain countries such as Egypt, where >20% Other groups with an increased frequency of HCV
of the population in some cities is infected. The high infection include patients who require hemodialysis and
frequency in Egypt is attributable to contaminated organ transplantation, those who require transfusions
equipment used for medical procedures and unsafe in the setting of cancer chemotherapy, HIV-infected
injection practices in the 1970s. In the United States, persons, and persons with unexplained serum amino-
African Americans and Mexican Americans have higher transferase elevations. In immunosuppressed individuals,
frequencies of HCV infection than whites. Between levels of anti-HCV may be undetectable, and a diag-
1988 and 1994, 30- to 40-year-old adult males had nosis may require testing for HCV RNA. Although
the highest prevalence of HCV infection; however, in new acute cases of hepatitis C are rare, newly diag-
a survey conducted between 1999 and 2000, the peak nosed cases are common among otherwise healthy per-
age decile had shifted to those age 40–49 years; an sons who experimented briefly with injection drugs, as
increase in hepatitis C–related mortality has paralleled noted earlier, 2 or 3 decades earlier. Such instances usu-
this secular trend, increasing since 1995 predominantly ally remain unrecognized for years, until unearthed by
in the 55- to 64-year age group. Thus, despite an 80% laboratory screening for routine medical examinations,
reduction in new HCV infections during the 1990s, the insurance applications, and attempted blood donation.
prevalence of HCV infection in the population was sus- Populations groups for whom HCV-infection screening
tained by an aging cohort that had acquired their infec- is recommended are listed in Table 38-4.
tions 2 to 3 decades earlier, during the 1960s and 1970s,
as a result predominantly of self-inoculation with recre- Hepatitis E
ational drugs. Hepatitis C accounts for 40% of chronic
liver disease, is the most frequent indication for liver This type of hepatitis, identified in India, Asia, Africa, the
transplantation, and is estimated to account for 8000– Middle East, and Central America, resembles hepatitis A
10,000 deaths per year in the United States.
The distribution of HCV genotypes varies in different
Table 38-4
parts of the world. Worldwide, genotype 1 is the most
common. In the United States, genotype 1 accounts for High-Risk Populations for Which
70% of HCV infections, while genotypes 2 and3 account HCV-Infection Screening Is Recommended
for the remaining 30%; among African Americans, the Persons who have used injection drugs or those who have
frequency of genotype 1 is even higher (i.e., 90%). Geno- used illicit drugs by noninjection routes
Persons with HIV infection
type 4 predominates in Egypt; genotype 5 is localized to
Hemophiliacs treated with clotting factor concentrates
South Africa, and genotype 6 to Hong Kong. prior to 1987
Most asymptomatic blood donors found to have Hemodialysis patients
anti-HCV and ∼20–30% of persons with reported cases Persons with unexplained elevations of aminotransferase levels
of acute hepatitis C do not fall into a recognized risk Transfusion or transplantation recipients prior to July 1992
group; however, many such blood donors do recall Children born to women with hepatitis C
risk-associated behaviors when questioned carefully. Health care, public safety, and emergency medical
As a bloodborne infection, HCV potentially can be personnel following needle injury or mucosal exposure to
HCV-contaminated blood
transmitted sexually and perinatally; however, both of Sexual partners of persons with hepatitis C infection
these modes of transmission are inefficient for hepatitis C.
in its primarily enteric mode of spread. The commonly liver enlargement and abnormalities in liver biochemi- 373
recognized cases occur after contamination of water cal tests are still evident. The duration of the posticteric
supplies such as after monsoon flooding, but sporadic, phase is variable, ranging 2–12 weeks, and is usually
isolated cases occur. An epidemiologic feature that dis- more prolonged in acute hepatitis B and C. Complete
tinguishes HEV from other enteric agents is the rarity of clinical and biochemical recovery is to be expected
secondary person-to-person spread from infected persons 1–2 months after all cases of hepatitis A and E and
to their close contacts. Infections arise in populations that 3–4 months after the onset of jaundice in three-quarters
are immune to HAV and favor young adults. In endemic of uncomplicated, self-limited cases of hepatitis B and
areas, the prevalence of antibodies to HEV is ≤40%. In C (among healthy adults, acute hepatitis B is self-lim-
CHAPTER 38
nonendemic areas of the world, such as the United States, ited in 95–99% while hepatitis C is self-limited in only
clinically apparent acute hepatitis E is extremely rare; ∼15%). In the remainder, biochemical recovery may be
however, the prevalence of antibodies to HEV can be delayed. A substantial proportion of patients with viral
as high as 20% in such areas. In nonendemic areas, HEV hepatitis never become icteric.
does not account for any of the sporadic “non-A, non-B” Infection with HDV can occur in the presence of
cases of hepatitis; however, cases imported from endemic acute or chronic HBV infection; the duration of HBV
areas have been found in the United States. Several infection determines the duration of HDV infection.
When jaundice appears, the serum bilirubin typically rises and C. Tests for fecal or serum HAV are not routinely
to levels ranging from 85–340 μmol/L (5–20 mg/dL). available. Therefore, a diagnosis of hepatitis A is based
The serum bilirubin may continue to rise despite fall- on detection of IgM anti-HAV during acute illness
ing serum aminotransferase levels. In most instances, (Fig. 38-2). Rheumatoid factor can give rise to false-
the total bilirubin is equally divided between the con- positive results in this test.
jugated and unconjugated fractions. Bilirubin levels A diagnosis of HBV infection can usually be made
>340 μmol/L (20 mg/dL) extending and persisting by detection of HBsAg in serum. Infrequently, levels of
Disorders of the Liver and Biliary Tree
late into the course of viral hepatitis are more likely HBsAg are too low to be detected during acute HBV
to be associated with severe disease. In certain patients infection, even with contemporary, highly sensitive
with underlying hemolytic anemia, however, such as immunoassays. In such cases, the diagnosis can be estab-
glucose-6-phosphate dehydrogenase deficiency and sickle lished by the presence of IgM anti-HBc.
cell anemia, a high serum bilirubin level is common, The titer of HBsAg bears little relation to the severity
resulting from superimposed hemolysis. In such patients, of clinical disease. Indeed, an inverse correlation exists
bilirubin levels >513 μmol/L (30 mg/dL) have been between the serum concentration of HBsAg and the
observed and are not necessarily associated with a poor degree of liver cell damage. For example, titers are high-
prognosis. est in immunosuppressed patients, lower in patients with
Neutropenia and lymphopenia are transient and are chronic liver disease (but higher in mild chronic than
followed by a relative lymphocytosis. Atypical lympho- in severe chronic hepatitis), and very low in patients
cytes (varying between 2 and 20%) are common dur- with acute fulminant hepatitis. These observations sug-
ing the acute phase. Measurement of the prothrombin gest that, in hepatitis B, the degree of liver cell damage
time (PT) is important in patients with acute viral hepa- and the clinical course are related to variations in the
titis, for a prolonged value may reflect a severe hepatic patient’s immune response to HBV rather than to the
synthetic defect, signify extensive hepatocellular necro- amount of circulating HBsAg. In immunocompetent
sis, and indicate a worse prognosis. Occasionally, a pro- persons, however, a correlation exists between markers
longed PT may occur with only mild increases in the of HBV replication and liver injury (discussed later).
serum bilirubin and aminotransferase levels. Prolonged Another serologic marker that may be of value in
nausea and vomiting, inadequate carbohydrate intake, patients with hepatitis B is HBeAg. Its principal clini-
and poor hepatic glycogen reserves may contribute to cal usefulness is as an indicator of relative infectivity.
hypoglycemia noted occasionally in patients with severe Because HBeAg is invariably present during early acute
viral hepatitis. Serum alkaline phosphatase may be hepatitis B, HBeAg testing is indicated primarily during
normal or only mildly elevated, while a fall in serum follow-up of chronic infection.
albumin is uncommon in uncomplicated acute viral In patients with hepatitis B surface antigenemia of
hepatitis. In some patients, mild and transient steator- unknown duration (e.g., blood donors found to be
rhea has been noted as well as slight microscopic hema- HBsAg-positive and referred to a physician for evalu-
turia and minimal proteinuria. ation), testing for IgM anti-HBc may be useful to
A diffuse but mild elevation of the γ globulin fraction distinguish between acute or recent infection (IgM
is common during acute viral hepatitis. Serum IgG and anti-HBc-positive) and chronic HBV infection (IgM
IgM levels are elevated in about one-third of patients anti-HBc-negative, IgG anti-HBc-positive). A false-
during the acute phase of viral hepatitis, but the serum positive test for IgM anti-HBc may be encountered in
IgM level is elevated more characteristically during patients with high-titer rheumatoid factor.
acute hepatitis A. During the acute phase of viral hepa- Anti-HBs is rarely detectable in the presence of
titis, antibodies to smooth muscle and other cell constit- HBsAg in patients with acute hepatitis B, but 10–20%
uents may be present, and low titers of rheumatoid fac- of persons with chronic HBV infection may harbor low-
tor, nuclear antibody, and heterophil antibody can also level anti-HBs. This antibody is directed not against
be found occasionally. In hepatitis C and D, antibodies the common group determinant, a, but against the
to LKM may occur; however, the species of LKM anti- heterotypic subtype determinant (e.g., HBsAg of sub-
bodies in the two types of hepatitis are different from type ad with anti-HBs of subtype y). In most cases, this
serologic pattern cannot be attributed to infection with DNA levels, increased expression of viral antigens, and 375
two different HBV subtypes, and the presence of necroinflammatory activity in the liver go hand in hand
this antibody is not a harbinger of imminent HBsAg unless immunosuppression interferes with cytolytic
clearance. When such antibody is detected, its presence T cell responses to virus-infected cells; reduction
is of no recognized clinical significance (see “Virology of HBV replication with antiviral drugs tends to be
and Etiology”). accompanied by an improvement in liver histology.
After immunization with hepatitis B vaccine, which Among patients with chronic hepatitis B, high lev-
consists of HBsAg alone, anti-HBs is the only serologic els of HBV DNA increase the risk of cirrhosis, hepatic
marker to appear. The commonly encountered sero- decompensation, and hepatocellular carcinoma (see
CHAPTER 38
logic patterns of hepatitis B and their interpretations “Complications and Sequelae”).
are summarized in Table 38-5. Tests for the detection In patients with hepatitis C, an episodic pattern of
of HBV DNA in liver and serum are now available. aminotransferase elevation is common. A specific sero-
Like HBeAg, serum HBV DNA is an indicator of HBV logic diagnosis of hepatitis C can be made by demon-
replication, but tests for HBV DNA are more sensitive strating the presence in serum of anti-HCV. When
and quantitative. First-generation hybridization assays contemporary immunoassays are used, anti-HCV can
for HBV DNA had a sensitivity of 105–106 virions/ be detected in acute hepatitis C during the initial phase
Table 38-5
Commonly Encountered Serologic Patterns of Hepatitis B Infection
HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe Interpretation
tis caused by an unidentified agent can be entertained. Liver biopsy is rarely necessary or indicated in acute
Amplification techniques are required to detect viral hepatitis, except when the diagnosis is question-
HCV RNA, and two types are available. One is a able or when clinical evidence suggests a diagnosis of
branched-chain complementary DNA (bDNA) assay, chronic hepatitis.
in which the detection signal (a colorimetrically detect- A diagnostic algorithm can be applied in the evalu-
able enzyme bound to a complementary DNA probe) is ation of cases of acute viral hepatitis. A patient with
amplified. The other involves target amplification (i.e., acute hepatitis should undergo four serologic tests,
Disorders of the Liver and Biliary Tree
synthesis of multiple copies of the viral genome). This HBsAg, IgM anti-HAV, IgM anti-HBc, and anti-HCV
can be done by PCR or TMA, in which the viral RNA (Table 38-6). The presence of HBsAg, with or with-
is reverse transcribed to complementary DNA and then out IgM anti-HBc, represents HBV infection. If IgM
amplified by repeated cycles of DNA synthesis. Both anti-HBc is present, the HBV infection is considered
can be used as quantitative assays and a measurement of acute; if IgM anti-HBc is absent, the HBV infection is
relative “viral load”; PCR and TMA, with a sensitiv-
ity of 10–102 IU/mL, are more sensitive than bDNA,
with a sensitivity of 103 IU/mL; assays are available with Table 38-6
a wide dynamic range (10–107 IU/mL). Determination Simplified Diagnostic Approach in Patients
of HCV RNA level is not a reliable marker of disease Presenting With Acute Hepatitis
severity or prognosis but is helpful in predicting relative Serologic Tests of Patient’s Serum
responsiveness to antiviral therapy. The same is true for
determinations of HCV genotype (Chap. 40). IgM IgM Anti- Diagnostic
HBsAg Anti-HAV Anti-HBc HCV Interpretation
A proportion of patients with hepatitis C have isolated
anti-HBc in their blood, a reflection of a common risk in + − + − Acute
certain populations of exposure to multiple bloodborne hepatitis B
hepatitis agents. The anti-HBc in such cases is almost + − − − Chronic
invariably of the IgG class and usually represents HBV hepatitis B
infection in the remote past (HBV DNA undetectable), + + − − Acute
rarely current HBV infection with low-level virus carriage. hepatitis A
The presence of HDV infection can be identified by superimposed
demonstrating intrahepatic HDV antigen or, more prac- on chronic
hepatitis B
tically, an anti-HDV seroconversion (a rise in titer of
anti-HDV or de novo appearance of anti-HDV). Circu- + + + − Acute hepatitis
lating HDV antigen, also diagnostic of acute infection, A and B
is detectable only briefly, if at all. Because anti-HDV is − + − − Acute
often undetectable once HBsAg disappears, retrospec- hepatitis A
tive serodiagnosis of acute self-limited, simultaneous − + + − Acute
HBV and HDV infection is difficult. Early diagnosis of hepatitis A
acute infection may be hampered by a delay of up to and B
(HBsAg below
30–40 days in the appearance of anti-HDV.
detection
When a patient presents with acute hepatitis and has threshold)
HBsAg and anti-HDV in serum, determination of the
− − + − Acute hepati-
class of anti-HBc is helpful in establishing the relation-
tis B (HBsAg
ship between infection with HBV and HDV. Although below
IgM anti-HBc does not distinguish absolutely between detection
acute and chronic HBV infection, its presence is a threshold)
reliable indicator of recent infection and its absence − − − + Acute
a reliable indicator of infection in the remote past. In hepatitis C
simultaneous acute HBV and HDV infections, IgM
considered chronic. A diagnosis of acute hepatitis B can and underlying debilitating disorders. Among patients 377
be made in the absence of HBsAg when IgM anti-HBc ill enough to be hospitalized for acute hepatitis B, the
is detectable. A diagnosis of acute hepatitis A is based on fatality rate is 1%. Hepatitis C is less severe during the
the presence of IgM anti-HAV. If IgM anti-HAV coex- acute phase than hepatitis B and is more likely to be
ists with HBsAg, a diagnosis of simultaneous HAV and anicteric; fatalities are rare, but the precise case fatality
HBV infections can be made; if IgM anti-HBc (with rate is not known. In outbreaks of waterborne hepatitis
or without HBsAg) is detectable, the patient has simul- E in India and Asia, the case fatality rate is 1–2% and up
taneous acute hepatitis A and B, and if IgM anti-HBc to 10–20% in pregnant women. Patients with simulta-
is undetectable, the patient has acute hepatitis A super- neous acute hepatitis B and hepatitis D do not necessar-
CHAPTER 38
imposed on chronic HBV infection. The presence of ily experience a higher mortality rate than do patients
anti-HCV supports a diagnosis of acute hepatitis C. with acute hepatitis B alone; however, in several recent
Occasionally, testing for HCV RNA or repeat anti- outbreaks of acute simultaneous HBV and HDV infec-
HCV testing later during the illness is necessary to tion among injection drug users, the case fatality rate
establish the diagnosis. Absence of all serologic markers has been ∼5%. In the case of HDV superinfection of a
is consistent with a diagnosis of “non-A, non-B, non- person with chronic hepatitis B, the likelihood of ful-
C” hepatitis, if the epidemiologic setting is appropriate. minant hepatitis and death is increased substantially.
fulminant cases of hepatitis A occur primarily in older tion is especially high among neonates, persons with
adults and in persons with underlying chronic liver Down’s syndrome, chronically hemodialyzed patients,
disease, including, according to some reports, chronic and immunosuppressed patients, including persons with
hepatitis B and C. Hepatitis B accounts for >50% of HIV infection.
fulminant cases of viral hepatitis, a sizable propor- Chronic hepatitis is an important late complication
tion of which are associated with HDV infection and of acute hepatitis B occurring in a small proportion of
another proportion with underlying chronic hepatitis C. patients with acute disease but more common in those
Disorders of the Liver and Biliary Tree
Fulminant hepatitis is hardly ever seen in hepatitis C, who present with chronic infection without having
but hepatitis E, as noted earlier, can be complicated experienced an acute illness, as occurs typically after
by fatal fulminant hepatitis in 1–2% of all cases and in neonatal infection or after infection in an immunosup-
up to 20% of cases in pregnant women. Patients usu- pressed host (Chap. 40). Certain clinical and laboratory
ally present with signs and symptoms of encephalopa- features suggest progression of acute hepatitis to chronic
thy that may evolve to deep coma. The liver is usually hepatitis: (1) lack of complete resolution of clinical
small and the PT excessively prolonged. The combina- symptoms of anorexia, weight loss, fatigue, and the per-
tion of rapidly shrinking liver size, rapidly rising biliru- sistence of hepatomegaly; (2) the presence of bridging/
bin level, and marked prolongation of the PT, even as interface or multilobular hepatic necrosis on liver biopsy
aminotransferase levels fall, together with clinical signs during protracted, severe acute viral hepatitis; (3) fail-
of confusion, disorientation, somnolence, ascites, and ure of the serum aminotransferase, bilirubin, and globu-
edema, indicates that the patient has hepatic failure with lin levels to return to normal within 6–12 months after
encephalopathy. Cerebral edema is common; brainstem the acute illness; and (4) the persistence of HBeAg for
compression, gastrointestinal bleeding, sepsis, respira- >3 months or HBsAg for >6 months after acute hepatitis.
tory failure, cardiovascular collapse, and renal failure are Although acute hepatitis D infection does not
terminal events. The mortality rate is exceedingly high increase the likelihood of chronicity of simultaneous
(>80% in patients with deep coma), but patients who acute hepatitis B, hepatitis D has the potential for
survive may have a complete biochemical and histologic contributing to the severity of chronic hepatitis B.
recovery. If a donor liver can be located in time, liver Hepatitis D superinfection can transform inactive or
transplantation may be life-saving in patients with ful- mild chronic hepatitis B into severe, progressive chronic
minant hepatitis (Chap. 46). hepatitis and cirrhosis; it also can accelerate the course
Documenting the disappearance of HBsAg after of chronic hepatitis B. Some HDV superinfections in
apparent clinical recovery from acute hepatitis B is par- patients with chronic hepatitis B lead to fulminant hep-
ticularly important. Before laboratory methods were atitis. As defined in longitudinal studies over 3 decades,
available to distinguish between acute hepatitis and acute the annual rates of cirrhosis and hepatocellular carci-
hepatitis-like exacerbations (spontaneous reactivations) of noma in patients with chronic hepatitis D are 4% and
chronic hepatitis B, observations suggested that ∼10% 2.8%, respectively. Although HDV and HBV infections
of previously healthy patients remained HBsAg-posi- are associated with severe liver disease, mild hepatitis
tive for >6 months after the onset of clinically appar- and even inactive carriage have been identified in some
ent acute hepatitis B. One-half of these persons cleared patients, and the disease may become indolent beyond
the antigen from their circulations during the next the early years of infection.
several years, but the other 5% remained chronically After acute HCV infection, the likelihood of remain-
HBsAg-positive. More recent observations suggest ing chronically infected approaches 85–90%. Although
that the true rate of chronic infection after clinically many patients with chronic hepatitis C have no symp-
apparent acute hepatitis B is as low as 1% in normal, toms, cirrhosis may develop in as many as 20% within
immunocompetent, young adults. Earlier, higher esti- 10–20 years of acute illness; in some series of cases
mates may have been confounded by inadvertent inclu- reported by referral centers, cirrhosis has been reported
sion of acute exacerbations in chronically infected in as many as 50% of patients with chronic hepatitis
patients; these patients, chronically HBsAg-positive C. Although chronic hepatitis C accounts for at least
before exacerbation, were unlikely to seroconvert to 40% of cases of chronic liver disease and of patients
undergoing liver transplantation for end-stage liver dis- other stigmata of alcoholism may be present. The find- 379
ease in the United States and Europe, in the majority of ing on liver biopsy of fatty infiltration, a neutrophilic
patients with chronic hepatitis C, morbidity and mortal- inflammatory reaction, and “alcoholic hyaline” would
ity are limited during the initial 20 years after the onset be consistent with alcohol-induced rather than viral
of infection. Progression of chronic hepatitis C may liver injury. Because acute hepatitis may present with
be influenced by age of acquisition, duration of infec- right upper quadrant abdominal pain, nausea and vom-
tion, immunosuppression, coexisting excessive alco- iting, fever, and icterus, it is often confused with acute
hol use, concomitant hepatic steatosis, other hepatitis cholecystitis, common duct stone, or ascending cholan-
virus infection, or HIV co-infection. In fact, instances gitis. Patients with acute viral hepatitis may tolerate sur-
CHAPTER 38
of severe and rapidly progressive chronic hepatitis B and gery poorly; therefore, it is important to exclude this
C are being recognized with increasing frequency in diagnosis, and in confusing cases, a percutaneous liver
patients with HIV infection. In contrast, neither HAV biopsy may be necessary before laparotomy. Viral hepa-
nor HEV causes chronic liver disease. titis in the elderly is often misdiagnosed as obstructive
Rare complications of viral hepatitis include pancreati- jaundice resulting from a common duct stone or car-
tis, myocarditis, atypical pneumonia, aplastic anemia, cinoma of the pancreas. Because acute hepatitis in the
transverse myelitis, and peripheral neuropathy. Persons elderly may be quite severe and the operative mortality
patients. In a German multicenter study of 44 patients longer recommended. Although gloves should be worn
with acute symptomatic hepatitis C, initiation of inten- when the bedpans or fecal material of patients with
sive interferon alfa therapy (5 million units SC daily for hepatitis A are handled, these precautions do not rep-
4 weeks, then three times a week for another 20 weeks) resent a departure from sensible procedure and con-
within an average of 3 months after infection resulted temporary universal precautions for all hospitalized
in a sustained virologic response rate of 98%. Although patients. For patients with hepatitis B and hepatitis C,
Disorders of the Liver and Biliary Tree
treatment of acute hepatitis C is recommended, the emphasis should be placed on blood precautions (i.e.,
optimum regimen, duration of therapy, and time to ini- avoiding direct, ungloved hand contact with blood and
tiate therapy remain to be determined. Many authori- other body fluids). Enteric precautions are unnecessary.
ties now opt for a 24-week course (beginning within The importance of simple hygienic precautions such
2–3 months after onset) of the best regimen identified as hand washing cannot be overemphasized. Univer-
for the treatment of chronic hepatitis C, long-acting sal precautions that have been adopted for all patients
pegylated interferon plus the nucleoside analogue apply to patients with viral hepatitis.
ribavirin, although the value of adding ribavirin has not Hospitalized patients may be discharged following
been demonstrated (see Chap. 40 for doses). Because substantial symptomatic improvement, a significant
of the marked reduction over the past 2 decades in the downward trend in the serum aminotransferase and
frequency of acute hepatitis C, opportunities to iden- bilirubin values, and a return to normal of the PT. Mild
tify and treat patients with acute hepatitis C are rare, aminotransferase elevations should not be considered
except in injection drug users. Hospital epidemiologists, contraindications to the gradual resumption of normal
however, will encounter health workers who sustain activity.
hepatitis C-contaminated needle sticks; when moni- In fulminant hepatitis, the goal of therapy is to sup-
toring for ALT elevations and HCV, RNA after these port the patient by maintenance of fluid balance, sup-
accidents identifies acute hepatitis C (risk only ∼3%), port of circulation and respiration, control of bleeding,
therapy should be initiated. correction of hypoglycemia, and treatment of other
Notwithstanding these specific therapeutic consid- complications of the comatose state in anticipation of
erations, in most cases of typical acute viral hepatitis, liver regeneration and repair. Protein intake should be
specific treatment generally is not necessary. Although restricted, and oral lactulose or neomycin administered.
hospitalization may be required for clinically severe ill- Glucocorticoid therapy has been shown in controlled
ness, most patients do not require hospital care. Forced trials to be ineffective. Likewise, exchange transfusion,
and prolonged bed rest is not essential for full recov- plasmapheresis, human cross-circulation, porcine liver
ery, but many patients will feel better with restricted cross-perfusion, hemoperfusion, and extracorporeal liver-
physical activity. A high-calorie diet is desirable, and assist devices have not been proven to enhance survival.
because many patients may experience nausea late in Meticulous intensive care that includes prophylactic
the day, the major caloric intake is best tolerated in the antibiotic coverage is the one factor that does appear
morning. Intravenous feeding is necessary in the acute to improve survival. Orthotopic liver transplantation is
stage if the patient has persistent vomiting and can- resorted to with increasing frequency, with excellent
not maintain oral intake. Drugs capable of producing results, in patients with fulminant hepatitis (Chap. 46).
adverse reactions such as cholestasis and drugs metab-
olized by the liver should be avoided. If severe pruritus
is present, the use of the bile salt-sequestering resin Prophylaxis
cholestyramine is helpful. Glucocorticoid therapy has Because application of therapy for acute viral hepatitis
no value in acute viral hepatitis, even in severe cases is limited and because antiviral therapy for chronic viral
associated with bridging necrosis, and may be deleteri- hepatitis is cumbersome and costly but effective in only
ous, even increasing the risk of chronicity (e.g., of acute a proportion of patients (Chap. 40), emphasis is placed
hepatitis B). on prevention through immunization. The prophylactic
approach differs for each of the types of viral hepatitis.
In the past, immunoprophylaxis relied exclusively on (protective levels of anti-HAV should last 20 years after 381
passive immunization with antibody-containing globu- vaccination), persons whose risk will be sustained (e.g.,
lin preparations purified by cold ethanol fractionation frequent travelers or those remaining in endemic areas
from the plasma of hundreds of normal donors. Cur- for prolonged periods) should be vaccinated, and vac-
rently, for hepatitis A and B, active immunization with cine should supplant the need for repeated IG injec-
vaccines is the preferable approach to prevention. tions. Shortly after its introduction, hepatitis A vaccine
was recommended for children living in communities
Hepatitis A with a high incidence of HAV infection; in 1999, this
recommendation was extended to include all children
CHAPTER 38
Both passive immunization with IG and active immu- living in states, counties, and communities with high
nization with killed vaccines are available. All prepara- rates of HAV infection. As of 2006, the Advisory
tions of IG contain anti-HAV concentrations sufficient Committee on Immunization Practices of the U.S.
to be protective. When administered before exposure Public Health Service recommended routine hepatitis A
or during the early incubation period, IG is effective in vaccination of all children. Other groups considered to be
preventing clinically apparent hepatitis A. For postexpo- at increased risk for HAV infection and who are can-
sure prophylaxis of intimate contacts (household, sexual, didates for hepatitis A vaccination include military per-
1–18 2 25 units (0.5 mL) 0, 6–18 adolescence, at age 11–12 years, was recommended, and
≥19 2 50 units (1 mL) 0, 6–18 this recommendation has been extended to include all
unvaccinated children age 0–19 years. In HBV-hyper-
a
A combination of this hepatitis A vaccine and hepatitis B vaccine, endemic areas (e.g., Asia), universal vaccination of chil-
TWINRIX, is licensed for simultaneous protection against both dren has resulted in a marked 10- to 15-year decline in
of these viruses among adults (age ≥18 years). Each 1-mL dose con-
tains 720 ELU of hepatitis A vaccine and 20 μg of hepatitis B vac-
hepatitis B and its complications, including hepatocel-
lular carcinoma.
Disorders of the Liver and Biliary Tree
CHAPTER 38
avoidance of percutaneous exposures and limitation of
Adolescents 3 or 4 5 μg (0.5 mL) 0–2, 1–4, 4–6
(11–19 years) or 0, 12, 24 or intimate contact with persons who have HDV infection
0, 1, 2, 12 are recommended.
or
2 10 μg (1 mL) 0, 4–6 (age
11–15) Hepatitis C
Adults (≥20 3 10 μg (1 mL) 0–2, 1–4, 4–6
IG is ineffective in preventing hepatitis C and is no
precautions are not recommended. For persons with Whether IG prevents hepatitis E remains undetermined.
multiple sexual partners or with sexually transmitted A safe and effective recombinant vaccine has been
diseases, the risk of sexual transmission of hepatitis C is developed and is available in endemic areas but not in
increased, and barrier precautions (latex condoms) are the United States.
Disorders of the Liver and Biliary Tree
CHAPTER 39
Jules L. Dienstag
Liver injury may follow the inhalation, ingestion, or liver injury has been postulated to represent another
parenteral administration of a number of pharmaco- mechanism of drug hepatotoxicity (discussed later). In
logic and chemical agents. These include industrial addition, a role has been shown for activation of nuclear
toxins (e.g., carbon tetrachloride, trichloroethylene, transporters, such as the constitutive androstane receptor
and yellow phosphorus); the heat-stable toxic bicy- (CAR), in the induction of drug hepatotoxicity.
clic octapeptides of certain species of Amanita and Galerina Most drugs, which are water-insoluble, undergo a
(hepatotoxic mushroom poisoning); and, more commonly, series of hepatic metabolic transformation steps, cul-
pharmacologic agents used in medical therapy. Among minating in a water-soluble form appropriate for renal
patients with acute liver failure, drug-induced liver or biliary excretion. This process begins with oxida-
injury is the cause in a majority of all cases, and liver tion or methylation initially mediated by the micro-
toxicity accounts for the abandonment of many new somal mixed-function oxygenases cytochrome P450
drugs during their development. It is essential that any (phase I reaction) followed by glucuronidation or sul-
patient presenting with jaundice or altered biochemi- fation (phase II reaction) or inactivation by glutathione.
cal liver tests be questioned carefully about exposure Most drug hepatotoxicity is mediated by a phase I toxic
to chemicals used in work or at home, drugs taken by metabolite, but glutathione depletion, precluding inactiva-
prescription or bought over the counter, and herbal or tion of harmful compounds by glutathione S-transferase,
alternative medicines. Hepatotoxic drugs can injure the can contribute as well.
hepatocyte directly (e.g., via a free-radical or metabolic In general, two major types of chemical hepatotoxicity
intermediate that causes peroxidation of membrane have been recognized: (1) direct toxic and (2) idio-
lipids and that results in liver cell injury). Alternatively, syncratic. As shown in Table 39-1, direct toxic hepa-
the drug or its metabolite can distort cell membranes titis occurs with predictable regularity in individuals
or other cellular molecules, bind covalently to intra- exposed to the offending agent and is dose-dependent.
cellular proteins, activate apoptotic pathways, interfere The latent period between exposure and liver injury
with bile salt export proteins, or block biochemical is usually short (often several hours), although clini-
pathways or cellular integrity (Fig. 39-1). Interference cal manifestations may be delayed for 24–48 h. Agents
with bile canalicular pumps can allow endogenous bile producing toxic hepatitis are generally systemic poisons
acids, which can injure the liver, to accumulate. Such or are converted in the liver to toxic metabolites. The
injuries, in turn, may lead to necrosis of hepatocytes; direct hepatotoxins result in morphologic abnormali-
injure bile ducts, producing cholestasis; or block path- ties that are reasonably characteristic and reproducible
ways of lipid movement, inhibit protein synthesis, or for each toxin. For example, carbon tetrachloride and
impair mitochondrial oxidation of fatty acids, resulting trichloroethylene characteristically produce a centri-
in lactic acidosis and intracellular triglyceride accumula- lobular zonal necrosis, whereas yellow phosphorus
tion (expressed histologically as microvesicular steatosis). poisoning typically results in periportal injury. The hepa-
In some cases, drug metabolites sensitize hepatocytes to totoxic octapeptides of Amanita phalloides usually pro-
toxic cytokines, and differences between susceptible and duce massive hepatic necrosis; the lethal dose of the
nonsusceptible drug recipients may be attributable to toxin is ∼10 mg, the amount found in a single death-
polymorphisms in elaboration of competing, protective cap mushroom. Tetracycline, when administered in IV
cytokines, as has been suggested for acetaminophen hep- doses >1.5 g daily, leads to microvesicular fat deposits in
atotoxicity (discussed later). Immunologically mediated the liver. Liver injury, which is often only one facet of
385
386 Six Mechanisms of Liver Injury
B
Membrane
Transport
Hepatocyte pumps (MRP3)
Canaliculus
SECTION VI
Heme
P450 Drug
Disorders of the Liver and Biliary Tree
Endoplasmic
reticulum
F
Triglycerides
Free fatty
Vesicle
acid
D Enzyme-drug
E Cell death adduct
Inhibition of
β-oxidation, respiration, Caspase
or both
Caspase Caspase
DD DD
DD DD
Cytolytic
Mitochondrion TNF-α receptor, T cell
Fas
Lactate
Figure 39-1
Potential mechanisms of drug-induced liver injury. The resistance–associated protein 3 (MRP3), which, in turn, pre-
normal hepatocyte may be affected adversely by drugs vents the excretion of bilirubin and other organic compounds;
through A. disruption of intracellular calcium homeostasis C. covalent binding of the heme-containing cytochrome P450
that leads to the disassembly of actin fibrils at the surface of enzyme to the drug, thus creating nonfunctioning adducts;
the hepatocyte, resulting in blebbing of the cell membrane, D. migration of these enzyme-drug adducts to the cell sur-
rupture, and cell lysis; B. disruption of actin filaments face in vesicles to serve as target immunogens for cytolytic
next to the canaliculus (the specialized portion of the cell attack by T cells, stimulating an immune response involv-
responsible for bile excretion), leading to loss of villous pro- ing cytolytic T cells and cytokines; E. activation of apoptotic
cesses and interruption of transport pumps such as multidrug pathways by tumor necrosis factor α (TNFα) receptor or
Table 39-1 387
Some Features of Toxic and Drug-Induced Hepatic Injury
Direct Toxic Effect* Idiosyncratic* Othera
(Oral
(Carbon Contraceptive
Features Tetrachloride) (Acetaminophen) (Halothane) (Isoniazid) (Chlorpromazine) Agents)
Predictable and + + 0 0 0 +
dose-related
CHAPTER 39
toxicity
Latent period Short Short Variable Variable Variable Variable
Arthralgia, 0 0 + 0 + 0
fever, rash,
eosinophilia
Liver Necrosis, fatty Centrilobular Similar to Similar Cholestasis with Cholestasis
morphology infiltration necrosis viral to viral portal inflammation without portal
a
The drugs listed are typical samples.
the toxicity produced by the direct hepatotoxins, may metabolites rather than by the intact compound. Even
go unrecognized until jaundice appears. the prototypes of idiosyncratic hepatotoxicity reactions,
In idiosyncratic drug reactions, the occurrence of halothane hepatitis and isoniazid hepatotoxicity, associ-
hepatitis is usually infrequent (1 in 103–105 patients) ated frequently with hypersensitivity manifestations, are
and unpredictable; the response is not as clearly dose- now recognized to be mediated by toxic metabolites
dependent as is injury associated with direct hepatotoxins, that damage liver cells directly. Currently, most idiosyn-
and liver injury may occur at any time during or shortly cratic reactions are thought to result from differences in
after exposure to the drug. Adding to the difficulty of metabolic reactivity to specific agents; host susceptibility
predicting or identifying idiosyncratic drug hepatotoxicity is mediated by the kinetics of toxic metabolite genera-
is the occurrence of mild, transient, nonprogressive tion, which differs among individuals, probably medi-
serum aminotransferase elevations that resolve with ated by genetic polymorphisms in drug-metabolizing
continued drug use. Such “adaptation,” the mecha- pathways (e.g., differences in cytochrome P450 enzyme
nism of which is unknown, occurs in such drugs as isotypes or in acetylation). Associations between certain
isoniazid, valproate, phenytoin, and HMG-CoA reduc- HLA haplotypes have been drawn with hepatotoxicity
tase inhibitors (statins). Extrahepatic manifestations of of such drugs as amoxicillin/clavulanate, statins, halo-
hypersensitivity, such as rash, arthralgias, fever, leuko- thane, nitrofurantoin, chlorpromazine, and flucloxacillin.
cytosis, and eosinophilia, occur in about one-quarter of Occasionally, however, the clinical features of an aller-
patients with idiosyncratic hepatotoxic drug reactions; gic reaction (prominent tissue eosinophilia, autoanti-
this observation and the unpredictability of idiosyn- bodies, etc.) are difficult to ignore. In vitro models have
cratic drug hepatotoxicity contributed to the hypothesis been described in which lymphocyte cytotoxicity can
that this category of drug reactions is immunologically be demonstrated against rabbit hepatocytes altered by
mediated. More recent evidence, however, suggests incubation with the potential offending drug. Further-
that, in most cases, even idiosyncratic reactions rep- more, several instances of drug hepatotoxicity are asso-
resent direct hepatotoxicity but are caused by drug ciated with the appearance of autoantibodies, including
Fas (DD denotes death domain), triggering the cascade of oxygen species (which may disrupt mitochondrial DNA).
intercellular caspases, resulting in programmed cell death; Toxic metabolites excreted in bile may damage bile-duct
or F. inhibition of mitochondrial function by a dual effect on epithelium (not shown). CTLs, cytolytic T lymphocytes.
both β-oxidation and the respiratory-chain enzymes, lead- (Reproduced from WM Lee: Drug-induced hepatotoxicity.
ing to failure of free fatty acid metabolism, a lack of aero- N Engl J Med 349:474, 2003, with permission.)
bic respiration, and accumulation of lactate and reactive
388 a class of antibodies to liver-kidney microsomes, anti- now-abandoned fialuridine, a fluorinated pyrimidine
LKM2, directed against a cytochrome P450 enzyme. analogue with potent antiviral activity against hepatitis B
Similarly, in selected cases, a drug or its metabolite has virus. Another potential target for idiosyncratic drug
been shown to bind to a host cellular component hepatotoxicity is sinusoidal lining cells; when these are
forming a hapten; the immune response to this injured, such as by high-dose chemotherapeutic agents
“neoantigen” is postulated to play a role in the patho- (e.g., cyclophosphamide, melphalan, busulfan) adminis-
genesis of liver injury. Therefore, some authorities tered prior to bone marrow transplantation, venoocclu-
subdivide idiosyncratic drug hepatotoxicity into hyper- sive disease can result.
sensitivity (allergic) and “metabolic” categories. Several Not all adverse hepatic drug reactions can be classi-
SECTION VI
unusual exceptions notwithstanding, true drug allergy fied as either toxic or idiosyncratic in type. For exam-
is difficult to support in most cases of idiosyncratic ple, oral contraceptives, which combine estrogenic
drug-induced liver injury. and progestational compounds, may result in impair-
Idiosyncratic reactions lead to a morphologic pattern ment of hepatic tests and, occasionally, jaundice;
that is more variable than those produced by direct tox- however, they do not produce necrosis or fatty change,
ins; a single agent is often capable of causing a variety of manifestations of hypersensitivity are generally absent, and
lesions, although certain patterns tend to predominate. susceptibility to the development of oral contraceptive–
Disorders of the Liver and Biliary Tree
Depending on the agent involved, idiosyncratic hepa- induced cholestasis appears to be genetically deter-
titis may result in a clinical and morphologic picture mined. Such estrogen-induced cholestasis is more
indistinguishable from that of viral hepatitis (e.g., common in women with cholestasis of pregnancy, a
halothane) or may simulate extrahepatic bile duct obstruc- disorder linked to genetic defects in multidrug resistance–
tion clinically with morphologic evidence of cholestasis. associated canalicular transporter proteins. Other instances
Drug-induced cholestasis ranges from mild to increas- of genetically determined drug hepatotoxicity have
ingly severe: (1) bland cholestasis with limited hepatocel- been identified. For example, ∼10% of the population
lular injury (e.g., estrogens, 17,α-substituted androgens); have an autosomal recessive trait associated with the
(2) inflammatory cholestasis (e.g., phenothiazines, absence of cytochrome P450 enzyme 2D6 and have
amoxicillin-clavulanic acid [the most frequently impli- impaired debrisoquine-4-hydroxylase enzyme activity.
cated antibiotic among cases of drug-induced liver As a result, they cannot metabolize, and are at increased
injury], oxacillin, erythromycin estolate); (3) sclerosing risk of hepatotoxicity resulting from certain compounds
cholangitis (e.g., after intrahepatic infusion of the che- such as desipramine, propranolol, and quinidine.
motherapeutic agent floxuridine for hepatic metastases Some forms of drug hepatotoxicity are so rare (e.g.,
from a primary colonic carcinoma); (4) disappearance occurring in <1:10,000 recipients), that they do not
of bile ducts, “ductopenic” cholestasis, similar to that become apparent during clinical trials, involving only
observed in chronic rejection following liver trans- several thousand recipients, conducted to obtain drug
plantation (e.g., carbamazepine, chlorpromazine, tricy- registration. An example of such rare, but serious, idio-
clic antidepressant agents). Cholestasis may result from syncratic drug hepatotoxicity followed the approval and
binding of drugs to canalicular membrane transporters, generalized use of troglitazone, a peroxisomal, prolif-
accumulation of toxic bile acids resulting from cana- erator activator–receptor γ agonist, the first introduced
licular pump failure, or genetic defects in canalicular example of a thiazolidinedione insulin-sensitizing agent.
transporter proteins. Morphologic alterations may also This instance of drug hepatotoxicity was not recognized
include bridging hepatic necrosis (e.g., methyldopa), or, until well after the drug was introduced, underlining
infrequently, hepatic granulomas (e.g., sulfonamides). the importance of postmarketing surveillance in iden-
Some drugs result in macrovesicular or microvesicu- tifying toxic drugs and in leading to their withdrawal
lar steatosis or steatohepatitis, which, in some cases, from use. Fortunately, such hepatotoxicity is not char-
has been linked to mitochondrial dysfunction and acteristic of the second-generation thiazolidinedione
lipid peroxidation. Severe hepatotoxicity associated insulin-sensitizing agents rosiglitazone and pioglitazone;
with steatohepatitis, most likely a result of mitochon- in clinical trials, the frequency of aminotransferase ele-
drial toxicity, is being recognized with increasing fre- vations in patients treated with these medications did
quency among patients receiving antiretroviral therapy not differ from that in placebo recipients, and isolated
with reverse transcriptase inhibitors (e.g., zidovudine, reports of liver injury among recipients are extremely
didanosine) or protease inhibitors (e.g., indinavir, rito- rare.
navir) for HIV infection. Generally, such mitochon- Because drug-induced hepatitis is often a presump-
drial hepatotoxicity of these antiretroviral agents is tive diagnosis and many other disorders produce a
reversible, but dramatic, nonreversible hepatotoxicity similar clinicopathologic picture, evidence of a causal
associated with mitochondrial injury (inhibition of relationship between the use of a drug and subsequent
DNA polymerase γ) was the cause of acute liver liver injury may be difficult to establish. The relation-
failure encountered during early clinical trials of ship is most convincing for the direct hepatotoxins,
which lead to a high frequency of hepatic impairment thorium dioxide. The latter three agents have also been 389
after a short latent period. Idiosyncratic reactions may associated with angiosarcoma of the liver. Oral contra-
be reproduced, in some instances, when rechallenge, ceptives have been implicated in the development of
after an asymptomatic period, results in a recurrence hepatic adenoma and, rarely, hepatocellular carcinoma
of signs, symptoms, and morphologic and biochemical and hepatic vein occlusion (Budd-Chiari syndrome).
abnormalities. Rechallenge, however, is often ethically Another unusual lesion, peliosis hepatis (blood cysts of
unfeasible, because severe reactions may occur. Causality- the liver), has been observed in some patients treated
assessment methodologies (scoring systematically based with anabolic steroids. The existence of these hepatic
on a checklist of such variables as index of suspicion, disorders expands the spectrum of liver injury induced
CHAPTER 39
time of onset, clinical-biochemical features, type of by chemical agents and emphasizes the need for a thor-
injury [direct, idiosyncratic], extrahepatic features, ough drug history in all patients with liver dysfunction.
course, histologic features, drug serum levels, genetic The following are patterns of adverse hepatic reac-
markers and polymorphisms, and exclusion of other tions for some prototypic agents.
potential causes) have been adopted to add objectiv-
ity to diagnoses of drug-induced liver injury; however,
even these approaches have their limitations and yield Acetaminophen Hepatotoxicity
Anticonvulsant Carbamazine
Antidepressant Duloxetine, mirtazapine, tricyclic antidepressants
Anti-inflammatory Sulindac
Antiplatelet Clopidogrel
Antihypertensive Irbesartan, fosinopril
Antithyroid Methimazole
Calcium channel blocker Nifedipine, verapamil
Disorders of the Liver and Biliary Tree
Immunosuppressive Cyclosporine
Lipid-lowering Ezetimibe
Oncotherapeutic Anabolic steroids, busulfan, tamoxifen, irinotecan,
cytarabine
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
Hepatitis Anesthetic Halothanec
Antiandrogen Flutamide
Antibiotic Isoniazid,c rifampicin, nitrofurantoin, telithromycin,
minocycline,d pyrazinamide, trovafloxacine
Anticonvulsant Phenytoin, carbamazine, valproic acid, phenobarbital
Antidepressant Iproniazid, amitriptyline, imipramine, trazodone, venlafaxine,
fluoxetine, paroxetine, duloxetine, sertraline, nefazodone,e
bupropion
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 Atomoxetine
inhibitor
Oral hypoglycemic Troglitazone,e acarbose
Mixed hepatitis/ Antibiotic Amoxicillin-clavulanic acid,
cholestatic trimethoprim-sulfamethoxazole
Antibacterial Clindamycin
Antifungal Terbinafine
Antihistamine Cyproheptadine
Immunosuppressive Azathioprine
Lipid-lowering Nicotinic acid, lovastatin, ezetimide
(continued )
Table 39-2 391
Principal Alterations of Hepatic Morphology Produced by Some Commonly Used Drugs
and Chemicalsa (Continued)
Principal
Morphologic
Change Class of Agent Example
CHAPTER 39
Mushroom Amanita phalloides
Solvent Dimethylformamide
Granulomas Antiarrhythmic Quinidine, diltiazem
Antibiotic Sulfonamides
Anticonvulsant Carbamazine
Anti-inflammatory Phenylbutazone
Xanthine oxidase inhibitor Allopurinol
in serum by high-performance liquid chromatogra- were identified in 31–44% of normal subjects treated for
phy, hold promise as diagnostic markers of acetamino- 14 days with the maximal recommended dose of acet-
phen hepatotoxicity. The binding of acetaminophen aminophen, 4 g daily (administered alone or as part of
to hepatocyte macromolecules is believed to lead to an acetaminophen/opioid combination); because these
hepatocyte necrosis; the precise sequence and mecha- changes were transient and never associated with
nism are unknown. Hepatic injury may be potenti- bilirubin elevation, the clinical relevance of these find-
ated by prior administration of alcohol, phenobarbital, ings remains to be determined. Although underly-
isoniazid, or other drugs; by conditions that stimulate ing HCV infection was found to be associated with an
the mixed-function oxidase system; or by conditions increased risk of acute liver injury in patients hospital-
such as starvation that reduce hepatic glutathione levels. ized for acetaminophen overdose, generally, in patients
The xenobiotic (environmental, exogenous substance) with nonalcoholic liver disease, acetaminophen taken
receptor CAR has been shown in a mouse model of in recommended doses, may be the safest analgesic/
acetaminophen hepatotoxicity to induce acetaminophen- antipyretic. In this vein, acetaminophen use in cir-
metabolizing enzymes and, thereby, regulate and rhotic patients has not been associated with hepatic
increase hepatotoxicity. Cimetidine, which inhibits decompensation. On the other hand, because of the
P450 enzymes, has the potential to reduce generation of link between acetaminophen use and liver injury, and
the toxic metabolite. Alcohol induces cytochrome P450 because of the limited safety margin between safe and
CYP2E1; consequently, increased levels of the toxic toxic doses, the Food and Drug Administration (FDA)
metabolite NAPQI are produced in chronic alcohol- has recommended that the daily dose of acetaminophen
ics after acetaminophen ingestion. In addition, alcohol be reduced from 4 g to 3.25 g (even lower for persons
suppresses hepatic glutathione production. Therefore, with chronic alcohol use), that all acetaminophen-
in chronic alcoholics, the toxic dose of acetaminophen containing products be labeled prominently as con-
may be as low as 2 g, and alcoholic patients should be taining acetaminophen, and that the potential for liver
warned specifically about the dangers of even standard injury be prominent in the packaging of acetaminophen
doses of this commonly used drug. Such “therapeutic and acetaminophen-containing products.
misadventures” also occur occasionally in patients with
severe, febrile illnesses or pain syndromes; in such a set-
ting, several days of anorexia and near-fasting coupled Treatment Acetaminophen Overdosage
with regular administration of extra-strength acetamin-
ophen formulations result in a combination of gluta- Treatment includes gastric lavage, supportive mea-
thione depletion and relatively high NAPQI levels in sures, and oral administration of activated charcoal or
the absence of a history of recognized acetaminophen cholestyramine to prevent absorption of residual drug.
overdose. In a 2006 study, aminotransferase elevations
392 4000
500 a local poison control center should be contacted. Treat-
3000 Lower limit for high-risk group
400 Lower limit for probable-risk group ment can be stopped when plasma acetaminophen
Study nomogram line
2000 300 levels indicate that the risk of liver damage is low. If signs
1300 200
of hepatic failure (e.g., progressive jaundice, coagulopathy,
Plasma acetaminophen concentration
50
plantation (lactate levels >3.5 mmol/L) from those likely
to survive without liver replacement.
µmol/L µg/mL 4 8 12 16 20 24 28
Hours after acetaminophen ingestion
Halothane Hepatotoxicity
(Idiosyncratic Reaction)
Figure 39-2
Although, currently, halothane anesthesia is adminis-
Nomogram to define risk of acetaminophen hepatotoxicity
according to initial plasma acetaminophen concentration.
tered in only rare situations, halothane hepatotoxic-
(After BH Rumack, H Matthew: Pediatrics 55:871, 1975.)
ity was one of the prototypical, and most intensively
studied, examples of idiosyncratic drug hepatotoxicity.
Administration of halothane, a nonexplosive fluori-
nated hydrocarbon anesthetic agent that is structurally
similar to chloroform, results in severe hepatic necrosis
Neither charcoal nor cholestyramine appears to be
in a small number of individuals, many of whom have
effective if given >30 min after acetaminophen inges-
previously been exposed to this agent. The failure to
tion; if they are used, the stomach lavage should be
produce similar hepatic lesions reliably in animals, the
done before other agents are administered orally. The
rarity of hepatic impairment in human beings, and the
chances of possible, probable, and high-risk hepatotox-
delayed appearance of hepatic injury suggest that halo-
icity can be derived from a nomogram plot (Fig. 39-2),
thane is not a direct hepatotoxin but rather a sensitizing
readily available in emergency departments as a func-
agent; however, manifestations of hypersensitivity are
tion of measuring acetaminophen plasma levels 8 h
seen in <25% of cases. A genetic predisposition leading
after ingestion. In patients with high acetaminophen
to an idiosyncratic metabolic reactivity has been postu-
blood levels (>200 μg/mL measured at 4 h or >100 μg/mL
lated and appears to be the most likely mechanism of
at 8 h after ingestion), the administration of sulfhydryl
halothane hepatotoxicity. Adults (rather than children),
compounds (e.g., cysteamine, cysteine, or N-acetylcysteine)
obese people, and women appear to be particularly
reduces the severity of hepatic necrosis. These agents
susceptible. Fever, moderate leukocytosis, and eosino-
appear to act by providing a reservoir of sulfhydryl
philia may occur in the first week following halothane
groups to bind the toxic metabolites or by stimulating
administration. Jaundice is usually noted 7–10 days after
synthesis and repletion of hepatic glutathione. Ther-
exposure but may occur earlier in previously exposed
apy should be begun within 8 h of ingestion but may
patients. Nausea and vomiting may precede the onset of
be effective even if given as late as 24–36 h after over-
jaundice. Hepatomegaly is often mild, but liver tender-
dose. Later administration of sulfhydryl compounds
ness is common, and serum aminotransferase levels are
is of uncertain value. Routine use of N-acetylcysteine
elevated. The pathologic changes at autopsy are indis-
has substantially reduced the occurrence of fatal
tinguishable from massive hepatic necrosis resulting
acetaminophen hepatotoxicity. When given orally,
from viral hepatitis. The case-fatality rate of halothane
N-acetylcysteine is diluted to yield a 5% solution. A load-
hepatitis is not known but may vary from 20–40% in
ing dose of 140 mg/kg is given, followed by 70 mg/kg
cases with severe liver involvement. Patients in whom
every 4 h for 15–20 doses. Whenever a patient with
unexplained spiking fever, especially delayed fever, or
potential acetaminophen hepatotoxicity is encountered,
jaundice develops after halothane anesthesia should
not receive this agent again. Because cross-reactions Liver biopsy reveals morphologic changes similar to 393
between halothane and methoxyflurane have been those of viral hepatitis or bridging hepatic necrosis.
reported, the latter agent should not be used after halo- The disease may be severe, with a case-fatality rate of
thane reactions. Later-generation halogenated hydro- 10%. Important liver injury appears to be age-related,
carbon anesthetics that have supplanted halothane increasing substantially after age 35; the highest fre-
except in rare instances (e.g., certain types of thoracic quency is in patients over age 50, the lowest under the
surgery) are believed to be associated with a lower risk age of 20. Even for patients >50 years of age moni-
of hepatotoxicity. tored carefully during therapy, hepatotoxicity occurs
in only ∼2%, well below the risk estimate derived
CHAPTER 39
from earlier experiences. Isoniazid hepatotoxicity is
Methyldopa Hepatotoxicity (Toxic enhanced by alcohol, rifampin, and pyrazinamide.
and Idiosyncratic Reaction) Fever, rash, eosinophilia, and other manifestations of
Minor alterations in liver tests are reported in ∼5% drug allergy are distinctly unusual. A reactive metabo-
of patients treated with this antihypertensive agent. lite of acetylhydrazine, a metabolite of isoniazid, may
These trivial abnormalities typically resolve despite be responsible for liver injury, and patients who are
continued drug administration. In <1% of patients, rapid acetylators would be more prone to such injury.
metabolites are normally metabolized further by epox- amiodarone has a long half-life, liver injury may persist
ide hydrolases. A defect (genetic or acquired) in epox- for months after the drug is stopped.
ide hydrolase activity could permit covalent binding of
arene oxides to hepatic macromolecules, thereby leading
to hepatic injury. Hepatic injury is usually manifest within Erythromycin Hepatotoxicity
the first 2 months after beginning phenytoin therapy. (Cholestatic Idiosyncratic Reaction)
With the exception of an abundance of eosinophils in
the liver, the clinical, biochemical, and histologic pic- The most important adverse effect associated with
ture resembles that of viral hepatitis. In rare instances, erythromycin, more common in children than adults,
bile duct injury may be the salient feature of phenyt- is the infrequent occurrence of a cholestatic reaction.
oin hepatotoxicity, with striking features of intrahepatic Although most of these reactions have been associated
cholestasis. Asymptomatic elevations of aminotransfer- with erythromycin estolate, other erythromycins may
ase and alkaline phosphatase levels have been observed also be responsible. The reaction usually begins during
in a sizable proportion of patients receiving long-term the first 2 or 3 weeks of therapy and includes nausea,
phenytoin therapy. These liver changes are believed vomiting, fever, right upper quadrant abdominal pain,
by some authorities to represent the potent hepatic jaundice, leukocytosis, and moderately elevated amino-
enzyme-inducing properties of phenytoin and are transferase and alkaline phosphatase levels. The clini-
accompanied histologically by swelling of hepatocytes in cal picture can resemble acute cholecystitis or bacterial
the absence of necroinflammatory activity or evidence cholangitis. Liver biopsy reveals variable cholestasis;
of chronic liver disease. portal inflammation comprising lymphocytes, polymor-
phonuclear leukocytes, and eosinophils; and scattered foci
of hepatocyte necrosis. Symptoms and laboratory findings
Amiodarone Hepatotoxicity (Toxic usually subside within a few days of drug withdrawal,
and Idiosyncratic Reaction) and evidence of chronic liver disease has not been
Therapy with this potent antiarrhythmic drug is accom- found on follow-up. The precise mechanism remains
panied in 15–50% of patients by modest elevations of ill-defined.
serum aminotransferase levels that may remain stable or
diminish despite continuation of the drug. Such abnor-
malities may appear days to many months after begin-
Oral Contraceptive Hepatotoxicity
ning therapy. A proportion of those with elevated
(Cholestatic Reaction)
aminotransferase levels have detectable hepatomegaly, The administration of oral contraceptive combina-
and clinically important liver disease develops in <5% tions of estrogenic and progestational steroids leads to
of patients. Features that represent a direct effect of the intrahepatic cholestasis with pruritus and jaundice in a
drug on the liver and that are common to the majority small number of patients weeks to months after taking
of long-term recipients are ultrastructural phospholipido- these agents. Especially susceptible seem to be patients
sis, unaccompanied by clinical liver disease, and interfer- with recurrent idiopathic jaundice of pregnancy, severe
ence with hepatic mixed-function oxidase metabolism pruritus of pregnancy, or a family history of these
of other drugs. The cationic amphiphilic drug and its disorders. With the exception of liver biochemical tests,
major metabolite desethylamiodarone accumulate in laboratory studies are normal, and extrahepatic mani-
hepatocyte lysosomes and mitochondria and in bile festations of hypersensitivity are absent. Liver biopsy
duct epithelium. The relatively common elevations in reveals cholestasis with bile plugs in dilated canaliculi
and striking bilirubin staining of liver cells. In contrast Biochemically and histologically, acute hepatocellular 395
to chlorpromazine-induced cholestasis, portal inflam- necrosis predominates, but cholestatic features are quite
mation is absent. The lesion is reversible on withdrawal frequent. Occasionally, cholestasis without necrosis
of the agent. The two steroid components appear to act occurs, and, very rarely, a severe cholangiolytic pattern
synergistically on hepatic function, although the estro- of liver injury is observed. In most cases, liver injury is
gen may be primarily responsible. Oral contraceptives self-limited, but rare fatalities have been recorded. The
are contraindicated in patients with a history of recur- hepatotoxicity is attributable to the sulfamethoxazole
rent jaundice of pregnancy. Primarily benign, but rarely component of the drug and is similar in features to that
malignant, neoplasms of the liver, hepatic vein occlu- seen with other sulfonamides; tissue eosinophilia and
CHAPTER 39
sion, and peripheral sinusoidal dilatation have also been granulomas may be seen. The risk of trimethoprim-
associated with oral contraceptive therapy. Focal nodular sulfamethoxazole hepatotoxicity is increased in persons
hyperplasia of the liver is not more frequent among with HIV infection.
users of oral contraceptives.
oxycholic acid, S-adenosyl methionine, and taurine. Implicated most frequently are combinations including
nucleoside analogue reverse transcriptase inhibitors zid-
ovudine, didanosine, and, to a lesser extent, stavudine;
protease inhibitors ritonavir and indinavir (and amprena-
“Alternative and Complementary vir when used together with ritonavir) as well as tiprana-
Medicines” (Idiosyncratic Hepatitis, vir; and nonnucleoside reverse transcriptase inhibitors
Steatosis) nevirapine and, to a lesser extent, efavirenz. These drugs
The misguided popularity of herbal medications that are cause predominantly hepatocellular injury but cholestatic
of scientifically unproven efficacy and that lack prospec- injury as well, and prolonged (>6 months) use of reverse
tive safety oversight by regulatory agencies has resulted transcriptase inhibitors has been associated with mitochondrial
in occasional instances of hepatotoxicity. Included injury, steatosis, and lactic acidosis. Indirect hyperbili-
among the herbal remedies associated with toxic hepa- rubinemia, resulting from direct inhibition of bilirubin-
titis are Jin Bu Huan, xiao-chai-hu-tang, germander, conjugating activity by UDP-glucuronosyltransferase, usually
chaparral, senna, mistletoe, skullcap, gentian, comfrey without elevation of aminotransferase or alkaline phospha-
(containing pyrrolizidine alkaloids), Ma huang, bee tase activities, occurs in ∼10% of patients treated with the
pollen, valerian root, pennyroyal oil, kava, celandine, protease inhibitor indinavir. Distinguishing the impact of
Impila (Callilepsis laureaola), LipoKinetix, Hyroxycut, HAART hepatotoxicity in patients with HIV and hepatitis
herbal nutritional supplements, and herbal teas. Well virus co-infection is made challenging by the following: (1)
characterized are the acute hepatitis-like histologic both chronic hepatitis B and hepatitis C can affect the natu-
lesions following Jin Bu Huan use: focal hepatocellular ral history of HIV infection and the response to HAART,
necrosis, mixed mononuclear portal tract infiltration, and (2) HAART can have an impact on chronic viral
coagulative necrosis, apoptotic hepatocyte degeneration, hepatitis. For example, immunologic reconstitution with
tissue eosinophilia, and microvesicular steatosis. Megadoses HAART can result in immunologically mediated liver-cell
of vitamin A can injure the liver, as can pyrrolizidine injury in patients with chronic hepatitis B co-infection if
alkaloids, which often contaminate Chinese herbal treatment with an antiviral agent for hepatitis B, e.g., the
preparations and can cause a venoocclusive injury lead- nucleoside analogue lamivudine, is withdrawn or if nucleo-
ing to sinusoidal hepatic vein obstruction. Because some side analogue resistance emerges. Infection with HIV, espe-
alternative medicines induce toxicity via active metab- cially with low CD4+ T cell counts, has been reported to
olites, alcohol and drugs that stimulate cytochrome increase the rate of hepatic fibrosis associated with chronic
P450 enzymes may enhance the toxicity of some of hepatitis C, and HAART therapy can increase levels of
these products. Conversely, some alternative medicines serum aminotransferases and hepatitis C virus RNA in
also stimulate cytochrome P450 and may result in or patients with hepatitis C co-infection. Didanosine or stavu-
amplify the toxicity of recognized drug hepatotoxins. dine should not be used with ribavirin in patients with
Given the widespread use of such poorly defined herbal HIV/hepatitis C virus co-infection, because of an increased
preparations, hepatotoxicity is likely to be encountered risk of severe mitochondrial toxicity and lactic acidosis.
with increasing frequency; therefore, a drug history
in patients with acute and chronic liver disease should
Acknowledgement
include use of “alternative medicines” and other non-
prescription preparations sold in so-called health food Kurt J. Isselbacher, MD, contributed to this chapter in previous
stores. editions of Harrison’s Principles of Internal Medicine.
Chapter 40
CHRONIC HEPATITIS
Jules L. Dienstag
Chronic hepatitis represents a series of liver disorders of clinical, serologic, and histologic variables. Classification
varying causes and severity in which hepatic inflamma- of chronic hepatitis is based on (1) its cause; (2) its histo-
tion and necrosis continue for at least 6 months. Milder logic activity, or grade; and (3) its degree of progression,
forms are nonprogressive or only slowly progressive, or stage. Thus, neither clinical features alone nor histo-
while more severe forms may be associated with scarring logic features—requiring liver biopsy—alone are suffi-
and architectural reorganization, which, when advanced, cient to characterize and distinguish among the several
lead ultimately to cirrhosis. Several categories of chronic categories of chronic hepatitis.
hepatitis have been recognized. These include chronic
viral hepatitis, druginduced chronic hepatitis (Chap. 305),
and autoimmune chronic hepatitis. In many cases, ClassifiCation by Cause
clinical and laboratory features are insufficient to allow Clinical and serologic features allow the establishment of a
assignment into one of these three categories; these diagnosis of chronic viral hepatitis, caused by hepatitis B, hepa-
“idiopathic” cases are also believed to represent auto- titis B plus D, or hepatitis C; autoimmune hepatitis, includ-
immune chronic hepatitis. Finally, clinical and laboratory ing several subcategories, I and II (perhaps III), based on
features of chronic hepatitis are observed occasionally serologic distinctions; drug-associated chronic hepatitis; and a
in patients with such hereditary/metabolic disorders as category of unknown cause, or cryptogenic chronic hepatitis
Wilson’s disease (copper overload) (Chaps. 308 and 360) (Table 40-1). These are addressed in more detail below.
and nonalcoholic fatty liver disease (Chap. 309) and even
occasionally in patients with alcoholic liver injury
(Chap. 307). Although all types of chronic hepatitis ClassifiCation by grade
share certain clinical, laboratory, and histopathologic fea- Grade, a histologic assessment of necroinflammatory
tures, chronic viral and chronic autoimmune hepatitis activity, is based on examination of the liver biopsy. An
are sufficiently distinct to merit separate discussions. For assessment of important histologic features includes the
discussion of acute hepatitis, see Chap. 304. degree of periportal necrosis and the disruption of the limit-
ing plate of periportal hepatocytes by inflammatory cells
(so-called piecemeal necrosis or interface hepatitis); the degree
ClassiFiCation oF ChroniC hepatitis of confluent necrosis that links or forms bridges between
vascular structures—between portal tract and portal tract
Common to all forms of chronic hepatitis are histo- or even more important bridges between portal tract and
pathologic distinctions based on localization and extent central vein—referred to as bridging necrosis; the degree
of liver injury. These vary from the milder forms, pre- of hepatocyte degeneration and focal necrosis within
viously labeled chronic persistent hepatitis and chronic lobular the lobule; and the degree of portal inflammation. Several
hepatitis, to the more severe form, formerly called chronic scoring systems that take these histologic features into
active hepatitis. When first defined, these designations account have been devised, and the most popular are the
were believed to have prognostic implications, which histologic activity index (HAI), used commonly in the
have been challenged by more recent observations. United States, and the METAVIR score, used in Europe
Categorization of chronic hepatitis based primarily on (Table 40-2). Based on the presence and degree of
histopathologic features has been replaced by a more these features of histologic activity, chronic hepatitis can
informative classification based on a combination of be graded as mild, moderate, or severe.
397
398 Table 40-1
Clinical and Laboratory Features of Chronic Hepatitis
Type of hepatitis Diagnostic test(s) Autoantibodies Therapy
tenofovir
Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1a PEG IFN-α plus ribavirin
Telaprevird
Boceprevird
Chronic hepatitis D Anti-HDV, HDV RNA, Anti-LKM3 IFN-α, PEG
HBsAg, IgG anti-HBc IFN-αc
Autoimmune ANAb (homogeneous), ANA, anti-LKM1 Prednisone,
Disorders of the Liver and Biliary Tree
a
Antibodies to liver-kidney microsomes type 1 (autoimmune hepatitis type II and some cases of hepatitis C)
b
Antinuclear antibody (autoimmune hepatitis type I)
c
Clinical trials suggest benefit of IFN-α therapy; PEG IFN-α is as effective, if not more so.
d
Expected approval date 2011.
e
Antibodies 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.
Classification by Stage with clinically silent acute infection but a 90% chance
of chronic infection, while infection in young adult-
The stage of chronic hepatitis, which reflects the level hood in immunocompetent persons is typically associ-
of progression of the disease, is based on the degree ated with clinically apparent acute hepatitis but a risk
of hepatic fibrosis. When fibrosis is so extensive that of chronicity of only approximately 1%. Most cases of
fibrous septa surround parenchymal nodules and alter chronic hepatitis B among adults, however, occur in
the normal architecture of the liver lobule, the histo- patients who never had a recognized episode of clini-
logic lesion is defined as cirrhosis. Staging is based on the cally apparent acute viral hepatitis. The degree of liver
degree of fibrosis as categorized on a numerical scale injury (grade) in patients with chronic hepatitis B is
from 0–6 (HAI) or 0–4 (METAVIR) (Table 40-2). variable, ranging from none in inactive carriers to mild
to moderate to severe. Among adults with chronic
Chronic Viral Hepatitis hepatitis B, histologic features are of prognostic impor-
tance. In one long-term study of patients with chronic
Both the enterically transmitted forms of viral hepatitis, hepatitis B, investigators found a 5-year survival rate of
hepatitis A and E, are self-limited and do not cause 97% for patients with mild chronic hepatitis, 86% for
chronic hepatitis (rare reports notwithstanding in which patients with moderate to severe chronic hepatitis, and
acute hepatitis A serves as a trigger for the onset of auto- only 55% for patients with chronic hepatitis and post-
immune hepatitis in genetically susceptible patients). necrotic cirrhosis. The 15-year survival in these cohorts
In contrast, the entire clinicopathologic spectrum of was 77, 66, and 40%, respectively. On the other hand,
chronic hepatitis occurs in patients with chronic viral more recent observations do not allow us to be so
hepatitis B and C as well as in patients with chronic sanguine about the prognosis in patients with mild chronic
hepatitis D superimposed on chronic hepatitis B. hepatitis; among such patients followed for 1–13 years,
progression to more severe chronic hepatitis and cirrhosis
has been observed in more than a quarter of cases.
Chronic Hepatitis B
More important to consider than histology alone
The likelihood of chronicity after acute hepatitis B varies in patients with chronic hepatitis B is the degree of
as a function of age. Infection at birth is associated hepatitis B virus (HBV) replication. As reviewed in
Table 40-2 399
Histologic Grading and Staging of Chronic Hepatitis
Histologic Activity Index (HAI)a METAVIRb
CHAPTER 40
Moderate 3 Severe 3
Severe 4
Bridging Yes
necrosis No
Intralobular Confluent —none 0 None or mild 0
necrosis —focal 1 Moderate 1
—Zone 3 some 2 Severe 2
Chronic Hepatitis
—Zone 3 most 3
—Zone 3 + BN few 4
—Zone 3 + BN multiple 5
—Panacinar/multiacinar 6
Focal —none 0
—≤1 focus/10x field 1
—2–4 foci/10x field 2
—5–10 foci/10x field 3
—>10 foci/10x field 4
Portal Inflammation None 0
Mild 1
Moderate 2
Moderate/marked 3
Marked 4
Total 0–18 A0–A3c
Fibrosis (stage)
None 0 F0
Portal fibrosis—some 1 F1
Portal fibrosis—most 2 F1
Bridging fibrosis—few 3 F2
Bridging fibrosis—many 4 F3
Incomplete cirrhosis 5 F4
Cirrhosis 6 F4
Total 6 4
a
J Hepatol 22:696, 1995
b
Hepatology 24:289, 1996
c
Necroinflammatory grade: A0 = none; A1 = mild; A2 = moderate; A3 = severe
Chap. 304, chronic HBV infection can occur in the pre phase is characterized by the absence of the conven-
sence or absence of serum hepatitis B e antigen (HBeAg), and tional serum marker of HBV replication (HBeAg), the
generally, for both HBeAg-reactive and HBeAg-negative appearance of anti-HBe, levels of HBV DNA below a
chronic hepatitis B, the level of HBV DNA correlates threshold of ∼103 virions/mL, the absence of intrahe-
with the level of liver injury and risk of progression. patocytic HBcAg, limited infectivity, and minimal liver
In HBeAg-reactive chronic hepatitis B, two phases have injury. Those patients in the replicative phase tend to
been recognized based on the relative level of HBV have more severe chronic hepatitis, while those in the
replication. The relatively replicative phase is character- nonreplicative phase tend to have minimal or mild
ized by the presence in the serum of HBeAg and HBV chronic hepatitis or to be inactive hepatitis B carriers;
DNA levels well in excess of 105–106 virions/mL, by however, distinctions in HBV replication and in histo-
the presence in the liver of detectable intrahepatocyte logic category do not always coincide. The likelihood
nucleocapsid antigens [primarily hepatitis B core anti- in a patient with HBeAg-reactive chronic hepatitis B of
gen (HBcAg)], by high infectivity, and by accompany- converting spontaneously from relatively replicative to non
ing liver injury. In contrast, the relatively nonreplicative replicative infection is approximately 10–15% per year.
400 In patients with HBeAg-reactive chronic HBV infec- and levels of HBV DNA that are either undetectable or
tion, especially when acquired at birth or in early child- present at levels ≤103 virions/mL. This serologic profile
hood, as recognized commonly in Asian countries, a can occur not only in inactive carriers but also in
dichotomy is common between very high levels of patients with HBeAg-negative chronic hepatitis B dur-
HBV replication and negligible levels of liver injury. ing periods of relative inactivity; distinguishing between
Yet despite the relatively immediate, apparently benign the two requires sequential biochemical and virologic
nature of liver disease for many decades in this popula- monitoring over many months.
tion, patients with childhood-acquired HBV infection The spectrum of clinical features of chronic hepatitis B
are the ones at ultimately increased risk later in life of is broad, ranging from asymptomatic infection to debili-
SECTION VI
cirrhosis and hepatocellular carcinoma (HCC) (Chap. 92). tating disease or even end-stage, fatal hepatic failure. As
A discussion of the pathogenesis of liver injury in noted above, the onset of the disease tends to be insidi-
patients with chronic hepatitis B appears in Chap. 304. ous in most patients, with the exception of the very
HBeAg-negative chronic hepatitis B [i.e., chronic few in whom chronic disease follows failure of resolu-
HBV infection with active virus replication, tion of clinically apparent acute hepatitis B. The clinical
readily detectable HBV DNA but without and laboratory features associated with progression from
HBeAg (anti-HBe-reactive)], is more common than acute to chronic hepatitis B are discussed in Chap. 304.
Disorders of the Liver and Biliary Tree
CHAPTER 40
lication and lower for persons in whom initially high- been effective in very young children infected at birth.
level HBV DNA falls spontaneously over time. Therefore, Similarly, IFN therapy has not been effective in immu-
management of chronic hepatitis B is directed at sup- nosuppressed persons, Asian patients with minimal-to-
pressing the level of virus replication. Although clinical mild ALT elevations, or patients with decompensated
trials tend to focus on clinical endpoints achieved over chronic hepatitis B (in whom such therapy can actually
1–2 years (e.g., suppression of HBV DNA to undetectable be detrimental, sometimes precipitating decompen-
Chronic Hepatitis
levels, loss of HBeAg/HBsAg, improvement in histology, sation, often associated with severe adverse effects).
normalization of ALT), these short-term gains translate Among patients with HBeAg loss during therapy, long-
into reductions in the risk of clinical progression, hepatic term follow-up has demonstrated that 80% experience
decompensation, and death. To date, seven drugs have eventual loss of HBsAg [i.e., all serologic markers of
been approved for treatment of chronic hepatitis B: infection, and normalization of ALT over a 9-year post-
injectable interferon (IFN) α pegylated interferon [long- treatment period]. In addition, improved longterm and
acting IFN bound to polyethylene glycol (PEG), known complication-free survival as well as a reduction in the
as PEG IFN]; and the oral agents lamivudine, adefovir frequency of HCC have been documented among inter-
dipivoxil, entecavir, telbivudine, and tenofovir. feron responders, supporting the conclusion that suc-
Antiviral therapy for hepatitis B has evolved rapidly cessful interferon therapy improves the natural history
since the mid-1990s, as has the sensitivity of tests for of chronic hepatitis B.
HBV DNA. When IFN and lamivudine were evaluated Initial trials of brief-duration IFN therapy in patients
in clinical trials, HBV DNA was measured by insensi- with HBeAg-negative chronic hepatitis B were dis
tive hybridization assays with detection thresholds of appointing, suppressing HBV replication transiently during
105–106 virions/mL; when adefovir, entecavir, telbivu- therapy but almost never resulting in sustained antivi-
dine, tenofovir, and PEG IFN were studied in clinical ral responses. In subsequent IFN trials among patients
trials, HBV DNA was measured by sensitive amplification with HBeAg-negative chronic hepatitis B, however, more
assays [polymerase chain reaction [(PCR)] with detection protracted courses, lasting up to 11/2 years, have been
thresholds of 101–103 virions/mL. Recognition of these reported to result in sustained remissions documented
distinctions is helpful when comparing results of clini- to last for several years, with suppressed HBV DNA and
cal trials that established the efficacy of these therapies aminotransferase activity, in ∼20%.
(reviewed below in chronological order of publication of Complications of IFN therapy include systemic “flu-
these efficacy trials). like” symptoms; marrow suppression; emotional lability
(irritability, depression, anxiety); autoimmune reactions
Interferon IFN-α was the first approved therapy (especially autoimmune thyroiditis); and miscellaneous
for chronic hepatitis B. Although it is no longer used side effects such as alopecia, rashes, diarrhea, and numb-
to treat hepatitis B, standard IFN is important histori- ness and tingling of the extremities. With the possible
cally, having provided important lessons about antiviral exception of autoimmune thyroiditis, all these side effects
therapy in general. For immunocompetent adults with are reversible upon dose lowering or cessation of therapy.
HBeAg-reactive chronic hepatitis B [who tend to have Although no longer competitive with the newer gen-
high-level HBV DNA (>105–106 virions/mL) and histo- eration of antivirals, IFN did represent the first success-
logic evidence of chronic hepatitis on liver biopsy], a ful antiviral approach and set a standard against which
16-week course of IFN given subcutaneously at a daily to measure subsequent drugs in the achievement of
dose of 5 million units, or three times a week at a dose durable virologic, serologic, biochemical, and histologic
of 10 million units, results in a loss of HBeAg and hybrid- responses; consolidation of virologic and biochemical
ization-detectable HBV DNA (i.e., a reduction to levels benefit in the ensuing years after therapy; and improve-
below 105–106 virions/mL) in ∼30% of patients, with ment in the natural history of chronic hepatitis B. Stan-
a concomitant improvement in liver histology. Sero- dard IFN has been supplanted by long-acting PEG IFN
conversion from HBeAg to anti-HBe occurs in approxi- (see below), and IFN nonresponders are now treated
mately 20%, and, in early trials, approximately 8% lost with one of the newer oral nucleoside analogues.
402
Lamivudine The first of the nucleoside analogues beyond the first year; after a cumulative course of
to be approved, the dideoxynucleoside lamivudine, 3 years of lamivudine therapy, necroinflammatory activity
inhibits reverse transcriptase activity of both HIV and is reduced in the majority of patients, and even cirrhosis
HBV and is a potent and effective agent for patients has been shown to regress to precirrhotic stages.
with chronic hepatitis B. Although generally super- Losses of HBsAg have been few during the first
seded by newer, more potent agents, lamivudine is still year of lamivudine therapy, and this observation had
used in regions of the world where newer agents are been cited as an advantage of IFN-based over lamivu-
not yet approved are or not affordable. In clinical trials dine therapy; however, in head-to-head comparisons
among patients with HBeAg-reactive chronic hepatitis B, between standard IFN and lamivudine monotherapy,
SECTION VI
lamivudine therapy at daily doses of 100 mg for 48–52 weeks HBsAg losses were rare in both groups. Trials in which
suppressed HBV DNA by a median of approximately lamivudine and IFN were administered in combination
5.5 log10 copies/mL and to undetectable levels, as failed to show a benefit of combination therapy over
measured by PCR amplification assays, in approxi- lamivudine monotherapy for either treatment-naïve
mately 40% of patients. Therapy was associated with patients or prior IFN nonresponders.
HBeAg loss in 32–33%; HBeAg seroconversion (i.e., In patients with HBeAg-negative chronic hepatitis B
Disorders of the Liver and Biliary Tree
conversion from HBeAg-reactive to anti-HBe-reactive) (i.e., in those with precore and core-promoter HBV
in 16–21%; normalization of ALT in 40–75%; improve- mutations), 1 year of lamivudine therapy results in HBV
ment in histology in 50–60%; retardation in fibrosis in DNA suppression and normalization of ALT in three-
20–30%; and prevention of progression to cirrhosis. quarters of patients and in histologic improvement in
HBeAg responses can occur even in subgroups who are approximately two-thirds. Therapy has been shown to
resistant to IFN (e.g., those with high-level HBV DNA) suppress HBV DNA by approximately 4.5 log10 copies/mL
or who failed in the past to respond to it. As is true for (baseline HBV DNA levels are lower than in patients
IFN therapy of chronic hepatitis B, patients with near- with HBeAg-reactive hepatitis B) and to undetectable
normal ALT activity tend not to experience HBeAg levels in approximately 70%, as measured by sensitive
responses (despite suppression of HBV DNA), and those PCR amplification assays. Lacking HBeAg at the outset,
with ALT levels exceeding five times the upper limit of patients with HBeAg-negative chronic hepatitis B cannot
normal can expect 1-year HBeAg seroconversion rates achieve an HBeAg response—a stopping point in
of 50–60%. Generally, HBeAg seroconversions are con- HBeAg-reactive patients; almost invariably, when ther-
fined to patients who achieve suppression of HBV DNA apy is discontinued, reactivation is the rule. Therefore,
to <104 genomes/mL. Among patients who undergo these patients require long-term therapy; with succes-
HBeAg responses during a year-long course of therapy sive years, the proportion with suppressed HBV DNA
and in whom the response is sustained for 4–6 months and normal ALT increases.
after cessation of therapy, the response is durable there- Clinical and laboratory side effects of lamivudine
after in the vast majority, >80%; therefore, the achieve- are negligible, indistinguishable from those observed
ment of an HBeAg response represents a viable stop- in placebo recipients. Still, lamivudine doses should be
ping point in therapy. Reduced durability has been reduced in patients with reduced creatinine clearance.
reported in some Asian experiences; however, in most During lamivudine therapy, transient ALT elevations,
western and Asian patient study populations, long- resembling those seen during IFN therapy and dur-
term durability of HBeAg responses is the rule, which, ing spontaneous HBeAg-to-anti-HBe seroconversions,
at least in western patients, is accompanied by a post- occur in one-fourth of patients. These ALT elevations
treatment HBsAg seroconversion rate comparable to may result from restored cytolytic T cell activation per-
that seen after IFN-induced HBeAg responses. To sup- mitted by suppression of HBV replication. Similar ALT
port the durability of HBeAg responses, patients receive elevations, however, occur at an identical frequency in
a period of consolidation therapy (at least 6 months in placebo recipients, but ALT elevations associated with
western patients, at least 1 year in Asian patients) after HBeAg seroconversion are confined to lamivudine-
HBeAg seroconversion; close posttreatment monitoring treated patients. When therapy is stopped after a year
is necessary to identify HBV reactivation promptly and of therapy, two- to threefold ALT elevations occur in
to resume therapy. If HBeAg is unaffected by lamivudine 20–30% of lamivudine-treated patients, represent-
therapy, the current approach is to continue therapy ing renewed liver-cell injury as HBV replication returns.
until an HBeAg response occurs, but longterm ther- Although these posttreatment flares are almost always
apy may be required to suppress HBV replication and, transient and mild, rare severe exacerbations, especially
in turn, limit liver injury; HBeAg seroconversions can in cirrhotic patients, have been observed, mandating
increase to a level of 50% after 5 years of therapy. His- close and careful clinical and virologic monitoring
tologic improvement continues to accrue with therapy after discontinuation of treatment. Many authorities
403
caution against discontinuing therapy in patients with last months of pregnancy to mothers with high-level
cirrhosis, in whom posttreatment flares could precipitate hepatitis B viremia (≥108 IU/ml) can reduce the likeli-
decompensation. hood of perinatal transmission of hepatitis B.
Long-term monotherapy with lamivudine is associated
with methionine-to-valine (M204V) or methionine-to- Adefovir Dipivoxil At an oral daily dose of
isoleucine (M204I) mutations, primarily at amino acid 10 mg, the acyclic nucleotide analogue adefovir dipivoxil,
204 in the tyrosine-methionine-aspartate-aspartate the prodrug of adefovir, reduces HBV DNA by approxi-
(YMDD) motif of HBV DNA polymerase, analogous to mately 3.5–4 log10 copies/mL and is equally effective
in treatment-naïve patients and IFN nonresponders. In
CHAPTER 40
mutations that occur in HIV-infected patients treated
with this drug. During a year of therapy, YMDD muta- HBeAg-reactive chronic hepatitis B, a 48-week course
tions occur in 15–30% of patients; the frequency of adefovir dipivoxil was shown to achieve histologic
increases with each year of therapy, reaching 70% at improvement (and reduce the progression of fibrosis)
year 5. Ultimately, patients with YMDD mutants experi- and normalization of ALT in just over one-half of
ence degradation of clinical, biochemical, and histo- patients, HBeAg seroconversion in 12%, HBeAg loss in
logic responses; therefore, if treatment is begun with 23%, and suppression to an undetectable level of HBV
Chronic Hepatitis
lamivudine monotherapy, the emergence of lamivudine DNA in 13–21%, as measured by PCR. Similar to IFN and
resistance, reflected clinically by a breakthrough from lamivudine, adefovir dipivoxil is more likely to achieve
suppressed levels of HBV DNA and ALT, is managed by an HBeAg response in patients with high baseline ALT
adding another antiviral to which YMDD variants are (e.g., among adefovir-treated patients with ALT level
sensitive (e.g., adefovir, tenofovir; see below). >5 times the upper limit of normal), HBeAg serocon-
Currently, although lamivudine is very safe and still versions occurred in 25%. The durability of adefovir-
used widely in other parts of the world, in the United induced HBeAg responses is high (91% in one study);
States and Europe, lamivudine has been eclipsed by therefore, HBeAg response can be relied upon as a stop-
more potent antivirals that have superior resistance pro- ping point for adefovir therapy, after a period of consoli-
files (see below). Still, as the first successful oral antivi- dation therapy, as outlined above. Although data on the
ral agent for use in hepatitis B, lamivudine has provided impact of additional therapy beyond 1 year are limited,
proof of the concept that polymerase inhibitors can biochemical, serologic, and virologic outcomes improve
achieve virologic, serologic, biochemical, and histologic progressively as therapy is continued.
benefits. In addition, lamivudine has been shown to be In patients with HBeAg-negative chronic hepatitis B, a
effective in the treatment of patients with decompen- 48-week course of 10 mg/d of adefovir dipivoxil resulted
sated hepatitis B (for whom IFN is contraindicated), in in histologic improvement in two-thirds, normalization
some of whom decompensation can be reversed. More- of ALT in threefourths, and suppression of HBV DNA to
over, among patients with cirrhosis or advanced fibrosis, PCR-undetectable levels in one-half to two-thirds. As
lamivudine has been shown to be effective in reducing was true for lamivudine, because HBeAg responses—a
the risk of progression to hepatic decompensation and, potential stopping point—cannot be achieved in this
marginally, the risk of HCC. group, reactivation is the rule when adefovir therapy
Because lamivudine monotherapy can result uni- is discontinued, and indefinite, long-term therapy
versally in the rapid emergence of YMDD variants in is required. Treatment beyond the first year consoli-
persons with HIV infection, patients with chronic hepatitis dates the gain of the first year; after 5 years of therapy,
B should be tested for anti-HIV prior to therapy; if HIV improvement in hepatic inflammation and regression
infection is identified, lamivudine monotherapy at the of fibrosis was observed in threefourths of patients, ALT
HBV daily dose of 100 mg is contraindicated. These was normal in 70%, and HBV DNA was undetectable in
patients should be treated for both HIV and HBV with almost 70%.
an HIV drug regimen that includes or is supplemented Adefovir contains a flexible acyclic linker instead
by at least two drugs active against HBV; highly active of the L-nucleoside ring of lamivudine, avoiding steric
antiretroviral therapy (HAART) often contains two drugs hindrance by mutated amino acids. In addition, the
with antiviral activity against HBV (e.g., tenofovir and molecular structure of phosphorylated adefovir is very
emtricitabine), but if lamivudine is part of the regimen, similar to that of its natural substrate; therefore muta-
the daily dose should be 300 mg (Chap. 189). The safety tions to adefovir would also affect binding of the natu-
of lamivudine during pregnancy has not been estab- ral substrate, dATP. Hypothetically, these are among
lished; however, the drug is not teratogenic in rodents the reasons that resistance to adefovir dipivoxil is much
and has been used safely in pregnant women with HIV less likely than resistance to lamivudine; no resistance
infection and with HBV infection. Limited data even was encountered in 1 year of clinical-trial therapy. In
suggest that administration of lamivudine during the subsequent years, however, adefovir resistance begins
404
to emerge [asparagine to threonine at amino acid 236 frequently administered, standard IFN, and several
(N236T) and alanine to valine or threonine at amino large-scale trials of PEG IFN versus oral nucleoside ana-
acid 181 (A181V/T), primarily], occurring in 2.5% after logues have been conducted among patients with
2 years, but in 29% after 5 years of therapy (reported HBeAg-reactive and HBeAg-negative chronic hepatitis B.
in HBeAg-negative patients). Among patients coin- In HBeAg-reactive chronic hepatitis B, two large-
fected with HBV and HIV and who have normal CD4+ scale studies were done, one with PEG IFN-α 2b (100 μg
T cell counts, adefovir dipivoxil is effective in suppress- weekly for 32 weeks, then 50 μg weekly for another
ing HBV dramatically (by 5 logs10 in one study). Moreover, 20 weeks for a total of 52 weeks, with a comparison
adefovir dipivoxil is effective in lamivudine-resistant, arm of combination PEG IFN with oral lamivudine) in
SECTION VI
YMDD-mutant HBV and can be used when such lami- 307 subjects; the other involved PEG IFN-α 2a (180 μg
vudine-induced variants emerge. When lamivudine weekly for 48 weeks) in 814 primarily Asian patients,
resistance occurs, adding adefovir (i.e., maintaining three-fourths of whom had ALT ≥2 × the upper limit of
lamivudine to preempt the emergence of adefovir normal, with comparison arms of lamivudine mono-
resistance), is superior to switching to adefovir. Almost therapy and combination PEG IFN plus lamivudine. At
invariably, patients with adefovir-mutant HBV respond the end of therapy (48–52 weeks) in the PEG IFN mono-
Disorders of the Liver and Biliary Tree
to lamivudine (or newer agents, such as entecavir, see therapy arms, HBeAg loss occurred in approximately
below). When, in the past, adefovir had been evaluated 30%, HBeAg seroconversion in 22–27%, undetectable
as therapy for HIV infection, doses of 60–120 mg were HBV DNA (<400 copies/mL by PCR) in 10–25%, normal
required to suppress HIV, and, at these doses, the drug ALT in 34–39%, and a mean reduction in HBV DNA of
was nephrotoxic. Even at 30 mg/d, creatinine elevations 2 log10 copies/mL (PEG IFN-α 2b) to 4.5 log10 copies/mL
of 44 μmol/L (0.5 mg/dL) occur in 10% of patients; how- (PEG IFN-α 2a). Six months after completing PEG IFN
ever, at the HBV-effective dose of 10 mg, such elevations monotherapy in these trials, HBeAg losses were present
of creatinine are rarely encountered. If any nephrotox- in approximately 35%, HBeAg seroconversion in approx-
icity does occur, it rarely appears before 6–8 months of imately 30%, undetectable HBV DNA in 7–14%, normal
therapy. Although renal tubular injury is a rare poten- ALT in 32–41%, and a mean reduction in HBV DNA of
tial side effect, and although creatinine monitoring is 2–2.4 log10 copies/mL. Although the combination of
recommended during treatment, the therapeutic index PEG IFN and lamivudine was superior at the end of ther-
of adefovir dipivoxil is high, and the nephrotoxicity apy in one or more serologic, virologic, or biochemical
observed in clinical trials at higher doses was reversible. outcomes, neither the combination arm (in both studies)
For patients with underlying renal disease, frequency of nor the lamivudine monotherapy arm (in the PEG IFN-α
administration of adefovir dipivoxil should be reduced 2a trial) demonstrated any benefit compared to the
to every 48 h for creatinine clearances of 20–49 mL/min; PEG IFN monotherapy arms 6 months after therapy.
to every 72 h for creatinine clearances of 10–19 mL/min; Moreover, HBsAg seroconversion occurred in 3–7% of
and once a week, following dialysis, for patients under- PEG IFN recipients (with or without lamivudine); some
going hemodialysis. Adefovir dipivoxil is very well tol- of these seroconversions were identified by the end of
erated, and ALT elevations during and after withdrawal therapy, but many were identified during the posttreat-
of therapy are similar to those observed and described ment follow-up period. The likelihood of HBeAg loss in
above in clinical trials of lamivudine. An advantage PEG IFN–treated HBeAg-reactive patients is associated
of adefovir is its relatively favorable resistance pro- with HBV genotype A > B > C > D (shown for PEG IFN
file; however, it is not as potent as the other approved α-2b but not for α-2a).
oral agents, it does not suppress HBV DNA as rapidly Based on these results, some authorities concluded
or as uniformly as the others, it is the least likely of all that PEG IFN monotherapy should be the first-line
agents to result in HBeAg seroconversion, and 20–50% therapy of choice in HBeAg-reactive chronic hepatitis B;
of patients fail to suppress HBV DNA by 2 log10 (“primary however, this conclusion has been challenged. Although
nonresponders”). For these reasons, adefovir has been a finite, 1-year course of PEG IFN results in a higher
supplanted in both treatment-naïve and lamivudine- rate of sustained response (6 months after treatment)
resistant patients by the more potent, less resistance- than is achieved with oral nucleoside/nucleotide ana-
prone nucleotide analogue tenofovir (see below). logue therapy, the comparison is confounded by the
fact that oral agents are not discontinued at the end
Pegylated Interferon After long-acting of 1 year. Instead, taken orally and free of side effects,
PEG IFN was shown to be effective in the treatment of therapy with oral agents is extended indefinitely or until
hepatitis C (see below), this more convenient drug was after the occurrence of an HBeAg response. The rate of
evaluated in the treatment of chronic hepatitis B. HBeAg responses after 2 years of oralagent nucleoside
Once-a-week PEG IFN is more effective than the more analogue therapy is at least as high as, if not higher
405
than, that achieved with PEG IFN after 1 year; favoring Entecavir Entecavir, an oral cyclopentyl gua-
oral agents is the absence of injections and difficult-to- nosine analogue polymerase inhibitor, appears to be
tolerate side effects as well as lower direct and indirect the most potent of the HBV antivirals and is just as well
medical costs and inconvenience. The association of tolerated as lamivudine. In a 709-subject clinical trial
HBsAg responses with PEG IFN therapy occurs in such a among HBeAg-reactive patients, oral entecavir, 0.5 mg
small proportion of patients that subjecting everyone to daily, was compared to lamivudine, 100 mg daily. At 48
PEG IFN for the marginal gain of HBsAg responses dur- weeks, entecavir was superior to lamivudine in suppres-
ing or immediately after therapy in such a very small sion of HBV DNA, mean 6.9 versus 5.5 log10 copies/mL
CHAPTER 40
minority is questionable. Moreover, HBsAg responses and in percent with undetectable HBV DNA (<300 copies/
occur in a comparable proportion of patients treated mL by PCR), 67% versus 36%; histologic improvement
with earlygeneration nucleoside/nucleotide analogues (≥2-point improvement in necroinflammatory HAI
in the years after therapy, and, with the newer, more score), 72% versus 62%; and normal ALT (68% versus
potent nucleoside analogues, the frequency of HBsAg 60%). The two treatments were indistinguishable in
loss during the first year of therapy equals that of PEG percent with HBeAg loss (22% versus 20%) and sero-
IFN and is exceeded during year 2 (see below). Of conversion (21% versus 18%). Among patients treated
Chronic Hepatitis
course, resistance is not an issue during PEG IFN ther- with entecavir for 96 weeks, HBV DNA was undetect-
apy, but the risk of resistance is much lower with new able cumulatively in 80% (versus 39% for lamivudine),
agents (≤1% up to 3–5 years in previously treatment- and HBeAg seroconversions had occurred in 31% (ver-
naïve, entecavir-treated and tenofovir-treated patients; sus 26% for lamivudine); the HBeAg seroconversion rate
see below). Finally, the level of HBV DNA inhibition that after 3 years of entecavir in this cohort was 39%. Simi-
can be achieved with the newer agents, and even with larly, in a 638-subject clinical trial among HBeAg-
lamivudine, exceeds that which can be achieved with negative patients, at week 48, oral entecavir, 0.5 mg
PEG IFN, in some cases by several orders of magnitude. daily, was superior to lamivudine, 100 mg daily, in sup-
In HBeAg-negative chronic hepatitis B, a trial of PEG pression of HBV DNA, mean 5.0 versus 4.5 log10 copies/
IFN-α 2a (180 μg weekly for 48 weeks versus compari- mL and in percent with undetectable HBV DNA, 90%
son arms of lamivudine monotherapy and of combi- versus 72%; histologic improvement, 70% versus 61%
nation therapy) in 564 patients showed that PEG IFN and normal ALT, 78% versus 71%. No resistance muta-
monotherapy resulted at the end of therapy in sup- tions were encountered in previously treatment-naïve,
pression of HBV DNA by a mean of 4.1 log10 copies/mL, entecavir-treated patients during 96 weeks of therapy,
undetectable HBV DNA (<400 copies/mL by PCR) in and in a cohort of subjects treated for up to 5 years,
63%, normal ALT in 38%, and loss of HBsAg in 4%. resistance emerged in 1.2%. Its high barrier to resistance
Although lamivudine monotherapy and combination coupled with its high potency renders entecavir a first-
lamivudine–PEG IFN therapy were both superior to PEG line drug for patients with chronic hepatitis B.
IFN at the end of therapy, no advantage of lamivudine Entecavir is also effective against lamivudine-resis-
monotherapy or combination therapy was apparent tant HBV infection. In a trial of 286 lamivudine-resistant
over PEG IFN monotherapy 6 months after therapy— patients, entecavir, at a higher daily dose of 1 mg, was
suppression of HBV DNA by a mean of 2.3 log10 copies/ superior to lamivudine, as measured at week 48, in
mL, undetectable HBV DNA in 19%, and normal ALT in achieving suppression of HBV DNA (mean 5.1 versus
59%. In subjects involved in this trial followed for up to 0.48 log10 copies/mL); undetectable HBV DNA, in 72%
5 years, among the two-thirds followed who had been versus 19%; normal ALT, in 61% versus 15%; HBeAg loss,
treated initially with PEG IFN, 17% maintained HBV DNA in 10% versus 3%; and HBeAg seroconversion, in 8% ver-
suppression to <400 copies/ml, but ALT remained nor- sus 3%. In this population of lamivudine-experienced
mal in only 22%; HBsAg loss increased gradually to 12%. patients, however, entecavir resistance emerged in 7%
Among the half followed who had been treated initially at 48 weeks. Although entecavir resistance requires
with lamivudine monotherapy, HBV DNA remained both a YMDD mutation and a second mutation at one
<400 copies/ml in 7% and ALT normal in 16%; by year of several other sites (e.g., T184A, S202G/I, or M250V),
5, 3.5% had lost HBsAg. As was the case for standard resistance to entecavir in lamivudineresistant chronic
IFN therapy in HBeAg-negative patients, longer after hepatitis B has been recorded to increase progressively
PEG IFN treatment, although a small subset maintained to 43% at 4 years; therefore, entecavir is not as attrac-
their responses, the proportion who benefited was very tive a choice as adefovir or tenofovir for patients with
small, raising questions about the relative value of a lamivudine-resistant hepatitis B.
finite period of PEG IFN, versus a longer course with a At the end of 2 years of entecavir therapy in clinical
potent, low-resistance oral nucleoside analogue in these trials among HBeAg-reactive patients, HBsAg serocon-
patients. version was observed in 5% (≤2% during the first year).
406
In addition, ontreatment and posttreatment ALT flares of tenofovir are very favorable as well; therefore, teno-
are relatively uncommon and relatively mild in entecavir- fovir has supplanted adefovir both as first-line therapy
treated patients. In clinical trials, entecavir has had an for chronic hepatitis B and as add-on therapy for lami-
excellent safety profile; doses should be reduced for vudineresistant chronic hepatitis B. Frequency of teno-
patients with reduced creatinine clearance. Entecavir fovir administration should be reduced for patients with
does have low-level antiviral activity against HIV and impaired creatinine clearance.
cannot be used as monotherapy to treat HBV infection A comparison of the six antiviral therapies in current
in HIVHBV co-infected persons. use appears in Table 40-3; their relative potencies in
suppressing HBV DNA are shown in Fig. 40-1.
SECTION VI
vudine at an oral daily dose of 600 mg suppressed HBV tion used for a year is no better than a year of PEG IFN
DNA to <300 copies/ml in 60% of HBeAg-positive and in achieving sustained responses. To date, combinations
88% of HBeAg-negative patients, reduced ALT to normal of oral nucleoside/nucleotide agents have not achieved
in 77% of HBeAg-positive and 74% of HBeAg-negative an enhancement in virologic, serologic, or biochemical
patients, and improved histology in 65% of HBeAg- efficacy over that achieved by the more potent of the
positive and 67% HBeAgnegative patients. Although combined drugs given individually. On the other hand,
resistance to telbivudine (M204I, not M204V mutations) combining agents that are not cross-resistant (e.g., lami-
was less frequent than resistance to lamivudine at the vudine and adefovir or tenofovir) has the potential to
end of 1 year, resistance mutations after 2 years of treat- reduce the risk or perhaps even to preempt entirely the
ment occurred in up to 22%. Generally well tolerated, emergence of drug resistance. In the future, the treat-
telbivudine has been associated with a low frequency ment paradigm may shift from the current approach of
of asymptomatic creatine kinase elevations and with a sequential monotherapy to preemptive combination
very low frequency of peripheral neuropathy; frequency therapy; however, designing and executing clinical tri-
of administration should be reduced for patients with als that demonstrate superior efficacy and resistance
impaired creatinine clearance. Its excellent potency profile of combination therapy over monotherapy with
notwithstanding, the inferior resistance profile of telbi- entecavir or tenofovir will be very challenging.
vudine has limited its appeal; telbivudine is neither rec- Novel Antivirals and Strategies In
ommended as first-line therapy nor widely used. addition to the seven approved antiviral drugs for
hepatitis B, emtricitabine, a fluorinated cytosine ana-
Tenofovir Tenofovir disoproxil fumarate, an
logue very similar to lamivudine in structure, efficacy, and
acyclic nucleotide analogue and potent antiretroviral
resistance profile, offers no advantage over lamivudine.
agent used to treat HIV infection, is similar to adefovir
A combination of emtricitabine and tenofovir is
but more potent in suppressing HBV DNA and induc-
approved for the treatment of HIV infection and is an
ing HBeAg responses; it is highly active against both
appealing combination therapy for hepatitis B; however,
wild-type and lamivudine-resistant HBV and active
neither emtricitabine nor the combination are approved
in patients whose response to adefovir is slow and/
yet for hepatitis B. Several initially promising antiviral
or limited. At an oral once-daily dose of 300 mg for
agents have been abandoned because of toxicity (e.g.,
48 weeks, tenofovir suppressed HBV DNA by 6.2 log10
clevudine, which was linked to myopathy during its clinical
[to undetectable levels (<400 copies/ml) in 76%] in HBeAg-
development). Because direct-acting antivirals have been
positive and 4.6 log10 (to undetectable levels in 93%) in
so successful in the management of chronic hepatitis B,
HBeAg-negative patients; reduced ALT to normal in 68%
more unconventional approaches—e.g., immunologic
of HBeAg-positive and 76% of HBeAg-negative patients;
or genetic manipulation—are not likely to be com-
and improved histology in 74% of HBeAg-positive and
petitive. Finally, initial emphasis in the development of
72% of HBeAg-negative patients. In HBeAg-positive
antiviral therapy for hepatitis B was placed on mono-
patients, HBeAg seroconversions occurred in 21% by the
therapy; whether combination regimens will yield addi-
end of year 1 and in 27% by the end of year 2 of tenofo-
tive or synergistic efficacy remains to be determined).
vir treatment; HBsAg loss occurred in 3% by the end of
year 1 and 6% by the end of year 2. The safety (negligible Treatment Recommendations Several
renal toxicity and mild reduction in bone density) and learned societies and groups of expert physicians have
resistance profile (none recorded through 3 years) issued treatment recommendations for patients with
Table 40-3 407
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
CHAPTER 40
monitoring monitoring
recommended recommended
HBeAg seroconversion
1 yr Rx 18–20% 16–21% 12% 21% 22% 21%
>1 yr Rx NA up to 50% 43% @ 3 yrsd 31% @ 2 yrs 30% @ 2 yrs 27% @ 2 yrs
@ 5 yrs 39% @ 3 yrs
Chronic Hepatitis
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;
<1,000 copies/ml for
adefovir) end of yr 1
HBeAg-reactive 10–25% 36–44% 13–21% 67% (91% @ 60% 76%
4 yrs)
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%
yr 2 12% 5 yr after no data 5% at yr 5 5% no data 6%
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% None @ 1 yr ≤1% @ 1 yre up to 0% @ yr 1
@ 1 yr 5% @ yr 1
70% 29% at 5 yrs 1.2% @ 5 yre up to 0% through
@ 5 yrs 22% @ yr 2 yr 3
Cost (US$) for 1 yr ∼$18,000 ∼$2,500 ∼$6,500 ∼$8,700f ∼$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.
b
Although 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.
c
Duration of therapy in clinical efficacy trials; use in clinical practice may vary.
d
Because 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.
e
7% during a year of therapy (43% at year 4) in lamivudine-resistant patients.
f
∼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.
408 0
group, when, eventually, ALT becomes elevated later in
–1 life, antiviral therapy should be instituted. For patients
–2 with HBeAg-negative chronic hepatitis B, ALT >2 × the
Log10 HBV DNA
–6.2
–6.4 ent (treatment in this subset would be recommended
–7
–6.9 according to EASL guidelines, because ALT is elevated).
ADV PEG IFN LAM TDF TBV ETV
For patients with compensated cirrhosis, because
Figure 40-1 antiviral therapy has been shown to retard clinical pro-
Relative potency of antiviral drugs for hepatitis B, as gression, treatment is recommended regardless of
reflected by median log10 HBV DNA reduction in HBeAg- HBeAg status and ALT as long as HBV DNA is detectable
Disorders of the Liver and Biliary Tree
positive chronic hepatitis B. These data are from individual at >2 × 103 IU/ml (detectable at any level according to
reports of large, randomized controlled registration trials that the EASL); monitoring without therapy is recommended
were the basis for approval of the drugs. In most instances, for those with HBV DNA <2 × 103 IU/ml, unless ALT is
these data do not represent direct comparisons among the elevated. For patients with decompensated cirrhosis,
drugs, because study populations were different, baseline treatment is recommended regardless of serologic and
patient variables were not always uniform, and the sensitivity biochemical status, as long as HBV DNA is detectable.
and dynamic range of the HBV DNA assays used in the trials Patients with decompensated cirrhosis should be evalu-
varied. ADV, adefovir dipivoxil; PEG IFN, pegylated interferon ated as candidates for liver transplantation.
α-2a; LAM, lamivudine; TDF, tenofovir disoproxil fumarate; Among the seven available drugs for hepatitis B, PEG
TBV, telbivudine; ETV, entecavir. IFN has supplanted standard IFN, entecavir has
supplanted lamivudine, and tenofovir has supplanted
adefovir. PEG IFN, entecavir, or tenofovir are recom-
chronic hepatitis B; the most authoritative and updated mended as first-line therapy (Table 40-3). PEG IFN requires
(and free of financial support by pharmaceutical com- finite-duration therapy, achieves the highest rate of
panies) are those of the American Association for the HBeAg responses after a year of therapy, and does not
Study of Liver Diseases (AASLD) and of the European support viral mutations, but it requires subcutaneous
Association for the Study of the Liver (EASL). Although injections and is associated with inconvenience and
the recommendations differ slightly, a consensus has intolerability. Oral nucleoside analogues require long-
emerged on most of the important points (Table 40-4). term therapy in most patients, and when used alone,
No treatment is recommended or available for inac- lamivudine and telbivudine foster the emergence of
tive “nonreplicative” hepatitis B carriers (undetectable viral mutations, adefovir somewhat less so, and entecavir
HBeAg with normal ALT and HBV DNA ≤103 IU/ml docu- (except in lamivudine-experienced patients) and teno-
mented serially over time). In patients with detectable fovir rarely at all. Oral agents do not require injections,
HBeAg and HBV DNA levels >2 ×104 IU/ml, treatment is are very well tolerated, lead to improved histology in
recommended by the AASLD for those with ALT levels 50–90% of patients, suppress HBV DNA more profoundly
above 2 × the upper limit of normal. (The EASL recom- than PEG IFN, and are effective even in patients who fail
mends treatment in HBeAg-positive patients for HBV to respond to IFN-based therapy. Although oral agents
DNA levels >2 × 103 IU/ml and ALT above the upper limit are less likely to result in HBeAg responses during the
of normal.) For HBeAgpositive patients with ALT ≤2 × first year of therapy, as compared to PEG IFN, treatment
the upper limit of normal, in whom sustained responses with oral agents tends to be extended beyond the first
are not likely and who would require multiyear ther- year and, by the end of the second year, yields HBeAg
apy, antiviral therapy is not recommended currently. responses (and even HBsAg responses) comparable
This pattern is common during the early decades of in frequency to those achieved after 1 year of PEG IFN
life among Asian patients infected at birth; even in this (and without the associated side effects) (Table 40-5).
group, therapy would be considered for those >40 years Although adefovir and tenofovir are safe, creatinine
of age, ALT persistently at the high end of the twofold monitoring is recommended. Substantial experience
range, and/or with a family history of hepatocellular car- with lamivudine during pregnancy (see above) has
cinoma, especially if the liver biopsy shows moderate identified no teratogenicity. Although interferons do
to severe necroinflammatory activity or fibrosis. In this not appear to cause congenital anomalies, interferons
Table 40-4 409
Recommendations for Treatment of Chronic Hepatitis Ba
HBeAg status Clinical HBV DNA (IU/ml) ALT Recommendation
HBeAg-reactive b
>2 × 10 4
≤2 × ULN c
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
CHAPTER 40
Cirrhosis >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
compensated
<2 × 103 >ULN Consider treatmentf
Cirrhosis Detectable < or > ULN Treate with oral agentsg, not PEG IFN; refer
decompensated for liver transplantation
Undetectable < or > ULN Observe; refer for liver transplantation
HBeAg-negative b
≤2 × 10 3
≤ULN Inactive carrier; treatment not necessary
Chronic Hepatitis
Chronic hepatitis >103 1->2 × ULNd Consider liver biopsy; treath if biopsy
shows moderate to severe inflammation
or fibrosis
Chronic hepatitis >104 >2 × ULNd Treath,i
Cirrhosis >2 × 103 < or > ULN Treate with oral agents, not PEG IFN
compensated
<2 × 103 >ULN Consider treatmentf
Cirrhosis Detectable < or > ULN Treath with oral agentsg, not PEG IFN; refer
decompensated 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).
b
Liver disease tends to be mild or inactive clinically; most such patients do not undergo liver biopsy.
c
This pattern is common during early decades of life in Asian patients infected at birth.
d
According to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/ml and ALT >ULN.
e
One 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 adminis-
tered 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.
g
Because 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.
h
Because HBeAg seroconversion is not an option, the goal of therapy is to suppress HBV DNA and maintain a normal ALT. PEG IFN is admin-
istered 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 indefi-
nitely or, until as very rarely occurs, virologic and biochemical responses are accompanied by HBsAg seroconversion.
i
For older patients and those with advanced fibrosis, consider lowering the HBV DNA threshold to >2 × 103 IU/ml.
Abbreviations: ALT, alanine aminotransferase; AASLD, American Association for the Study of Liver Diseases; 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 limits of normal.
have antiproliferative properties and should not be used available, the other antivirals for hepatitis B should
during pregnancy. Adefovir during pregnancy has not be avoided or used with extreme caution during
been associated with birth defects; however, there may pregnancy.
be an increased risk of spontaneous abortion. Data on As noted above, some physicians prefer to begin with
the safety of entecavir during pregnancy have not been PEG IFN, while other physicians and patients prefer oral
published. Sufficient data in animals and limited data in agents as first-line therapy. For patients with decompen-
humans suggest that telbivudine and tenofovir can be sated cirrhosis, the emergence of resistance can result in
used safely during pregnancy. In general, except per- further deterioration and loss of antiviral effectiveness.
haps for lamivudine, and until additional data become Therefore, in this patient subset, the threshold for
410 Table 40-5
relying on therapy with a very favorable resistance
Pegylated Interferon Versus Oral
Nucleoside Analogues for the Treatment of profile (e.g., entecavir or tenofovir) or on combination
Chronic Hepatitis B therapy (e.g., lamivudine or telbivudine with adefovir) is
low. PEG IFN should not be used in patients with com-
Nucleoside
PEG IFN Analogues pensated or decompensated cirrhosis.
For patients with end-stage chronic hepatitis B who
Administration Weekly injection Daily, orally undergo liver transplantation, reinfection of the new
Tolerability Poorly tolerated, Well tolerated, liver is almost universal in the absence of antiviral
intensive limited therapy. The majority of patients become high-level
SECTION VI
monitoring monitoring
viremic carriers with minimal liver injury. Before the
Duration of Finite 48 weeks ≥1 year, indefinite availability of antiviral therapy, an unpredictable propor-
therapy in most patients tion experienced severe hepatitis B–related liver injury,
Maximum mean 4.5 log10 6.9 log10 sometimes a fulminant-like hepatitis, sometimes a rapid
HBV DNA recapitulation of the original severe chronic hepatitis B
suppression (Chap. 304). Currently, however, prevention of recurrent
Disorders of the Liver and Biliary Tree
Effective in high- No Yes hepatitis B after liver transplantation has been achieved
level HBV DNA definitively by combining hepatitis B immune globulin
(≥109 IU/ml) with one of the oral nucleoside or nucleotide analogues
HBeAg seroconversion (Chap. 310).
During 1 year of ∼30% ∼20% For patients treated with the more resistance-prone
therapy
(lamivudine, telbivudine) or less potent (adefovir) oral
During >1 year of Not applicable 30% (year
agents, assessment of response at 24 weeks (48 weeks
therapy 2)–50% (year 5)
for adefovir) can identify those at high risk for inad-
HBeAg-negative
equate response and breakthrough resistance (i.e.,
posttreatment 17% @ 5 years 7% @ 4 years
HBV (lamivudine)
the presence of residual detectable viremia). When
DNA suppression such inadequate responses are identified, a second,
noncross-resistant agent can be added or the initial
HBsAg loss
During 1 year of 3–4% 0–3%
agent can be replaced by a more potent agent. This
therapy “roadmap” approach has been rendered irrelevant by
During >1 year of Not applicable 3–6% @ 2 years the use of the current generation of highly potent,
therapy of therapy low-resistant agents entecavir and tenofovir. Still, at
After 1 year 12% @ 5 years 3.5% @ 5 years 24 weeks, if HBV DNA exceeds 2 × 103 IU/ml, switch-
of therapy– ing to a different agent or adding a second agent is
HBeAg- advisable.
negative
Patients with HBV-HIV co-infection can have pro-
Antiviral None Lamivudine: gressive HBV-associated liver disease and, occasion-
resistance ∼30% year 1,
ally, a severe exacerbation of hepatitis B resulting from
∼70% year 5
Adefovir: 0% year 1,
immunologic reconstitution following highly active
∼30% year 5 antiretroviral therapy. Lamivudine should never be
Telbivudine: up to used as monotherapy in patients with HBVHIV infec-
4% year 1, 22% tion because HIV resistance emerges rapidly to both
year 2 viruses. Adefovir has been used successfully to treat
Entecavir: ≤1.2% chronic hepatitis B in HBV-HIV co-infected patients but
through year 5 is no longer considered a first-line agent for HBV. Ente-
Tenofovir: 0%
cavir has low-level activity against HIV and can result
through year 3
in selection of HIV resistance; therefore, it should be
Use in cirrhosis, No Yes
avoided in HBV-HIV co-infection. Tenofovir and the
transplantation,
immuno
combination of tenofovir and emtricitabine in one pill
suppressed are approved therapies for HIV and represent excel-
lent choices for treating HBV infection in HBV-HIV
Cost, 1 year of ++++ + to ++
therapy
co-infected patients. Generally, even for HBV-HIV co-
infected patients who do not yet meet treatment cri-
Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; teria for HIV infection, treating for both HBV and HIV is
HBsAg, hepatitis B surface antigen; IU/ml, international units per recommended.
milliliter; PEG IFN, pegylated interferon.
411
Patients with chronic hepatitis B who undergo cyto- Treatment Chronic Hepatitis D
toxic chemotherapy for treatment of malignancies
as well as patients treated with immunosuppressive, Management is not well defined. Glucocorticoids are
anticytokine, or antitumor necrosis factor therapies ineffective and are not used. Preliminary experimental
experience enhanced HBV replication and viral expres- trials of IFN-α suggested that conventional doses and
sion on hepatocyte membranes during chemotherapy durations of therapy lower levels of HDV RNA and ami-
coupled with suppression of cellular immunity. When notransferase activity only transiently during treatment
chemotherapy is withdrawn, such patients are at risk but have no impact on the natural history of the dis-
ease. In contrast, high-dose IFN-α (9 million units three
CHAPTER 40
for reactivation of hepatitis B, often severe and occa-
sionally fatal. Such rebound reactivation represents times a week) for 12 months may be associated with a
restoration of cytolytic T cell function against a target sustained loss of HDV replication and clinical improve-
organ enriched in HBV expression. Preemptive treat- ment in up to 50% of patients. Moreover, the benefi-
ment with lamivudine prior to the initiation of che- cial impact of treatment has been observed to persist
motherapy has been shown to reduce the risk of such for 15 years and to be associated with a reduction in
reactivation. In all likelihood, the newer, more potent grade of hepatic necrosis and inflammation, reversion
Chronic Hepatitis
oral antiviral agents will work as well and with a lower of advanced fibrosis (improved stage), and clearance of
risk of antiviral drug resistance. The optimal duration HDV RNA in some patients. A suggested approach to
of antiviral therapy after completion of chemotherapy therapy has been high-dose, long-term IFN for at least a
is not known, but a suggested approach is 6 months year and, in responders, extension of therapy until HDV
for inactive hepatitis B carriers and longer-duration RNA and HBsAg clearance. PEG IFN has also been shown
therapy in patients with baseline HBV DNA levels to be effective in the treatment of chronic hepatitis
>2 × 103 IU/ml, until standard clinical endpoints are D and is likely to become a more convenient replace-
met (Table 40-4). ment for standard IFN. None of the nucleoside analogue
antiviral agents for hepatitis B is effective in hepatitis D.
In patients with end-stage liver disease secondary to
chronic hepatitis D, liver transplantation has been effective.
Chronic Hepatitis D (Delta Hepatitis) If hepatitis D recurs in the new liver without the expres-
Chronic hepatitis D (HDV) may follow acute co- sion of hepatitis B (an unusual serologic profile in
infection with HBV but at a rate no higher than immunocompetent persons but common in transplant
the rate of chronicity of acute hepatitis B. That is, patients), liver injury is limited. In fact, the outcome of
although HDV co-infection can increase the severity transplantation for chronic hepatitis D is superior to that
of acute hepatitis B, HDV does not increase the like- for chronic hepatitis B; in such patients, combination
lihood of progression to chronic hepatitis B. When, hepatitis B immune globulin and nucleoside analogue
however, HDV super-infection occurs in a person therapy for hepatitis B is indicated (Chap. 310).
who is already chronically infected with HBV, long-
term HDV infection is the rule and a worsening of
Chronic Hepatitis C
the liver disease the expected consequence. Except for
severity, chronic hepatitis B plus D has similar clini- Regardless of the epidemiologic mode of acquisition
cal and laboratory features to those seen in chronic of hepatitis C virus (HCV) infection, chronic hepatitis
hepatitis B alone. Relatively severe and progressive follows acute hepatitis C in 50–70% of cases; chronic
chronic hepatitis, with or without cirrhosis, is the rule, infection is common even in those with a return to
and mild chronic hepatitis is the exception. Occasion- normal in aminotransferase levels after acute hepatitis C,
ally, mild hepatitis or even, rarely, inactive carriage adding up to an 85% likelihood of chronic HCV infec-
occurs in patients with chronic hepatitis B plus D, and tion after acute hepatitis C. Few clues had emerged to
the disease may become indolent after several years of explain host differences associated with chronic infec-
infection. A distinguishing serologic feature of chronic tion until recently, when variation in a single nucleo-
hepatitis D is the presence in the circulation of anti- tide polymorphism (SNP) on chromosome 19, IL28B
bodies to liver-kidney microsomes (anti-LKM); how- (which codes for interferon-λ3), was identified that dis-
ever, the anti-LKM seen in hepatitis D, anti-LKM3, tinguished between responders and nonresponders to
are directed against uridine diphosphate glucurono- antiviral therapy (see below). The same variants corre-
syltransferase and are distinct from anti-LKM1 seen lated with spontaneous resolution after acute infection:
in patients with autoimmune hepatitis and in a subset 53% in genotype C/C, 30% in genotype C/T, but only
of patients with chronic hepatitis C (see below). The 23% in genotype T/T.
clinical and laboratory features of chronic HDV infec- In patients with chronic hepatitis C followed for
tion are summarized in Chap. 304. 20 years, progression to cirrhosis occurs in about
412 20–25%. Such is the case even for patients with relatively because HCV infection is so prevalent, and because a
clinically mild chronic hepatitis, including those without proportion of patients progress inexorably to endstage
symptoms, with only modest elevations of aminotrans- liver disease, hepatitis C is the most frequent indica-
ferase activity and with mild chronic hepatitis on liver tion for liver transplantation (Chap. 310). Referral bias
biopsy. Even in cohorts of well-compensated patients may account for the more severe outcomes described
with chronic hepatitis C referred for clinical research tri- in cohorts of patients reported from tertiary care centers
als (no complications of chronic liver disease and with (20-year progression of ≥20%) versus the more benign
normal hepatic synthetic function), the prevalence of cir- outcomes in cohorts of patients monitored from initial
rhosis may be as high as 50%. Most cases of hepatitis C blood-product-associated acute hepatitis or identified in
SECTION VI
are identified initially in asymptomatic patients who have community settings (20-year progression of only 4–7%).
no history of acute hepatitis C (e.g., those discovered Still unexplained, however, are the wide ranges in
while attempting to donate blood, while undergoing lab reported progression to cirrhosis, from 2% over 17 years
testing as part of an application for life insurance, or as a in a population of women with hepatitis C infection
result of routine laboratory tests). The source of HCV acquired from contaminated anti-D immune globulin to
infection in many of these cases is not defined, although 30% over ≤11 years in recipients of contaminated intra-
a long-forgotten percutaneous exposure in the remote venous immune globulin.
Disorders of the Liver and Biliary Tree
past can be elicited in a substantial proportion and proba- Progression of liver disease in patients with chronic
bly accounts for most infections; most of these infections hepatitis C has been reported to be more likely in
were acquired in the 1960s and 1970s, coming to clinical patients with older age, longer duration of infec-
attention decades later. tion, advanced histologic stage and grade, genotype 1,
Approximately one-third of patients with chronic more complex quasispecies diversity, increased hepatic
hepatitis C have normal or near-normal aminotrans- iron, concomitant other liver disorders (alcoholic liver
ferase activity; although one-third to one-half of these disease, chronic hepatitis B, hemochromatosis, α1-
patients have chronic hepatitis on liver biopsy, the antitrypsin deficiency, and steatohepatitis), HIV infection,
grade of liver injury and stage of fibrosis tend to be mild and obesity. Among these variables, however, duration
in the vast majority. In some cases, more severe liver of infection appears to be one of the most important,
injury has been reported—even, rarely, cirrhosis, most and some of the others probably reflect disease duration
likely the result of previous histologic activity. Among to some extent (e.g., quasispecies diversity, hepatic iron
patients with persistent normal aminotransferase activity accumulation). No other epidemiologic or clinical fea-
sustained over ≥5–10 years, histologic progression has tures of chronic hepatitis C (e.g., severity of acute hepa-
been shown to be rare; however, approximately one- titis, level of aminotransferase activity, level of HCV
fourth of patients with normal aminotransferase activity RNA, presence or absence of jaundice during acute
experience subsequent aminotransferase elevations, and hepatitis) are predictive of eventual outcome. Despite
histologic injury can be progressive once abnormal bio- the relatively benign nature of chronic hepatitis C over
chemical activity resumes. Therefore, continued clinical time in many patients, cirrhosis following chronic hepa-
monitoring is indicated, even for patients with normal titis C has been associated with the late development,
aminotransferase activity. after several decades, of HCC (Chap. 88); the annual
Despite this substantial rate of progression of chronic rate of HCC in cirrhotic patients with hepatitis C is
hepatitis C, and despite the fact that liver failure can 1–4%, occurring primarily in patients who have had
result from end-stage chronic hepatitis C, the long- HCV infection for 30 years or more.
term prognosis for chronic hepatitis C in a majority of Perhaps the best prognostic indicator in chronic hep-
patients is relatively benign. Mortality over 10–20 years atitis C is liver histology; the rate of hepatic fibrosis may
among patients with transfusion-associated chronic be slow, moderate, or rapid. Patients with mild necrosis
hepatitis C has been shown not to differ from mortal- and inflammation as well as those with limited fibrosis
ity in a matched population of transfused patients in have an excellent prognosis and limited progression to
whom hepatitis C did not develop. Although death in cirrhosis. In contrast, among patients with moderate to
the hepatitis group is more likely to result from liver severe necroinflammatory activity or fibrosis, includ-
failure, and although hepatic decompensation may ing septal or bridging fibrosis, progression to cirrhosis
occur in ∼15% of such patients over the course of a is highly likely over the course of 10–20 years. Among
decade, the majority (almost 60%) of patients remain patients with compensated cirrhosis associated with
asymptomatic and well compensated, with no clinical hepatitis C, the 10-year survival rate is close to 80%;
sequelae of chronic liver disease. Overall, chronic hepa- mortality occurs at a rate of 2–6% per year; decompen-
titis C tends to be very slowly and insidiously progres- sation at a rate of 4–5% per year; and, as noted above,
sive, if at all, in the vast majority of patients, while in HCC at a rate of 1–4% per year. A discussion of the
approximately one-fourth of cases, chronic hepatitis C pathogenesis of liver injury in patients with chronic
will progress eventually to end-stage cirrhosis. In fact, hepatitis C appears in Chap. 304.
Clinical features of chronic hepatitis C are similar to Peginterferon and Ribavirin 413
those described above for chronic hepatitis B. Gener- 7
ally, fatigue is the most common symptom; jaundice is 6
CHAPTER 40
to cutaneous vasculitis and membranoproliferative glo- 0
merulonephritis as well as lymphoproliferative disorders –8 –4 –2 0 4 8 12 16 20 24 32 40 48 52 60 72
such as B-cell lymphoma and unexplained monoclonal Weeks after start of therapy
gammopathy. In addition, chronic hepatitis C has been Figure 40-2
associated with extrahepatic complications unrelated Virologic responses during a 48-week course of antiviral
to immune-complex injury. These include Sjögren’s therapy in patients with hepatitis C, genotype 1 or 4 (for
syndrome, lichen planus, porphyria cutanea tarda,
Chronic Hepatitis
genotypes 2 or 3, the course would be 24 weeks). Non-
type-II diabetes mellitus and the metabolic syndrome responders can be classified as null responders (HCV RNA
(including insulin resistance and steatohepatitis). reduction of <2 log10 IU/ml) or partial responders (HCV RNA
Laboratory features of chronic hepatitis C are similar to reduction ≥2 log10 IU/ml but not suppressed to undetect-
those in patients with chronic hepatitis B, but amino- able) by week 24 of therapy. In responders, HCV RNA can
transferase levels tend to fluctuate more (the character- become undetectable, as shown with sensitive amplification
istic episodic pattern of aminotransferase activity) and assays, within 4 weeks (RVR, rapid virologic response); can
to be lower, especially in patients with long-standing be reduced by ≥2 log10 IU/ml within 12 weeks (early virologic
disease. An interesting and occasionally confusing find- response, EVR; if HCV RNA is undetectable at 12 weeks, the
ing in patients with chronic hepatitis C is the presence designation is “complete” EVR); or at the end of therapy,
of autoantibodies. Rarely, patients with autoimmune 48 weeks (ETR, end-treatment response). In responders,
hepatitis (see below) and hyperglobulinemia have false- if HCV RNA remains undetectable for 24 weeks after ETR,
positive immunoassays for anti-HCV. On the other week 72, the patient has a sustained virologic response
hand, some patients with serologically confirmable chronic (SVR), but if HCV RNA becomes detectable again, the
hepatitis C have circulating anti-LKM. These antibod- patient is considered to have relapsed. (Reproduced with
ies are anti-LKM1, as seen in patients with autoimmune permission, courtesy of Marc G. Ghany, National Institute of
hepatitis type 2 (see below), and are directed against a Diabetes and Digestive and Kidney Diseases, National Insti-
tutes of Health and the American Association for the Study of
33-aminoacid sequence of cytochrome P450 IID6. The
Liver Diseases Hepatology 49:1335, 2009.)
occurrence of anti-LKM1 in some patients with chronic
hepatitis C may result from the partial sequence homology
between the epitope recognized by anti-LKM1 and two
segments of the HCV polyprotein. In addition, the pres-
ence of this autoantibody in some patients with chronic therapy—but not increasing the dose or changing IFN
hepatitis C suggests that autoimmunity may be playing a preparations—increased the SVR rate to ∼20%, and
role in the pathogenesis of chronic hepatitis C. addition to the regimen of daily ribavirin, an oral gua-
Histopathologic features of chronic hepatitis C, espe- nosine nucleoside, increased the SVR rate to 40%. When
cially those that distinguish hepatitis C from hepatitis B, used alone, ribavirin is ineffective and does not reduce
are described in Chap. 304. HCV RNA levels, but ribavirin enhances the efficacy
of IFN by reducing the likelihood of virologic relapse
after the achievement of an end-treatment response
Treatment Chronic Hepatitis C (ETR) (Fig. 40-2) (response measured during, and main-
tained to the end of, treatment). Proposed mechanisms
Therapy for chronic hepatitis C has evolved substantially to explain the role of ribavirin include subtle direct
in the two decades since IFN-α was introduced for this reduction of HCV replication, inhibition of host inosine
indication. When first approved, IFN-α was adminis- monophosphate dehydrogenase activity (and associ-
tered via subcutaneous injection three times a week for ated depletion of guanosine pools), immune modula-
6 months but achieved a sustained virologic response, tion, induction of virologic mutational catastrophe, and
SVR (Fig. 40-2) (a reduction of HCV RNA to undetectable enhancement of interferon-stimulated gene expression.
levels by PCR when measured ≥6 months after comple- Interferon therapy results in activation of the JAKSTAT
tion of therapy) below 10%. Doubling the duration of signal transduction pathway, which culminates in the
414
intracellular elaboration of genes and their protein prod- Hispanic patients as in whites. Moreover, the likelihood of a
ucts that have antiviral properties. Hepatitis C proteins sustained response is best if adherence to the treatment
inhibit JAK-STAT signaling at several steps along the regimen is high (i.e., if patients receive ≥80% of the IFN
pathway, and exogenous interferon restores expression and ribavirin doses and if they continue treatment for
of interferon-stimulated genes and their antiviral effects. ≥80% of the anticipated duration of therapy). Other
The current standard of care is the combination of variables reported to correlate with increased respon-
longacting pegylated IFN (PEG IFN) and ribavirin, which siveness include brief duration of infection, low HCV
has increased responsiveness (frequency of SVR) to as quasispecies diversity, immunocompetence, absence
high as 55% overall, >40% in genotypes 1 and 4 and to of hepatic steatosis and insulin resistance, and low liver
SECTION VI
>80% in genotypes 2 and 3. Still, many important iron levels. High levels of HCV RNA, more histologically
lessons about antiviral therapy for chronic hepatitis C were advanced liver disease, and high quasispecies diversity
learned from the experience with IFN monotherapy and all go hand in hand with advanced duration of infec-
combination IFN-ribavirin therapy. Even in the absence of tion, which may be the single most important clinical
biochemical and virologic responses, histologic improve- variable determining IFN responsiveness. The ironic
ment occurs in approximately three-fourths of all treated fact, then, is that patients whose disease is least likely
Disorders of the Liver and Biliary Tree
patients. In chronic hepatitis C, unlike the case in hepati- to progress are the ones most likely to respond to inter-
tis B, responses to therapy are not accompanied by tran- feron and vice versa.
sient, acute hepatitis-like aminotransferase elevations. Genetic changes in the virus may explain differ-
Instead, ALT levels fall precipitously during therapy. Up to ences in treatment responsiveness in some patients
90% of virologic responses are achieved within the first (e.g., among patients with genotype 1b, responsiveness
12 weeks of therapy; responses thereafter are rare. Most to IFN is enhanced in those with amino-acid-substitu-
relapses occur within the first 12 weeks after treatment. tion mutations in the nonstructural protein 5A gene).
Sustained virologic responses are very durable; normal As described above in the discussion of spontaneous
ALT, improved histology, and absence of HCV RNA in recovery from acute hepatitis C, interferon gene vari-
serum and liver have been documented a decade after ants discovered recently in gene-wide association stud-
successful therapy, and “relapses” 2 years after sustained ies have been shown to have a substantial impact on
responses are almost unheard of. Thus, an SVR to antiviral responsiveness of patients with genotype 1 to antiviral
therapy of chronic hepatitis C is tantamount to a cure. therapy. In studies of patients treated with PEG IFN and
Patient variables that tend to correlate with sustained ribavirin, variants of the IL28B SNP that code for
virologic responsiveness to IFN-based therapy include IFN-λ3 (a type-III IFN, the receptors for which are more
favorable genotype (genotypes 2 and 3 as opposed to discretely distributed than IFN α receptors and more
genotypes 1 and 4), low baseline HCV RNA level (<2 mil- concentrated in hepatocytes) correlate significantly
lion copies/mL, which is equivalent to ∼800,000 IU/ml, with responsiveness. Patients homozygous for the C
the current convention of quantitation), histologically allele at this locus have the highest frequency of achiev-
mild hepatitis and minimal fibrosis, age <40, absence ing an SVR (∼80%), those homozygous for the T allele at
of obesity as well as insulin resistance and type-II this locus are least likely to achieve an SVR (∼25%), and
diabetes mellitus, and female gender. Patients with cir- those heterozygous at this locus (C/T) have an interme-
rhosis can respond, but they are less likely to do so. diate level of responsiveness (SVRs in ∼35%). The fact
Studies of combination IFN-ribavirin therapy have that C/C is common in whites of European ancestry and
shown that in patients with genotype 1, therapy should even more so in Japanese persons but rare in African
last a full 48 weeks, while in those with genotypes 2 Americans helps explain the differences in observed
and 3, a 24-week course of therapy suffices (although responsiveness among these population groups.
more recent observations allow refined tailoring of Side effects of IFN therapy are described above in the
treatment duration based on rapidity of response, see section on treatment of chronic hepatitis B. The most pro-
below). The response rate in African Americans is dis- nounced side effect of ribavirin therapy is hemolysis; a
appointingly low for reasons that are not fully under- reduction in hemoglobin of up to 2–3 g or in hematocrit
stood. Potentially contributing to, but not explaining of 5–10% can be anticipated. A small, unpredictable pro-
entirely, low responsiveness in African Americans are a portion of patients experience profound, brisk hemolysis,
higher proportion with genotype 1, slower early viral resulting in symptomatic anemia; therefore, close moni-
kinetics during therapy, impaired HCV-specific immu- toring of blood counts is crucial, and ribavirin should be
nity, and recently recognized host genetic differences avoided in patients with anemia or hemoglobinopathies
in IL28B alleles, described below. The response rate in and in patients with coronary artery disease or cerebro-
Latino patients is also low, despite the fact that the fre- vascular disease, in whom anemia can precipitate an isch-
quency of the favorable IL28B C allele is as common in emic event. When symptomatic anemia occurs, ribavirin
415
dose reductions or addition of erythropoietin to boost short-acting IFNs, administration of PEG IFNs results
red blood cell levels may be required; erythropoietin has in drug concentrations that are more stable and sus-
been shown to improve patients’ quality of life but not tained over time. Once-a-week PEG IFN monotherapy is
the likelihood of achieving an SVR. If ribavirin is stopped twice as effective as monotherapy with its standard IFN
during therapy, SVR rates fall, but responsiveness can be counterpart, approaches the efficacy of combination
maintained as long as the ribavirin is not stopped and standard IFN plus ribavirin, and is as well tolerated as
the total ribavirin dose exceed 60% of the planned dose. standard IFNs, without more difficult-to-manage throm-
In addition, ribavirin, which is renally excreted, should bocytopenia and leukopenia than standard IFNs. The
CHAPTER 40
not be used in patients with renal insufficiency; the drug current standard of care, however, is a combination of
is teratogenic, precluding its use during pregnancy and PEG IFN plus ribavirin.
mandating the scrupulous use of efficient contraception Two PEG IFNs are available: PEG IFN α-2b and α-2a.
during therapy (interferons, too, because of their antiprolif- PEG IFN α-2b consists of a 12-kD, linear PEG molecule
erative properties, are contraindicated during pregnancy). bound to IFN α-2b, while PEG IFN α-2a consists of a
Ribavirin can also cause nasal and chest congestion, larger, 40kD, branched PEG molecule bound to IFN α-2a;
pruritus, and precipitation of gout. Combination IFN- because of its larger size and smaller volume of extra-
Chronic Hepatitis
ribavirin therapy is more difficult to tolerate than IFN vascular distribution, PEG IFN α-2a can be given at a uni-
monotherapy. In one large clinical trial of combination form dose independent of weight, while the dose of the
therapy versus monotherapy, among those in the 1-year smaller PEG IFN α-2b, which has a much wider volume
treatment group, 21% of the combination group (but distribution, must be weight-based (Table 40-6). In the
only 14% of the monotherapy group) had to discon- registration trial for PEG IFN α-2b plus ribavirin, the best
tinue treatment, while 26% of the combination group regimen was 48 weeks of 1.5 μg/kg of PEG IFN once a
(but only 9% of the monotherapy group) required dose week plus 800 mg of ribavirin daily. A post hoc analysis
reductions. suggested that weight-based dosing of ribavirin would
Studies of viral kinetics have shown that despite have been more effective than the fixed 800-mg dose
a virion halflife in serum of only 2–3 h, the level of used in the study. In the first registration trial for PEG
HCV is maintained by a high replication rate of 1012 IFN α-2a plus ribavirin, the best regimen was 48 weeks
hepatitis C virions per day. IFN-α blocks virion produc- of 180 μg of PEG IFN plus 1000 mg (for patients <75 kg)
tion or release with an efficacy that increases with to 1200 mg (for patients ≥75 kg) of ribavirin. Sustained
increasing drug doses; moreover, the calculated death virologic responses of 54 and 56% were reported in
rate for infected cells during IFN therapy is inversely these two studies, respectively. A subsequent study of
related to viral load; patients with the most rapid death PEG IFN α-2a plus ribavirin showed that, for patients
rate of infected hepatocytes are more likely to achieve with genotypes 2 and 3, a duration of 24 weeks and a
undetectable HCV RNA at 3 months; in practice, failure ribavirin dose of 800 mg was sufficient. Among the
to achieve an early virologic response (EVR), a ≥2-log10 three studies, for patients in the optimal treatment arm,
reduction in HCV RNA by week 12, predicts failure to SVR rates for patients with genotype 1 were 42–51%
experience a subsequent SVR. Similarly, patients in and for patients with genotypes 2 and 3 rates were
whom HCV RNA becomes undetectable within 4 weeks 76–82%. Between genotypes 2 and 3, genotype 3 is
[i.e., who achieve a rapid virologic response (RVR)], have somewhat more refractory, and some authorities would
a very high likelihood of achieving a sustained virologic extend therapy for a full 48 weeks in patients with geno-
response (Fig. 40-2). Therefore, to achieve rapid viral type 3, especially if they have advanced hepatic fibrosis
clearance from serum and the liver, high-dose induction or cirrhosis and/or high-level HCV RNA.
therapy has been advocated. In practice, however, high- In the initial registration trials for combination PEG
dose induction with IFN-based therapy has not yielded IFN plus ribavirin, both combination PEG IFN regimens
higher sustained response rates. were compared to standard IFN α-2b plus ribavirin.
Side effects of the combination PEG IFN α-2b regimen
Treatment of Choice For the treatment of were comparable to those for the combination stan-
chronic hepatitis C, standard IFNs have now been sup- dard IFN regimen; however, when the combination
planted by PEG IFNs. These have elimination times PEG IFN α-2a regimen was compared to the combina-
up to sevenfold longer than standard IFNs (i.e., a sub- tion standard IFN α-2b regimen, flu-like symptoms and
stantially longer half-life), and achieve prolonged con- depression were less common in the combination PEG
centrations, permitting administration once (rather IFN group. Although ascertainment of side effects dif-
than three times) a week. Instead of the frequent drug fered between studies of the two drugs, when each was
peaks (linked to side effects) and troughs (when drug tested against standard IFN α-2b plus ribavirin, combi-
is absent) associated with frequent administration of nation PEG IFN α-2a plus ribavirin appeared to be better
416 Table 40-6
tolerated. In a recent head-to-head trial of the two PEG
Pegylated Interferon `-2a and `-2b for
Chronic Hepatitis C IFNs (the “IDEAL” trial), the two PEG IFNs were found
to be comparable in efficacy (achievement of SVR)
PEG IFN `-2b PEG IFN `-2a
(Fig. 40-3) and tolerability, although headache, nausea,
PEG size 12 kD linear 40 kD branched fever, myalgia, depression, and drug discontinuation
Elimination half-life 54 hours 65 hours for any reason were less frequent in patients treated
with PEG IFN α-2a than standard-dose PEG IFN α-2b. In
Clearance 725 mL/hour 60 mL/hour
contrast, neutropenia and rash were more frequent in
Dose 1.5 μg/kg (weight- 180 μg patients treated with PEG IFN α-2a than standarddose
SECTION VI
based)
PEG IFN α-2b. In two subsequent head-to-head trials
Storage Room temperature Refrigerated and a systematic review of randomized trials, PEG IFN
Ribavirin dose α–2a was more effective than α–2b (SVR in genotype
Genotype 1 800–1400 mga 1000–1200 mgb 1-4: 48–55% versus 32–40%, respectively). In trials of
Genotype 2/3 800 mg 800 mg PEG IFN α-2b among patients with HCV genotype 1, a
Duration of therapy broader range of weight-based daily ribavirin doses has
Disorders of the Liver and Biliary Tree
Genotype 1 48 weeks 48 weeks been validated: 800 mg for weight <65 kg, 1000 mg for
Genotype 2/3 48 weeksc 24 weeks weight 65–85 kg, 1200 mg for weight >85–105 kg, and
Efficacy of 54% 56% 1400 mg for weight >105 kg. Recommended doses for
combination Rxd the two PEG IFNs plus ribavirin and other comparisons
Genotype 1 40–42% 41–51% between the two therapies are shown in Table 40-6.
Genotype 2/3 82% 76–78%
Unless ribavirin is contraindicated (see above), com-
bination PEG IFN plus ribavirin is the recommended
a
In the registration trial for PEG IFN α-2b plus ribavirin, the optimal
regimen was 1.5 μg of PEG IFN plus 800 mg of ribavirin; however,
course of therapy—24 weeks for genotypes 2 and 3
a posthoc analysis of this study suggested that higher ribavirin and 48 weeks for genotype 1. Measurement of quanti
doses are better. In subsequent trials of PEG IFN α-2b with ribavirin tative HCV RNA levels at 12 weeks is helpful in guid-
in patients with genotype 1, the following daily ribavirin doses have ing therapy; if a 2-log10 drop in HCV RNA has not been
been validated: 800 mg for patients weighing <65 kg, 1000 mg for
patients weighing >65-85 kg, 1200 for patients weighing >85–105 kg,
achieved by this time, chances for an SVR are negligible.
and 1400 mg for patients weighing >105 kg. If the 12-week HCV RNA has fallen by two logs10 (EVR),
b
1000 mg for patients weighing <75 kg; 1200 mg for patients weighing the chances for an SVR at the end of therapy are approx-
≥75 kg. imately two-thirds; if the 12-week HCV RNA is undetect-
c
In the registration trial for PEG IFN α-2b plus ribavirin, all patients
were treated for 48 weeks; however, data from other trials of stan-
able (“complete” EVR), the chances for a sustained viro-
dard interferons and the other PEG IFN demonstrated that 24 weeks logic response exceed 80% (Fig. 40-2). Because absence
suffices for patients with genotypes 2 and 3. For patients with geno- of an EVR is such a strong predictor of the absence of an
type 3 who have advanced fibrosis/cirrhosis and/or high-level HCV ultimate sustained virologic response, failure to achieve
RNA, a full 48 weeks is preferable.
d
Attempts to compare the two PEG IFN preparations based on the
a 12-week 2-log10 drop in HCV RNA (EVR) may be used
results of registration clinical trials are confounded by differences as a signal to discontinue therapy.
between trials of the two agents in methodological details (differ- Studies have suggested that the frequency of an SVR
ent ribavirin doses, different methods for recording depression, and to PEG IFN/ribavirin therapy can be increased in patients
other side effects) and study-population composition (different pro-
portion with bridging fibrosis/cirrhosis, proportion from the United
with baseline variables weighing against a response
States versus international, mean weight, proportion with genotype 1, (e.g., HCV RNA >8 × 105 IU/ml, weight >85 kg) by rais-
and proportion with high-level HCV RNA). In the head-to-head ing the dose of PEG IFN (e.g., to as high as 270 μg of PEG
comparison of the two PEG IFN preparations in the “IDEAL” trial IFN α-2a) and/or the dose of ribavirin to as high as 1600
reported in 2009, the two drugs were comparable in tolerability and
efficacy. PEG IFN α-2b was administered at a weekly weight-based
mg daily (if tolerated or supplemented by erythropoi-
dose of 1.0 μg/kg or 1.5 μg/kg, and PEG IFN α-2a was administered etin) or by tailoring treatment based on viral response
at a weekly fixed dose of 180 μg. For PEG IFN α-2b, daily ribavirin to prolong the duration of viral clearance before dis-
weight-based doses ranged between 800–1400 mg based on weight continuing therapy, i.e., extending therapy from 48 to
criteria (see footnote a, above), while for PEG IFN α-2a, daily ribavirin
weight-based doses ranged between 1000–1200 mg (footnote b,
72 weeks for patients with genotype 1 and a slow viro-
above). For the two PEG IFN α-2b study arms, ribavirin dose reduc- logic response, i.e., those whose HCV RNA has not fallen
tions for ribavirin-associated adverse effects were done in 200–400-mg rapidly to undetectable levels within 4 weeks (absence
decrements; for PEG IFN α-2a, the ribavirin dose was reduced to of “rapid virologic response”). Tailoring therapy based on
600 mg for intolerability. Sustained virologic responses occurred in
38.0% of the low-dose PEG IFN α-2b group, 39.8% of the standard,
the kinetics of HCV RNA reduction has also been applied
full-dose PEG IFN α-2b group, and 40.9% of the PEG IFN α-2a to abbreviating the duration of therapy in patients with
group. genotype 1 (and 4). The results of several clinical trials
Abbreviations: PEG, polyethylene glycol; PEG IFN, pegylated suggest that, in patients with genotype 1 (and 4) who
interferon; HCV RNA, hepatitis C virus RNA.
100% 417
80%
64%
60% 53%
45%
40% 40% 41%
40% 32%
24%
20% 11% 12%
CHAPTER 40
0%
RVR EVR ETR SVR Relapse
Figure 40-3
Head-to-head comparison of standard-dose PEG IFN α-2b of treatment week 48; SVR, sustained virologic response,
1.5 μg/kg weekly and PEG IFN α-2a 180 μg weekly adminis- HCV RNA remaining undetectable 24 weeks after complet-
tered with daily ribavirin in the “IDEAL” trial. Percent achiev- ing 48 weeks of therapy. Relapse, reappearance of detect-
ing treatment milestones for PEG IFN α-2b (green boxes) able HCV RNA by week 72 in patients with an end-treatment
Chronic Hepatitis
and PEG IFN α-2a (orange boxes). RVR, rapid virologic response at week 48. PEG IFN α-2a suppressed HCV RNA
response, HCV RNA undetectable at week 4; EVR, early in a higher proportion of patients at weeks 12 and 48 but,
virologic response, HCV RNA undetectable at week 12; because of a higher relapse rate at week 72, resulted in the
ETR, end-treatment response, HCV RNA undetectable at end same SVR rate as PEG IFN α-2b.
have a 4-week RVR (which occurs in ≤20%), especially including the development of hepatocellular carcinoma.
in the subset with a baseline low level of HCV RNA, 24 For PEG IFN/ribavirin nonresponders who have had
weeks of therapy with PEG IFN and weight-based riba- a full, adequate course of therapy, the benefit of
virin suffices, yielding SVR rates of ∼90% and comparable retreatment—with higher doses or a longer course of
to those achieved in this cohort with 48 weeks of therapy. the original PEG IFN regimen or the alternative PEG IFN
Although initial reports suggested that, for patients regimen or with a different type of IFN preparation (e.g.,
with genotype 2 and (somewhat less so) genotype 3, consensus IFN)—is marginal at best.
in rapid virologic responders with undetectable HCV
RNA at week 4, the total duration of therapy required to Indications for Antiviral Therapy
achieve an SVR could be as short as 12–16 weeks, a very Patients with chronic hepatitis C who have detectable
sizable, definitive subsequent trial showed that relapse HCV RNA in serum, whether or not aminotransferase
is increased if treatment duration is curtailed and that a levels are increased, and chronic hepatitis of at least
full 24 weeks is superior for these genotypes (except for moderate grade and stage (portal or bridging fibrosis)
the minority with very low baseline levels of HCV RNA). are candidates for antiviral therapy with PEG IFN plus
Persons with chronic HCV infection have been shown ribavirin. Most authorities recommend 800 mg of rib-
to suffer increased liver-related mortality. On the other avirin for patients with genotypes 2 and 3 for both
hand, successful antiviral therapy of chronic hepatitis C types of PEG IFN and weight-based 1000–1200 mg
resulting in an SVR has been shown to improve survival, (when used with PEG IFN α-2a) or 800–1400 mg (when
to lower the risk of liver failure and liver-related death, used with PEG IFN α-2b) ribavirin for patients with
to slow the progression of chronic hepatitis C, and to genotype 1 (and 4), unless ribavirin is contraindicated
reverse fibrosis and even cirrhosis. Although successful (Table 40-7). Although patients with persistently normal
treatment reduces mortality in cirrhotic patients (and ALT activity tend to progress histologically very slowly
those with advanced fibrosis) and reduces the likelihood or not at all, they respond to antiviral therapy just as
of hepatocellular carcinoma, the risk of decompensa- well as do patients with elevated ALT levels; therefore,
tion, death, and liver cancer persists, albeit at a much while observation without therapy is an option, such
reduced level, necessitating continued clinical moni- patients are potential candidates for antiviral therapy.
toring and cancer surveillance after SVR in cirrhotics. As noted above, therapy with IFN has been shown to
On the other hand, in the absence of an SVR, IFNbased improve survival and complication-free survival and to
therapy does not reduce the risk of hepatocellular slow progression of fibrosis.
carcinoma. Similarly, for nonresponders to PEG IFN/riba- Prior to therapy, HCV genotype should be deter-
virin therapy, three trials of long-term maintenance ther- mined, and the genotype dictates the duration of ther-
apy with PEG IFN have shown no benefit in reducing the apy: 48 weeks for patients with genotype 1, 24 weeks
risk of histologic progression or clinical decompensation, for those with genotypes 2 and 3. For patients with
418 Table 40-7
Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis C
Standard Indications for Therapy
A course of PEG IFN plus ribavirin (retreatment not recommended with PEG IFN/ribavirin if relapse occurred after a full
course of PEG IFN/ribavirin).
Nonresponders to a previous course of standard IFN monotherapy or combination standard IFN/ribavirin therapy.
A course of PEG IFN plus ribavirin—more likely to achieve a sustained virologic response in white patients without previous
ribavirin therapy, with low baseline HCV RNA levels, with a ≥2-log10 reduction in HCV RNA during previous therapy, with
genotypes 2 and 3, and without reduction in ribavirin dose. (Retreatment not recommended with PEG IFN/ribavirin if
nonresponse occurred to a full course of PEG IFN/ribavirin.)
Disorders of the Liver and Biliary Tree
Antiviral Therapy not Recommended Routinely but Management Decisions Made on an Individual Basis
Age >60
Mild hepatitis on liver biopsy.
Persons with severe renal insufficiency (glomerular filtration rate <60 ml/min) who do not require hemodialysis (reduced-dose
PEG IFN and ribavirin). Antiviral therapy in patients requiring hemodialysis is more complicated, less successful, and
associated with more adverse effects; if treatment is pursued, either standard doses of standard interferon 3 times a week or
reduced doses of weekly PEG IFN in combination with reduced doses of daily ribavirin should be used.
Long-Term Maintenance Therapy Recommended
Cutaneous vasculitis and glomerulonephritis associated with chronic hepatitis C.
Long-Term Maintenance Therapy in Nonresponders not Recommended
Antiviral Therapy not Recommended
Decompensated cirrhosis (except, perhaps, in transplantation centers with experience in graded escalation, low-dose
treatment to achieve undetectable HCV RNA prior to transplantation; results are mixed).
Pregnancy (teratogenicity of ribavirin).
Contraindications to use of interferon or ribavirin.
Standard Therapeutic Regimens
First-line treatment: PEG IFN subcutaneously once a week plus daily ribavirin orally
HCV genotypes 1 and 4—48 weeks of therapy
PEG IFN α-2a 180 μg weekly plus ribavirin 1000 mg/day (weight <75 kg) to 1200 mg/day (weight <75 kg) or
PEG IFN α-2b 1.5 μg/kg weekly plus daily oral ribavirin 800 mg for weight <65 kg, 1000 mg for weight 65–85 kg, 1200 mg
for weight >85–105 kg, and 1400 mg for weight >105 kg
HCV genotypes 2 and 3—24 weeks of therapy
PEG IFN α-2a 180 μg weekly plus ribavirin 800 mg/day or
PEG IFN α-2b 1.5 μg/kg weekly plus ribavirin 800 mg/day (For patients with genotype 3 who have advanced fibrosis and/or
high-level HCV RNA, a full 48 weeks of therapy may be preferable.)
Alternative regimen: PEG IFN (α-2a 180 μg or α-2b 1.0 μg/kg) subcutaneously once a week (primarily for patients in whom
ribavirin is contraindicated or not tolerated) for 24 (genotypes 2 and 3) or 48 (genotypes 1 and 4) weeks.
Early discontinuation: Failure to achieve an EVR, i.e., ≥2 log10 HCV RNA reduction by week 12 or, if EVR is achieved, failure to
achieve suppression of HCV RNA to undetectable by week 24.
“Tailored” Therapeutic Regimens Based on Rapid Treatment Milestones
HCV genotypes 1 and 4.
For RVR, i.e., undetectable HCV RNA at week 4, especially in patients with low baseline HCV RNA, consider truncating the
course of therapy to 24 weeks.
For patients with slow, delayed response, i.e., who clear detectable HCV RNA between weeks 12 and 24, consider prolonging
the course of therapy to 72 weeks.
“Tailored” Therapeutic Regimens Based on Baseline Variables Associated with Reduced Responsiveness
HCV genotypes 1 and 4
For patients with HCV RNA >8 × 105 IU/ml and weighing >85 kg, consider increasing the weekly PEG IFN dose (e.g., for
PEG IFN α-2a up to 270 μg) and the daily ribavirin dose (e.g., up to 1600 mg).
For HCV-HIV co-infected patients: 48 weeks, regardless of genotype, of weekly PEG IFN α-2a (180 μg) or PEG IFN α-2b
(1.5 μg/kg) plus a daily ribavirin dose of at least 600–800 mg, up to full weight-based dosing, at doses comparable to those
for HCV-monoinfected patients, if tolerated.
(continued )
Table 40-7 419
Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis C (CONTINUED )
Features Associated with Reduced Responsiveness
Single nucleotide polymorphism (SNP) T allele (as opposed to C allele) at IL28B locus
Genotype 1
High-level HCV RNA (>2 × 106 copies/ml or >8 × 105 IU/ml)
Advanced fibrosis (bridging fibrosis, cirrhosis)
Long-duration disease
Age >40
CHAPTER 40
High HCV quasispecies diversity
Immunosuppression
African-American ethnicity
Latino ethnicity
Obesity
Hepatic steatosis
Insulin resistance, type-II diabetes mellitus
Reduced adherence (lower drug doses and reduced duration of therapy)
Chronic Hepatitis
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; PEG IFN, pegylated interferon; IU, international units (1 IU/ml
is equivalent to ∼2.5 copies/ml).
genotype 1 (and 4), especially those with low baseline virologic responses to retreatment of nonresponders are
HCV RNA, 24 weeks of PEG IFN/ribavirin therapy may more frequent in those who had never received ribavi-
suffice if HCV RNA becomes undetectable within 4 rin in the past, those with genotypes 2 and 3, those with
weeks (RVR); for patients with genotypes 2 and 3, a full, low pretreatment HCV RNA levels, and noncirrhotics,
24-week course is most effective, although the duration but less frequent in African Americans, those who failed
may be reduced to 12–16 weeks for patients with geno- to achieve a substantial reduction in HCV RNA during
type 2, a low baseline level of viremia, and an RVR, espe- their previous course of therapy (null responders,
cially to be considered for patients who tolerate therapy Fig. 40-2), and those who required ribavirin-dose reduc-
poorly. As noted above, the absence of a 2-log10 drop in tions. Potential approaches to improving responsive-
HCV RNA at week 12 (EVR) weighs heavily against the ness to PEG IFN/ribavirin in prior nonresponders include
likelihood of an SVR; therefore, measuring HCV RNA at longer duration of treatment; higher doses of either PEG
12 weeks is recommended routinely (Fig. 40-2), espe- IFN, ribavirin, or both; and switching to a different IFN
cially for patients with genotype 1, and therapy can be preparation; however, as noted above, none of these
discontinued if an EVR is not achieved. Among patients approaches achieves more than a marginal benefit.
with an EVR (≥2-log10 HCV RNA reduction) but with HCV Early treatment is indicated for persons with acute
RNA still detectable at week 24, an SVR is unlikely, and hepatitis C (Chap. 304). In patients with biochemically
therapy can be discontinued. Although response rates and histologically mild chronic hepatitis C, the rate of
are lower in patients with certain pretreatment vari- progression is slow, and monitoring without therapy is
ables, selection for treatment should not be based on an option; however, such patients respond just as well
symptoms, genotype, HCV RNA level, mode of acquisi- to combination PEG IFN plus ribavirin therapy as those
tion of hepatitis C, or advanced hepatic fibrosis. Patients with elevated ALT and more histologically severe hepatitis.
with cirrhosis can respond and should not be excluded Therefore, therapy for these patients should be consid-
as candidates for therapy. ered and the decision made based on such factors as
Patients who have relapsed (Fig. 40-2) after a course patient motivation, genotype, stage of fibrosis, age, and
of IFN monotherapy are candidates for retreatment comorbid conditions. A pretreatment liver biopsy to
with PEG IFN plus ribavirin (i.e., a more effective treat- assess histologic grade and stage provides substantial
ment regimen is required). For nonresponders to a information about progression of hepatitis C in the past,
prior course of IFN monotherapy, retreatment with IFN has prognostic value for future progression, and can
monotherapy or combination IFN plus ribavirin therapy identify such histologic factors as steatosis and stage of
is unlikely to achieve a sustained virologic response; fibrosis, which can influence responsiveness to therapy.
however, a trial of combination PEG IFN plus ribavirin As therapy has improved for patients with a broad range
may be worthwhile. End-treatment virologic responses of histologic severity, and as noninvasive laboratory
as high as 40% can occur in this setting, but an SVR markers and imaging correlates of fibrosis have gained
is the outcome in <15–20% of patients. Sustained popularity, some authorities, especially in Europe, have
420
placed less value on, and do not recommend, pretreat- plus ribavirin (daily doses ranging from flat-dosed
ment liver biopsies. On the other hand, serum markers 600–800 mg to weight-based 1000/1200 mg) is supe-
of fibrosis are not considered sufficiently accurate, and rior to standard IFN regimens; however, SVR rates were
histologic findings provide important prognostic infor- lower than in HCV-monoinfected patients, ranging from
mation to physician and patient. Therefore, although 14 to 38% for patients with genotypes 1 and 4 and from
the contemporary role of a pretreatment liver biopsy 44 to 73% for patients with genotypes 2 and 3. In the
commands less of a consensus, a pretreatment liver three largest trials, all patients, including those with
biopsy still provides useful information and should be genotypes 2 and 3, were treated for a full 48 weeks. In
considered. addition, tolerability of therapy was lower than in HCV-
SECTION VI
Patients with compensated cirrhosis can respond monoinfected patients; therapy was discontinued
to therapy, although their likelihood of a sustained because of side effects in 12–39% of patients in these
response is lower than in noncirrhotics; moreover, clinical trials. Based on these trials, weekly PEG IFN plus
survival has been shown to improve after successful daily ribavirin at a daily dose of at least 600–800 mg,
antiviral therapy in cirrhotics. Similarly, although several up to full weight-based doses, at doses recommended
retrospective studies have suggested that antiviral ther- for HCV-monoinfected patients, if tolerated, is recom-
Disorders of the Liver and Biliary Tree
apy in cirrhotics with chronic hepatitis C, independent mended for a full 48 weeks, regardless of genotype. An
of treatment outcome per se, reduces the frequency alternative recommendation for ribavirin doses was
of HCC, less advanced disease in the treated cirrhot- issued by a European Consensus Conference and con-
ics, not treatment itself (i.e., lead-time bias), may have sisted of standard, weight-based 1000–1200 mg for
accounted for the reduced frequency of HCC observed genotypes 1 and 4, but 800 mg for genotypes 2 and 3.
in the treated cohorts in these reports; prospective A head-to-head trial of combination PEG IFN/ribavirin
studies to address this question have failed to demon- therapy in HCV/HIV co-infection demonstrated statisti-
strate benefit, unless a sustained virologic response is cally indistinguishable efficacy of the two types of PEG
achieved. Patients with decompensated cirrhosis are not IFN, despite a small advantage for PEG IFN α-2a: for PEG
candidates for IFN-based antiviral therapy but should be IFN α-2b and α-2a, SVRs occurred in 28% versus 32%,
referred for liver transplantation. Some liver-transplan- respectively, of patients with genotypes 1 and 4 and in
tation centers have evaluated progressively escalated, 62% versus 71%, respectively, of patients with geno-
low-dose antiviral therapy in an attempt to eradicate types 2 and 3. In HCV/HIV-infected patients, ribavirin
hepatitis C viremia prior to transplantation; however, can potentiate the toxicity of didanosine (e.g., lactic aci-
such therapy has been shown to reduce but not to pre- dosis) and the lipoatrophy of stavudine, and zidovudine
vent the risk of HCV reinfection after transplantation. can exacerbate ribavirin-associated hemolytic anemia;
After liver transplantation for end-stage liver disease therefore, these drug combinations should be avoided.
caused by hepatitis C, recurrent hepatitis C is the rule, Patients with a history of injection-drug use and alco-
and the pace of disease progression is more accelerated holism can be treated successfully for chronic hepatitis C,
than in immunocompetent patients (Chap. 310). Current preferably in conjunction with drug- and alcohol-
therapy with PEG IFN and ribavirin after liver transplan- treatment programs. Because ribavirin is excreted
tation is unsatisfactory in most patients, but attempts to renally, patients with end-stage renal disease, includ-
minimize immunosuppression are beneficial. The cuta- ing those undergoing dialysis (which does not clear
neous and renal vasculitis of HCV-associated essential ribavirin), are not ideal candidates for ribavirin therapy.
mixed cryoglobulinemia (Chap. 304) may respond to Rare reports suggest that reduced-dose ribavirin can
antiviral therapy, but sustained responses are rare after be used, but the frequency of anemia is very high and
discontinuation of therapy; therefore, prolonged, per- data on efficacy are limited. If patients with renal fail-
haps indefinite, therapy is recommended in this group. ure (glomerular filtration rate <60 ml/min) are treated,
Anecdotal reports suggest that antiviral therapy may the PEG IFN α-2a dose should be reduced from 180 to
be effective in porphyria cutanea tarda or lichen planus 135 μg weekly and the PEG IFN α-2b dose reduced from
associated with hepatitis C. 1.5 to 1 μg/kg weekly; similarly, the daily ribavirin dose in
In patients with HCV/HIV co-infection, hepatitis C is this population should be reduced to 200–800 mg (but
more progressive and severe than in HCV-monoinfected not used or used cautiously at very low doses) if hemo-
patients. Although patients with HCV/HIV co-infection dialysis is required. Neither the optimal regimen nor the
respond to antiviral therapy for hepatitis C, they do not efficacy of therapy is well established in this population.
respond as well as patients with HCV infection alone.
Four large national and international trials of antivi- Novel Antivirals To date, attempts to develop
ral therapy among patients with HCV/HIV co-infection better-tolerated ribavirin successors or improved types
have shown that PEG IFN (both α-2a and α-2b) of IFN α or longer acting IFNs than PEG IFN have not
the broader categories of “idiopathic” or cryptogenic 421
been successful. The demonstration that responsiveness chronic hepatitis, many, perhaps the majority, are
to antiviral therapy is influenced by genetic variation probably autoimmune in origin. Cases in which
in IL28B, which codes for IFN-λ (as noted above), raises hepatotropic viruses, metabolic/genetic derangements,
the possibility that IFN-λ might be an effective or even and hepatotoxic drugs have been excluded represent a
more effective IFN for treating hepatitis C; early trials are spectrum of heterogeneous liver disorders of unknown
in progress. Among the most exciting new approaches cause, a proportion of which are most likely auto
to antiviral therapy are orally administered direct anti- immune hepatitis.
virals that target HCV polymerase or protease. Two pro-
CHAPTER 40
tease inhibitors that are in late stages of development,
are expected to be approved in 2011. The NS3-4A
Immunopathogenesis
serine protease inhibitors telaprevir and boceprevir
suppress HCV RNA profoundly and, when used together The weight of evidence suggests that the progres-
with PEG IFN and ribavirin in patients with genotype-1 sive liver injury in patients with autoimmune hepatitis
HCV infection, can increase RVR rates to as high as 80% is the result of a cell-mediated immunologic attack
(telaprevir) and SVR rates from those achieved with cur- directed against liver cells. In all likelihood, predisposi-
Chronic Hepatitis
rent standard-of-care therapy by 20–30% to ∼65–75%, tion to autoimmunity is inherited, while the liver speci-
in most patients with only half the duration of current ficity of this injury is triggered by environmental (e.g.,
therapy. These triple-drug combinations appear to chemical or viral) factors. For example, patients have
yield even higher rates of SVR in >50% of prior relapsers been described in whom apparently self-limited cases of
(>70–90%) but also to achieve SVR in prior nonre- acute hepatitis A, B, or C led to autoimmune hepatitis,
sponders, even in null responders to PEG IFN/ribavirin presumably because of genetic susceptibility or pre
therapy (∼30%). Although these new drugs add disposition. Evidence to support an autoimmune patho-
elements of additional toxicity (severe rash in ∼5% of genesis in this type of hepatitis includes the following:
telaprevir-treated patients and anemia in half of bocepre- (1) In the liver, the histopathologic lesions are com-
vir-treated patients), they represent an opportunity for posed predominantly of cytotoxic T cells and plasma
curing a substantially larger proportion of patients with cells; (2) circulating autoantibodies (nuclear, smooth
shorter treatment courses. Because resistance to these muscle, thyroid, etc.; see below), rheumatoid factor,
oral agents used alone has been both anticipated and and hyperglobulinemia are common; (3) other autoim-
observed, polymerase and protease inhibitors are being mune disorders—such as thyroiditis, rheumatoid arthritis,
evaluated in combinations with PEG IFN and ribavirin autoimmune hemolytic anemia, ulcerative colitis, mem-
to preempt the emergence of resistance. Potentially, in branoproliferative glomerulonephritis, juvenile diabetes
the future, combinations of direct antiviral agents will mellitus, celiac disease, and Sjögren’s syndrome—occur
be used in drug cocktails that may replace IFN-based reg- with increased frequency in patients and in their rela-
imens entirely. tives who have autoimmune hepatitis; (4) histocom-
patibility haplotypes associated with autoimmune
diseases, such as HLA-B1, -B8, -DR3, and -DR4 as
well as extended haplotype DRB1 alleles, are common
Autoimmune Hepatitis in patients with autoimmune hepatitis; and (5) this type
of chronic hepatitis is responsive to glucocorticoid/
Definition immunosuppressive therapy, effective in a variety of
Autoimmune hepatitis is a chronic disorder char- autoimmune disorders.
acterized by continuing hepatocellular necrosis and Cellular immune mechanisms appear to be important
inflammation, usually with fibrosis, which can prog- in the pathogenesis of autoimmune hepatitis. In vitro
ress to cirrhosis and liver failure. When fulfilling cri- studies have suggested that in patients with this disor-
teria of severity, this type of chronic hepatitis, when der, lymphocytes are capable of becoming sensitized
untreated, may have a 6-month mortality of as high as to hepatocyte membrane proteins and of destroying
40%. Based on contemporary estimates of the natural liver cells. Abnormalities of immunoregulatory con-
history of treated autoimmune hepatitis, the 10-year trol over cytotoxic lymphocytes (impaired regulatory
survival is 80–90%. The prominence of extrahepatic CD4+CD25+ T cell influences) may play a role as well.
features of autoimmunity as well as seroimmunologic Studies of genetic predisposition to autoimmune hepa-
abnormalities in this disorder supports an autoimmune titis demonstrate that certain haplotypes are associated
process in its pathogenesis; this concept is reflected in with the disorder, as enumerated above. The precise
the labels lupoid, plasma cell, or autoimmune hepatitis. triggering factors, genetic influences, and cytotoxic and
Autoantibodies and other typical features of autoim- immunoregulatory mechanisms involved in this type of
munity, however, do not occur in all cases; among liver injury remain incompletely defined.
422 Intriguing clues into the pathogenesis of autoim- “aggressive” histologic lesions—bridging necrosis or
mune hepatitis come from the observation that circu- multilobular collapse, cirrhosis), the 6-month mortal-
lating autoantibodies are prevalent in patients with this ity without therapy may be as high as 40%. Such severe
disorder. Among the autoantibodies described in these disease accounts for only 20% of cases; the natural his-
patients are antibodies to nuclei [so-called antinuclear tory of milder disease is variable, often accentuated by
antibodies (ANAs), primarily in a homogeneous pat- spontaneous remissions and exacerbations. Especially
tern] and smooth muscle (so-called anti-smooth-muscle poor prognostic signs include the presence histologi-
antibodies, directed at actin), anti-LKM (see below), cally of multilobular collapse at the time of initial pre-
antibodies to “soluble liver antigen/liver pancreas anti- sentation and failure of the bilirubin to improve after 2
SECTION VI
gen” (directed against a uracil-guanineadenine transfer weeks of therapy. Death may result from hepatic fail-
RNA suppressor protein), as well as antibodies to the ure, hepatic coma, other complications of cirrhosis (e.g.,
liver-specific asialoglycoprotein receptor (or “hepatic variceal hemorrhage), and intercurrent infection. In
lectin”) and other hepatocyte membrane proteins. patients with established cirrhosis, HCC may be a late
Although some of these provide helpful diagnostic complication (Chap. 92) but occurs less frequently than
markers, their involvement in the pathogenesis of auto- in cirrhosis associated with viral hepatitis.
immune hepatitis has not been established. Laboratory features of autoimmune hepatitis are similar
Disorders of the Liver and Biliary Tree
Humoral immune mechanisms have been shown to to those seen in chronic viral hepatitis. Liver biochemi-
play a role in the extrahepatic manifestations of auto- cal tests are invariably abnormal but may not correlate
immune and idiopathic hepatitis. Arthralgias, arthritis, with the clinical severity or histopathologic features in
cutaneous vasculitis, and glomerulonephritis occur- individual cases. Many patients with autoimmune hepa-
ring in patients with autoimmune hepatitis appear to be titis have normal serum bilirubin, alkaline phosphatase,
mediated by the deposition of circulating immune com- and globulin levels with only minimal aminotransferase
plexes in affected tissue vessels, followed by comple- elevations. Serum AST and ALT levels are increased and
ment activation, inflammation, and tissue injury. While fluctuate in the range of 100–1000 units. In severe cases,
specific viral antigen-antibody complexes can be identi- the serum bilirubin level is moderately elevated [51–171
fied in acute and chronic viral hepatitis, the nature of μmol/L (3–10 mg/dL)]. Hypoalbuminemia occurs in
the immune complexes in autoimmune hepatitis has not patients with very active or advanced disease. Serum
been defined. alkaline phosphatase levels may be moderately ele-
Many of the clinical features of autoimmune hepatitis vated or near normal. In a small proportion of patients,
are similar to those described for chronic viral hepatitis. marked elevations of alkaline phosphatase activity occur;
The onset of disease may be insidious or abrupt; the in such patients, clinical and laboratory features overlap
disease may present initially like, and be confused with, with those of primary biliary cirrhosis (Chap. 308). The
acute viral hepatitis; a history of recurrent bouts of what prothrombin time is often prolonged, particularly late in
had been labeled acute hepatitis is not uncommon. A the disease or during active phases.
subset of patients with autoimmune hepatitis has dis- Hypergammaglobulinemia (>2.5 g/dL) is common
tinct features. Such patients are predominantly young to in autoimmune hepatitis. Rheumatoid factor is com-
middle-aged women with marked hyperglobulinemia mon as well. As noted above, circulating autoantibod-
and high-titer circulating ANAs. This is the group with ies are also prevalent. The most characteristic are ANAs
positive lupus erythematosus (LE) preparations (initially in a homogeneous staining pattern. Smoothmuscle
labeled “lupoid” hepatitis) in whom other autoimmune antibodies are less specific, seen just as frequently in
features are common. Fatigue, malaise, anorexia, amen- chronic viral hepatitis. Because of the high levels of
orrhea, acne, arthralgias, and jaundice are common. globulins achieved in the circulation of some patients
Occasionally arthritis, maculopapular eruptions (includ- with autoimmune hepatitis, occasionally the globulins
ing cutaneous vasculitis), erythema nodosum, colitis, may bind nonspecifically in solid-phase binding immu-
pleurisy, pericarditis, anemia, azotemia, and sicca syn- noassays for viral antibodies. This has been recognized
drome (keratoconjunctivitis, xerostomia) occur. In some most commonly in tests for antibodies to hepatitis C
patients, complications of cirrhosis, such as ascites and virus, as noted above. In fact, studies of autoantibodies
edema (associated with hypoalbuminemia), encephalop- in autoimmune hepatitis have led to the recognition of
athy, hypersplenism, coagulopathy, or variceal bleeding new categories of autoimmune hepatitis. Type I auto
may bring the patient to initial medical attention. immune hepatitis is the classic syndrome occurring in young
The course of autoimmune hepatitis may be vari- women, associated with marked hyperglobulinemia,
able. In those with mild disease or limited histologic lupoid features, circulating ANAs, and HLA-DR3 or
lesions (e.g., piecemeal necrosis without bridging), HLA-DR4 (especially B8-DRB1*03). Also associated
progression to cirrhosis is limited. In those with severe with type I autoimmune hepatitis are autoantibodies
symptomatic autoimmune hepatitis (aminotransferase against actin as well as atypical perinuclear antineutro-
levels >10 times normal, marked hyperglobulinemia, philic cytoplasmic antibodies (pANCA).
Type II autoimmune hepatitis, often seen in children, globulin elevation; presence of nuclear, smooth mus- 423
more common in Mediterranean populations, and cle, LKM1, and other autoantibodies; concurrent other
linked to HLA-DRB1 and HLA-DQB1 haplotypes, is autoimmune diseases; characteristic histologic features
associated not with ANA but with anti-LKM. Actu- (interface hepatitis, plasma cells, rosettes); HLA DR3 or
ally, anti-LKM represent a heterogeneous group of DR4 markers; and response to treatment (see below).
antibodies. In type II autoimmune hepatitis, the anti- Weighing against the diagnosis are predominant alka-
body is anti-LKM1, directed against cytochrome P450 line phosphatase elevation, mitochondrial antibodies,
2D6. This is the same anti-LKM seen in some patients markers of viral hepatitis, history of hepatotoxic drugs
with chronic hepatitis C. Anti-LKM2 is seen in drug- or excessive alcohol, histologic evidence of bile duct
CHAPTER 40
induced hepatitis, and anti-LKM3 is seen in patients injury, or such atypical histologic features as fatty infil-
with chronic hepatitis D. Another autoantibody tration, iron overload, and viral inclusions.
observed in type II autoimmune hepatitis is directed
against liver cytosol formiminotransferase cyclode-
Differential Diagnosis
aminase (anti-liver cytosol 1). More controversial is
whether or not a third category of autoimmune hepa- Early during the course of chronic hepatitis, autoim-
titis exists, type III autoimmune hepatitis. These patients mune hepatitis may resemble typical acute viral hepatitis
Chronic Hepatitis
lack ANA and anti-LKM1 but have circulating antibod- (Chap. 304). Without histologic assessment, severe
ies to soluble liver antigen/liver pancreas antigen. Most chronic hepatitis cannot be readily distinguished based
of these patients are women and have clinical features on clinical or biochemical criteria from mild chronic
similar to, perhaps more severe than, those of patients hepatitis. In adolescence, Wilson’s disease (Chaps. 308
with type I autoimmune hepatitis. Type III autoim- and 360) may present with features of chronic hepatitis
mune hepatitis does not appear to represent a distinct long before neurologic manifestations become apparent
category but, instead, is part of the spectrum of type I and before the formation of Kayser-Fleischer rings.
autoimmune hepatitis; this subcategory has not been In this age group, serum ceruloplasmin and serum and
adopted by a consensus of international experts. urinary copper determinations plus measurement of
Liver biopsy abnormalities are similar to those liver copper levels will establish the correct diagnosis.
described for chronic viral hepatitis. Expanding por- Postnecrotic or cryptogenic cirrhosis and primary biliary cirrho-
tal tracts and extending beyond the plate of periportal sis (Chap. 308) share clinical features with autoimmune
hepatocytes into the parenchyma (designated interface hepatitis, and both alcoholic hepatitis (Chap. 307) and
hepatitis or piecemeal necrosis) is a mononuclear cell infil- nonalcoholic steatohepatitis (Chap. 309) may present
trate that, in autoimmune hepatitis, may include the with many features common to autoimmune hepatitis;
presence of plasma cells. Necroinflammatory activ- historic, biochemical, serologic, and histologic assess-
ity characterizes the lobular parenchyma, and evidence ments are usually sufficient to allow these entities to be
of hepatocellular regeneration is reflected by “rosette” distinguished from autoimmune hepatitis. Of course,
formation, the occurrence of thickened liver cell plates, the distinction between autoimmune and chronic viral
and regenerative “pseudolobules.” Septal fibrosis, bridg- hepatitis is not always straightforward, especially when
ing fibrosis, and cirrhosis are frequent. Bile duct injury viral antibodies occur in patients with autoimmune
and granulomas are uncommon; however, a subgroup disease or when autoantibodies occur in patients with
of patients with autoimmune hepatitis has histologic, viral disease. Furthermore, the presence of extrahepatic
biochemical, and serologic features overlapping those of features such as arthritis, cutaneous vasculitis, or
primary biliary cirrhosis (Chap. 308). pleuritis—not to mention the presence of circulating
autoantibodies—may cause confusion with rheumatologic
disorders such as rheumatoid arthritis and systemic lupus
Diagnostic Criteria
erythematosus. The existence of clinical and biochemi-
An international group has suggested a set of criteria for cal features of progressive necroinflammatory liver dis-
establishing a diagnosis of autoimmune hepatitis. Exclu- ease distinguishes chronic hepatitis from these other
sion of liver disease caused by genetic disorders, viral disorders, which are not associated with severe liver
hepatitis, drug hepatotoxicity, and alcohol are linked disease.
with such inclusive diagnostic criteria as hyperglobu- Finally, occasionally, features of autoimmune hepa-
linemia, autoantibodies, and characteristic histologic titis overlap with features of autoimmune biliary disor-
features. This international group has also suggested ders such as primary biliary cirrhosis, primary sclerosing
a comprehensive diagnostic scoring system that, rarely cholangitis (Chaps. 308 and 311), or, even more rarely,
required for typical cases, may be helpful when typi- mitochondrial antibody-negative autoimmune cholan-
cal features are not present. Factors that weigh in favor gitis. Such overlap syndromes are difficult to categorize,
of the diagnosis include female gender; predomi- and often response to therapy may be the distinguishing
nant aminotransferase elevation; presence and level of factor that establishes the diagnosis.
424
Treatment Autoimmune Hepatitis Serum aminotransferase levels usually drop promptly,
but improvements in AST and ALT alone do not appear
The mainstay of management in autoimmune hepa- to be reliable markers of recovery in individual patients;
titis is glucocorticoid therapy. Several controlled clini- histologic improvement, characterized by a decrease in
cal trials have documented that such therapy leads mononuclear infiltration and in hepatocellular necro-
to symptomatic, clinical, biochemical, and histologic sis, may be delayed for 6–24 months. Still, if interpreted
improvement as well as increased survival. A therapeu- cautiously, aminotransferase levels are valuable indi-
tic response can be expected in up to 80% of patients. cators of relative disease activity, and many authori-
Unfortunately, therapy has not been shown to prevent ties do not advocate for serial liver biopsies to assess
SECTION VI
ultimate progression to cirrhosis; however, instances therapeutic success or to guide decisions to alter or
of reversal of fibrosis and cirrhosis have been reported stop therapy. Rapidity of response is more common in
in patients responding to treatment. Although some older patients (≥69 years) and those with HLA DBR1*04;
advocate the use of prednisolone (the hepatic metabo- although rapid responders may progress less slowly to
lite of prednisone), prednisone is just as effective and is cirrhosis and liver transplantation, they are no less likely
favored by most authorities. Therapy may be initiated than slower responders to relapse after therapy. Therapy
Disorders of the Liver and Biliary Tree
at 20 mg/d, but a popular regimen in the United States should continue for at least 12–18 months. After taper-
relies on an initiation dose of 60 mg/d. This high dose is ing and cessation of therapy, the likelihood of relapse
tapered successively over the course of a month down is at least 50%, even if posttreatment histology has
to a maintenance level of 20 mg/d. An alternative, but improved to show mild chronic hepatitis, and the major-
equally effective, approach is to begin with half the ity of patients require therapy at maintenance doses
prednisone dose (30 mg/d) along with azathioprine indefinitely. Continuing azathioprine alone (2 mg/kg
(50 mg/d). With azathioprine maintained at 50 mg/d, the body weight daily) after cessation of prednisone
prednisone dose is tapered over the course of a month therapy may reduce the frequency of relapse.
down to a maintenance level of 10 mg/d. The advantage In medically refractory cases, an attempt should be
of the combination approach is a reduction, over the made to intensify treatment with high-dose gluco-
span of an 18-month course of therapy, in serious, life- corticoid monotherapy (60 mg daily) or combination
threatening complications of steroid therapy from 66% glucocorticoid (30 mg daily) plus high-dose azathioprine
down to under 20%. In combination regimens, 6-mer- (150 mg daily) therapy. After a month, doses of predni-
captopurine may be substituted for its prodrug aza- sone can be reduced by 10 mg a month, and doses of
thioprine, but this is rarely required. Azathioprine alone, azathioprine can be reduced by 50 mg a month toward
however, is not effective in achieving remission, nor is ultimate, conventional maintenance doses. Patients
alternateday glucocorticoid therapy. Limited experience refractory to this regimen may be treated with cyclo-
with budesonide in noncirrhotic patients suggests that sporine, tacrolimus, or mycophenolate mofetil; however,
this steroid side effect–sparing drug may be effective. to date, only limited anecdotal reports support these
Although therapy has been shown to be effective for approaches. If medical therapy fails, or when chronic
severe autoimmune hepatitis (AST ≥10 times the upper hepatitis progresses to cirrhosis and is associated with
limit of normal or ≥5 times the upper limit of normal in life-threatening complications of liver decompensation,
conjunction with serum globulin greater than or equal liver transplantation is the only recourse (Chap. 310);
to twice normal; bridging necrosis or multilobular failure of the bilirubin to improve after 2 weeks of ther-
necrosis on liver biopsy; presence of symptoms), ther- apy should prompt early consideration of the patient
apy is not indicated for mild forms of chronic hepatitis, for liver transplantation. Recurrence of autoimmune
and the efficacy of therapy in mild or asymptomatic hepatitis in the new liver occurs rarely in most experi-
autoimmune hepatitis has not been established. ences but in as many as 35–40% of cases in others.
Improvement of fatigue, anorexia, malaise, and
jaundice tends to occur within days to several weeks;
biochemical improvement occurs over the course of Acknowledgment
several weeks to months, with a fall in serum bilirubin
Kurt J. Isselbacher, MD, contributed to this chapter in previous
and globulin levels and an increase in serum albumin.
editions of Harrison’s.
CHAPTER 41
MAA
cacy of interferon-based antiviral therapy. adducts
Our understanding of the pathogenesis of alcoholic
liver injury is incomplete. Alcohol is a direct hepa-
totoxin, but ingestion of alcohol initiates a variety of Stellate cell
metabolic responses that influence the final hepatotoxic Kupffer cell
response. The initial concept of malnutrition as the TNF-α IL-1
major pathogenic mechanism has been replaced by the Autoantibodies Collagen TGF-β IL-6
understanding that the hepatic metabolism of alcohol
Autoimmune Fibrotic Inflammatory
initiates a pathogenic process including the production response response response
of toxic protein-aldehyde adducts, the generation of
reducing equivalents that promotes lipogenesis, and the FIGURE 41-1
inhibition of fatty-acid oxidation. Endotoxins, oxida- Biomedical and cellular pathogenesis of liver injury
tive stress, immunologic activity, and pro-inflammatory secondary to chronic ethanol ingestion. MAA, malond-
cytokine release contribute to the resulting liver injury ialdehyde-acetaldehyde; TNF, tumor necrosis factor; TGF,
(Fig. 41-1). The complex interaction of intestinal and transforming growth factor; IL, interleukin; PPAR, peroxisome
hepatic cells is crucial to alcohol-mediated liver injury. proliferator-activated receptor; RXR, retinoid X receptor.
Tumor necrosis factor α (TNF-α) and intestine-derived
endotoxemia facilitate hepatocyte apoptosis and necrosis.
Stellate cell activation and collagen production are key and certain pathologic features such as giant mitochon-
events in hepatic fibrogenesis. The resulting fibrosis dria, perivenular fibrosis, and macrovesicular fat may be
determines the architectural derangement of the liver associated with progressive liver injury.
following chronic alcohol ingestion. The transition between fatty liver and the develop-
ment of alcoholic hepatitis is blurred. The hallmark of
alcoholic hepatitis is hepatocyte injury characterized by
PATHOLOGY ballooning degeneration, spotty necrosis, polymorpho-
The liver has a limited repertoire in response to injury. nuclear infiltrate, and fibrosis in the perivenular and
Fatty liver is the initial and most common histologic perisinusoidal space of Disse. Mallory bodies are often
response to hepatotoxic stimuli, including excessive present in florid cases but are neither specific nor neces-
alcohol ingestion. The accumulation of fat within the sary to establishing the diagnosis. Alcoholic hepatitis is
perivenular hepatocytes coincides with the location of thought to be a precursor to the development of cirrhosis.
alcohol dehydrogenase, the major enzyme responsible However, like fatty liver, it is potentially reversible
for alcohol metabolism. Continuing alcohol ingestion with cessation of drinking. Cirrhosis is present in up to
results in fat accumulation throughout the entire hepatic 50% of patients with biopsy-proven alcoholic hepatitis
lobule. Despite extensive fatty change and distortion of and its regression is uncertain, even with abstention.
the hepatocytes with macrovesicular fat, the cessation
of drinking results in normalization of hepatic archi-
CLINICAL FEATURES
tecture and fat content within the liver. Alcoholic fatty
liver has traditionally been regarded as entirely benign, The clinical manifestations of alcoholic fatty liver are
but similar to the spectrum of nonalcoholic fatty-liver subtle and characteristically detected as a consequence
disease (Chap. 309), the appearance of steatohepatitis of the patient’s visit for a seemingly unrelated matter.
Previously unsuspected hepatomegaly is often the only Hyperbilirubinemia is common and is accompanied 427
clinical finding. Occasionally, patients with fatty liver will by modest increases in the alkaline phosphatase level.
present with right upper quadrant discomfort, nausea, and, Derangement in hepatocyte synthetic function indicates
rarely, jaundice. Differentiation of alcoholic fatty liver more serious disease. Hypoalbuminemia and coagulop-
from nonalcoholic fatty liver is difficult unless an accu- athy are common in advanced liver injury. Ultrasono
rate drinking history is ascertained. In every instance graphy is useful in detecting fatty infiltration of the liver
where liver disease is present, a thoughtful and sensitive and determining liver size. The demonstration by ultra-
drinking history should be obtained. Standard, validated sound of portal vein flow reversal, ascites, and intraab-
questions accurately detect alcohol-related problems dominal collaterals indicates serious liver injury with less
CHAPTER 41
(Chap. 392). Alcoholic hepatitis is associated with a potential for complete reversal of liver disease.
wide gamut of clinical features. Fever, spider nevi, jaun-
dice, and abdominal pain simulating an acute abdomen
represent the extreme end of the spectrum, while many PROGNOSIS
patients will be entirely asymptomatic. Portal hyper- Critically ill patients with alcoholic hepatitis have short-
tension, ascites, or variceal bleeding can occur in the term (30-day) mortality rates >50%. Severe alcoholic
absence of cirrhosis. Recognition of the clinical fea-
p = .001
75
Cumulative survival, %
Alcohol abstinence
65.1 4.8% Nutritional support
50
Discriminant function ≥ 32
or MELD ≥ 21
25 (with absence of co-morbidity)
SECTION VI
0 Treatment options
0 7 14 21 28
Days
Preferred Alternative
FIGURE 41-2
Disorders of the Liver and Biliary Tree
Bruce R. Bacon
Pathogenesis
chronic liver disease, including ascites, edema, or upper
Alcohol is the most commonly used drug in the United gastrointestinal (GI) hemorrhage. Many cases present
States, and more than two-thirds of adults drink alco- incidentally at the time of autopsy or elective surgery.
hol each year. Thirty percent have had a binge within Other clinical manifestations include the development
the past month, and over 7% of adults regularly con- of jaundice or encephalopathy. The abrupt onset of any
sume more than two drinks per day. Unfortunately, of these complications may be the first event prompt-
more than 14 million adults in the United States meet ing the patient to seek medical attention. Other patients
the diagnostic criteria for alcohol abuse or dependence. may be identified in the course of an evaluation of rou-
In the United States, chronic liver disease is the tenth tine laboratory studies that are found to be abnormal.
most common cause of death in adults, and alcoholic On physical examination, the liver and spleen may be
cirrhosis accounts for approximately 40% of deaths due enlarged, with the liver edge being firm and nodular.
to cirrhosis. Other frequent findings include scleral icterus, palmar
Ethanol is mainly absorbed by the small intestine and, erythema (Fig. 42-1), spider angiomas (Fig. 42-2),
to a lesser degree, through the stomach. Gastric alcohol parotid gland enlargement, digital clubbing, muscle
dehydrogenase (ADH) initiates alcohol metabolism. wasting, or the development of edema and ascites. Men
Three enzyme systems account for metabolism of may have decreased body hair and gynecomastia as well
alcohol in the liver. These include cytosolic ADH, the as testicular atrophy, which may be a consequence of
microsomal ethanol oxidizing system (MEOS), and hormonal abnormalities or a direct toxic effect of alco-
peroxisomal catalase. The majority of ethanol oxida- hol on the testes. In women with advanced alcoholic
tion occurs via ADH to form acetaldehyde, which is a cirrhosis, menstrual irregularities usually occur, and
highly reactive molecule that may have multiple effects.
Ultimately, acetaldehyde is metabolized to acetate by
aldehyde dehydrogenase (ALDH). Intake of ethanol
increases intracellular accumulation of triglycerides by
increasing fatty acid uptake and by reducing fatty acid
oxidation and lipoprotein secretion. Protein synthesis,
glycosylation, and secretion are impaired. Oxidative
damage to hepatocyte membranes occurs due to the
formation of reactive oxygen species; acetaldehyde is a
highly reactive molecule that combines with proteins
to form protein-acetaldehyde adducts. These adducts
may interfere with specific enzyme activities, including
microtubular formation and hepatic protein trafficking.
With acetaldehyde-mediated hepatocyte damage, cer-
tain reactive oxygen species can result in Kupffer cell
activation. As a result, profibrogenic cytokines are pro-
duced that initiate and perpetuate stellate cell activation, Figure 42-1
with the resultant production of excess collagen and Palmar erythema. This figure shows palmar erythema in a
extracellular matrix. Connective tissue appears in both patient with alcoholic cirrhosis. The erythema is peripheral
periportal and pericentral zones and eventually connects over the palm with central pallor.
liver disease (e.g., chronic viral hepatitis or metabolic or 431
autoimmune liver diseases) must be considered or ruled
out or, if present, an estimate of relative causality along
with the alcohol use should be determined. Liver biopsy
can be helpful to confirm a diagnosis, but generally
when patients present with alcoholic hepatitis and are
still drinking, liver biopsy is withheld until abstinence
has been maintained for at least 6 months to determine
residual, nonreversible disease.
CHAPTER 42
In patients who have had complications of cirrhosis
and who continue to drink, there is a <50% 5-year
survival. In contrast, in those patients who are able to
remain abstinent, the prognosis is significantly improved.
In patients with advanced liver disease, the prognosis
Figure 42-2 remains poor; however, in those individuals who are
Spider angioma. This figure shows a spider angioma in able to remain abstinent, liver transplantation is a viable
CHAPTER 42
from the use of immunosuppressive therapy.
Patients with nonalcoholic steatohepatitis are increas- plantation is the treatment of choice for patients with
ingly being found to have progressed to cirrhosis. With decompensated cirrhosis due to PBC. A variety of ther-
the epidemic of obesity that continues in Western apies have been proposed, but ursodeoxycholic acid
countries, more and more patients are identified with (UDCA) is the only approved treatment that has some
nonalcoholic fatty liver disease. Of these, a significant degree of efficacy by slowing the rate of progression of
subset have nonalcoholic steatohepatitis and can prog- the disease.
Pathology
Biliary Cirrhosis
Histopathologic analyses of liver biopsies of patients
Biliary cirrhosis has pathologic features that are different with PBC have resulted in identifying four distinct
from either alcoholic cirrhosis or posthepatitic cirrhosis, stages of the disease as it progresses. The earliest lesion
yet the manifestations of end-stage liver disease are the is termed chronic nonsuppurative destructive cholangitis and is
same. Cholestatic liver disease may result from necro- a necrotizing inflammatory process of the portal tracts.
inflammatory lesions, congenital or metabolic processes, Medium and small bile ducts are infiltrated with lym-
or external bile duct compression. Thus, two broad phocytes and undergo duct destruction. Mild fibrosis
categories reflect the anatomic sites of abnormal bile and sometimes bile stasis can occur. With progression,
retention: intrahepatic and extrahepatic. The distinction is the inflammatory infiltrate becomes less prominent, but
important for obvious therapeutic reasons. Extrahepatic the number of bile ducts is reduced and there is prolif-
obstruction may benefit from surgical or endoscopic eration of smaller bile ductules. Increased fibrosis ensues
biliary tract decompression, whereas intrahepatic choles- with the expansion of periportal fibrosis to bridging
tatic processes will not improve with such interventions fibrosis. Finally, cirrhosis, which may be micronodular
and require a different approach. or macronodular, develops.
The major causes of chronic cholestatic syndromes
are primary biliary cirrhosis (PBC), autoimmune chol-
Clinical features
angitis (AIC), primary sclerosing cholangitis (PSC), and
idiopathic adulthood ductopenia. These syndromes are Currently, most patients with PBC are diagnosed well
usually clinically distinguished from each other by anti- before the end-stage manifestations of the disease are
body testing, cholangiographic findings, and clinical present, and, as such, most patients are actually asymp-
presentation. However, they all share the histopatho- tomatic. When symptoms are present, they most promi-
logic features of chronic cholestasis, such as cholate nently include a significant degree of fatigue out of
stasis; copper deposition; xanthomatous transformation proportion to what would be expected for either the
of hepatocytes; and irregular, so-called biliary fibrosis. severity of the liver disease or the age of the patient.
In addition, there may be chronic portal inflammation, Pruritus is seen in approximately 50% of patients at the
interface activity, and chronic lobular inflammation. time of diagnosis, and it can be debilitating. It might
Ductopenia is a result of this progressive disease as be intermittent and usually is most bothersome in the
patients develop cirrhosis. evening. In some patients, pruritus can develop toward
434 the end of pregnancy, and there are examples of patients
is greatest when therapy is initiated early; the likeli-
having been diagnosed with cholestasis of pregnancy
hood of significant improvement with UDCA is low in
rather than PBC. Pruritus that presents prior to the
patients with PBC who present with manifestations of
development of jaundice indicates severe disease and a
cirrhosis. UDCA is given in doses of 13–15 mg/kg per
poor prognosis.
day; the medication is usually well-tolerated, although
Physical examination can show jaundice and other
some patients have worsening pruritus with initiation
complications of chronic liver disease, including hepa-
of therapy. A small proportion of patients may have
tomegaly, splenomegaly, ascites, and edema. Other
diarrhea or headache as a side effect of the drug. UDCA
features that are unique to PBC include hyperpigmenta-
has been shown to slow the rate of progression of PBC,
SECTION VI
CHAPTER 42
should be treated (see above).
There is no specific proven treatment for PSC, although
studies are currently ongoing using high-dose (20 mg/kg
Laboratory findings per day) UDCA to determine its benefit. Endoscopic
dilatation of dominant strictures can be helpful, but the
Patients with PSC typically are identified in the course
ultimate treatment is liver transplantation. A dreaded
of an evaluation of abnormal liver enzymes. Most
complication of PSC is the development of cholangio-
United States. Treatment is based on management of affecting Caucasians of Northern European descent.
the underlying cardiac disease. A biliary-type cirrhosis can occur, and some patients
derive benefit from the chronic use of UDCA.
CHAPTER 42
associated with each episode of bleeding. The portal tension in the United States, and clinically significant
venous system normally drains blood from the stomach, portal hypertension is present in >60% of patients with
intestines, spleen, pancreas, and gallbladder, and the cirrhosis. Portal vein obstruction may be idiopathic or
portal vein is formed by the confluence of the superior can occur in association with cirrhosis or with infection,
mesenteric and splenic veins. Deoxygenated blood from pancreatitis, or abdominal trauma.
the small bowel drains into the superior mesenteric Coagulation disorders that can lead to the develop-
vein along with blood from the head of the pancreas, ment of portal vein thrombosis include polycythemia
CHAPTER 42
topenia is a common feature of patients with cirrhosis
and is usually the first indication of portal hypertension.
Compensated cirrhosis Decompensated cirrhosis
Child’s class A Child’s class B or C
aldosterone leading to sodium retention also contrib- concentration <1 g/dL. The development of the serum
ute to the development of ascites. Sodium retention ascites-to-albumin gradient (SAAG) has replaced the
causes fluid accumulation and expansion of the extra- description of exudative or transudative fluid. When
cellular fluid volume, which results in the formation the gradient between the serum albumin level and the
of peripheral edema and ascites. Sodium retention is ascitic fluid albumin level is >1.1 g/dL, the cause of the
the consequence of a homeostatic response caused ascites is most likely due to portal hypertension; this is
by underfilling of the arterial circulation secondary usually in the setting of cirrhosis. When the gradient
Disorders of the Liver and Biliary Tree
to arterial vasodilation in the splanchnic vascular bed. is <1.1 g/dL, infectious or malignant causes of asci-
Because the retained fluid is constantly leaking out of tes should be considered. When levels of ascitic fluid
the intravascular compartment into the peritoneal cav- proteins are very low, patients are at increased risk for
ity, the sensation of vascular filling is not achieved, and developing SBP. A high level of red blood cells in the
the process continues. Hypoalbuminemia and reduced ascitic fluid signifies a traumatic tap or perhaps a hepa-
plasma oncotic pressure also contribute to the loss of tocellular cancer or a ruptured omental varix. When
fluid from the vascular compartment into the peritoneal the absolute level of polymorphonuclear leukocytes is
cavity. Hypoalbuminemia is due to decreased synthetic >250/μL, the question of ascitic fluid infection should
function in a cirrhotic liver. be strongly considered. Ascitic fluid cultures should be
obtained using bedside inoculation of culture media.
Clinical features
Patients typically note an increase in abdominal girth
that is often accompanied by the development of Treatment Ascites
peripheral edema. The development of ascites is often
Patients with small amounts of ascites can usually be
insidious, and it is surprising that some patients wait so
managed with dietary sodium restriction alone. Most
long and become so distended before seeking medical
average diets in the United States contain 6 to 8 g of
attention. Patients usually have at least 1–2 L of fluid
sodium per day, and if patients eat at restaurants or
in the abdomen before they are aware that there is an
fast-food outlets, the amount of sodium in their diet can
increase. If ascitic fluid is massive, respiratory function
exceed this amount. Thus, it is often extremely difficult
can be compromised, and patients will complain of
to get patients to change their dietary habits to ingest
shortness of breath. Hepatic hydrothorax may also occur
<2 g of sodium per day, which is the recommended
in this setting, contributing to respiratory symptoms.
amount. Patients are frequently surprised to realize
Patients with massive ascites are often malnourished
how much sodium is in the standard U.S. diet; thus,
and have muscle wasting and excessive fatigue and
it is important to make educational pamphlets avail-
weakness.
able to the patient. Often, a simple recommendation
is to eat fresh or frozen foods, avoiding canned or pro-
Diagnosis cessed foods, which are usually preserved with sodium.
When a moderate amount of ascites is present, diuretic
Diagnosis of ascites is by physical examination and is
therapy is usually necessary. Traditionally, spironolac-
often aided by abdominal imaging. Patients will have
tone at 100–200 mg/d as a single dose is started, and
bulging flanks, may have a fluid wave, or may have
furosemide may be added at 40–80 mg/d, particularly
the presence of shifting dullness. This is determined by
in patients who have peripheral edema. In patients who
taking patients from a supine position to lying on either
have never received diuretics before, the failure of the
their left or right side and noting the movement of the
above-mentioned dosages suggests that they are not
dullness to percussion. Subtle amounts of ascites can be
being compliant with a low-sodium diet. If compliance
detected by ultrasound or CT scanning. Hepatic hydro-
is confirmed and ascitic fluid is not being mobilized,
thorax is more common on the right side and implicates
spironolactone can be increased to 400–600 mg/d and
a rent in the diaphragm with free flow of ascitic fluid
furosemide increased to 120–160 mg/d. If ascites is
into the thoracic cavity.
TREATMENT OF REFRACTORY ASCITES
If more than two organisms are identified, secondary 441
bacterial peritonitis due to a perforated viscus should
Refractory ascites
be considered. The diagnosis of SBP is made when the
fluid sample has an absolute neutrophil count >250/μL.
Large volume paracentesis (LVP) + albumin
Bedside cultures should be obtained when ascitic fluid
is tapped. Patients with ascites may present with fever,
Dietary sodium restriction + diuretics
altered mental status, elevated white blood cell count,
and abdominal pain or discomfort, or they may present
Ascites reaccumulation without any of these features. Therefore, it is necessary
CHAPTER 42
to have a high degree of clinical suspicion, and perito-
Consider TIPS Continue LVP with Consider liver neal taps are important for making the diagnosis. Treat-
albumin as needed transplantation ment is with a second-generation cephalosporin, with
cefotaxime being the most commonly used antibiotic.
In patients with variceal hemorrhage, the frequency of
Figure 42-5
SBP is significantly increased, and prophylaxis against
Treatment of refractory ascites. In patients who develop
SBP is recommended when a patient presents with
Hepatorenal Syndrome
The hepatorenal syndrome (HRS) is a form of func-
still present with these dosages of diuretics in patients tional renal failure without renal pathology that occurs
who are compliant with a low-sodium diet, then they in about 10% of patients with advanced cirrhosis or
are defined as having refractory ascites, and alternative acute liver failure. There are marked disturbances in
treatment modalities including repeated large-volume the arterial renal circulation in patients with HRS;
paracentesis, or a TIPS procedure should be considered these include an increase in vascular resistance accom-
(Fig. 42-5). Recent studies have shown that TIPS, while panied by a reduction in systemic vascular resistance.
managing the ascites, does not improve survival in The reason for renal vasoconstriction is most likely
these patients. Unfortunately, TIPS is often associated multifactorial and is poorly understood. The diagno-
with an increased frequency of hepatic encephalopa- sis is made usually in the presence of a large amount
thy and must be considered carefully on a case-by-case of ascites in patients who have a stepwise progres-
basis. The prognosis for patients with cirrhosis with asci- sive increase in creatinine. Type 1 HRS is character-
tes is poor, and some studies have shown that <50% of ized by a progressive impairment in renal function and
patients survive 2 years after the onset of ascites. Thus, a significant reduction in creatinine clearance within
there should be consideration for liver transplantation 1–2 weeks of presentation. Type 2 HRS is character-
in patients with the onset of ascites. ized by a reduction in glomerular filtration rate with
an elevation of serum creatinine level, but it is fairly
stable and is associated with a better outcome than that
Spontaneous Bacterial Peritonitis
of Type 1 HRS.
SBP is a common and severe complication of ascites HRS is often seen in patients with refractory asci-
characterized by spontaneous infection of the ascitic tes and requires exclusion of other causes of acute renal
fluid without an intraabdominal source. In patients failure. Treatment has, unfortunately, been difficult,
with cirrhosis and ascites severe enough for hospitaliza- and in the past, dopamine or prostaglandin analogues
tion, SBP can occur in up to 30% of individuals and can were used as renal vasodilating medications. Carefully
have a 25% in-hospital mortality rate. Bacterial translo- performed studies have failed to show clear-cut benefit
cation is the presumed mechanism for development of from these therapeutic approaches. Currently, patients
SBP, with gut flora traversing the intestine into mesen- are treated with midodrine, an α-agonist, along with
teric lymph nodes, leading to bacteremia and seeding octreotide and intravenous albumin. The best therapy
of the ascitic fluid. The most common organisms are for HRS is liver transplantation; recovery of renal func-
Escherichia coli and other gut bacteria; however, gram- tion is typical in this setting. In patients with either type
positive bacteria, including Streptococcus viridans, Staph- 1 or type 2 HRS, the prognosis is poor unless transplant
ylococcus aureus, and Enterococcus sp., can also be found. can be achieved within a short period of time.
442 Hepatic Encephalopathy patients have encephalopathy for the first time, they are
unaware of what is transpiring, but once they have been
Portosystemic encephalopathy is a serious complica- through the experience for the first time, they can iden-
tion of chronic liver disease and is broadly defined as tify when this is developing in subsequent situations and
an alteration in mental status and cognitive function can often self-medicate to impair the development or
occurring in the presence of liver failure. In acute liver worsening of encephalopathy.
injury with fulminant hepatic failure, the development
of encephalopathy is a requirement for a diagnosis of
fulminant failure. Encephalopathy is much more com-
monly seen in patients with chronic liver disease. Gut- Treatment Hepatic Encephalopathy
SECTION VI
CHAPTER 42
patients may have thrombocytopenia from hypersplenism
due to portal hypertension. Vitamin K–dependent clot- mass, treatment should be administered with bisphospho-
ting factors are Factors II, VII, IX, and X. Vitamin K nates that are effective at inhibiting resorption of bone
requires biliary excretion for its subsequent absorption; and efficacious in the treatment of osteoporosis.
thus, in patients with chronic cholestatic syndromes,
vitamin K absorption is frequently diminished. Intra-
Hematologic Abnormalities
venous or intramuscular vitamin K can quickly cor-
in Cirrhosis
Although clinical and laboratory features yield clues to that expands and spills over beyond the border of peri-
the extent of inflammatory processes (disease grade), the portal hepatocytes in chronic hepatitis C, autoimmune
degree of scarring and architectural distortion (disease hepatitis, and liver allograft rejection) or centrizonal
stage), and the nature of the disease process, the liver areas (e.g., acute acetaminophen hepatotoxicity). Other
biopsy is felt to represent the gold standard for assess- histologic features of importance include hepatic steato-
ing the degree of liver injury and fibrosis. Examination sis (observed in alcoholic liver injury, in nonalcoholic
of liver histology provides not only a basis for quantita- fatty liver disorders, in metabolic disorders—including
tive scoring of disease activity and progression but also mitochondrial injury—and in patients with chronic
a wealth of qualitative information that can direct and viral hepatitis); injury of bile ducts in the portal tract,
inform diagnosis and management. an important diagnostic hallmark of primary biliary cir-
A normal liver lobule consists of portal (zone 1), lobular rhosis, primary sclerosing cholangitis, as well as of liver
(midzonal or zone 2), and central (zone 3) zones. The por- allograft rejection; cholestasis in intrahepatic or extrahe-
tal tract contains the hepatic artery (HA) and portal vein patic biliary obstruction or in infiltrative disorders; duct-
(PV), which represent the dual vascular supply to the ular proliferation in the setting of marked hepatocellular
liver, as well as the bile duct (BD). The lobular area con- necrosis; plasma cell infiltration common in autoimmune
tains cords of liver cells surrounded by vascular sinusoids, hepatitis; portal inflammation affecting portal veins
and the central zone consists of the central vein (CV), the (“endothelialitis”) in liver allograft rejection; and mild-
terminal branch of the hepatic vein (see figure below). to-severe fibrosis, in varying distribution and pattern, as a
consequence of liver injury common to many disorders.
Liver cells
(All magnifications reflect the objective lens used.)
BD
HA
CV
PV
Sinusoids
Portal tract
CHAPTER 43
FIGURE 43-2 FIGURE 43-5
FIGURE 43-6
FIGURE 43-3
Lobular inflammation with acidophilic body (apoptotic
Chronic hepatitis C with portal lymphoid infiltrate and
body) surrounded by lymphoid cells (H&E, 40×).
lymphoid follicle containing germinal center (H&E, 10×).
FIGURE 43-11
Primary biliary cirrhosis with degenerating bile duct epithelium
Disorders of the Liver and Biliary Tree
FIGURE 43-8
(“florid ductular lesion”) (arrow) surrounded by epithelioid
Chronic hepatitis B with hepatocellular nuclear staining for
granulomatous reaction and lymphoplasmacytic infiltrate
hepatitis B core antigen (immunoperoxidase, 20×).
(H&E, 40×).
FIGURE 43-12
Chronic hepatitis C with bridging fibrosis (arrow) (Masson
FIGURE 43-9
trichrome, 10×).
Autoimmune hepatitis with portal and lobular inflammation,
interface hepatitis, and cholestasis (H&E, 10×).
CHAPTER 43
FIGURE 43-14 FIGURE 43-17
FIGURE 43-18
FIGURE 43-15 `1 antitrypsin deficiency with cytoplasmic periodic acid–
Liver allograft with cytomegalovirus infection showing Schiff (PAS)-positive, diastase-resistant globules in many
hepatocytes with nuclear inclusions (arrows) surrounded by a hepatocytes, predominantly at the periphery of a cirrhotic
neutrophilic and lymphoid infiltrate (H&E, 10×). nodule (PAS, 20×).
cellular carcinoma; brown hemosiderin pigment (iron) is ductular fibrosis (Masson trichrome, 4×).
present in the cirrhotic liver, while the hepatocellular carci-
noma nodules are hemosiderin-free (H&E, 4×).
FIGURE 43-24
FIGURE 43-21 Primary sclerosing cholangitis showing the extrahepatic bile
Cirrhosis secondary to hemochromatosis with hepato- duct (in a liver explant obtained at the time of hepatectomy
cellular carcinoma at higher magnification, demonstrat- for orthotopic liver transplantation) with marked mural chronic
ing nodules of large malignant cells with highly disorganized inflammation and fibrosis as well as peribiliary glands (H&E, 2×).
architecture (H&E, 10×).
CHAPTER 43
Atlas of Liver Biopsies
FIGURE 43-26 FIGURE 43-28
Nonalcoholic steatohepatitis (NASH) showing steatosis, Acute hepatitis with submassive hepatic necrosis with
ballooned hepatocytes, and Mallory bodies with surrounding marked parenchymal collapse, remnant islands of surviving
polymorphonuclear leukocytes (arrow) (H&E, 20×). hepatocytes, and a marked ductular reaction (H&E, 10×).
FIGURE 43-27
Nonalcoholic steatohepatitis (NASH) showing steatosis FIGURE 43-29
with perisinusoidal and pericellular fibrosis (H&E, 20×). Wilson’s disease showing cirrhosis, extensive collapse, and
ductular reaction in a teenager with an acute presentation
(H&E, 4×).
450
SECTION VI
Disorders of the Liver and Biliary Tree
FIGURE 43-30
Wilson’s disease showing extensive hepatocyte cytoplasmic red granular staining for copper in a cirrhotic nodule (rhodanine
copper stain, 20×).
CHAPTER 44
Bruce R. Bacon
There are a number of disorders of the liver that fit and signs of chronic liver disease. Increasingly, most
within the categories of genetic, metabolic, and infiltra- patients are now identified before they have symp-
tive disorders. Inherited disorders include hemochroma- toms, either through family studies or from the per-
tosis, Wilson’s disease, α1 antitrypsin (α1AT) deficiency, formance of screening iron studies. Several prospective
and cystic fibrosis (CF). Hemochromatosis is the most population studies have shown that C282Y homozygos-
common inherited disorder affecting Caucasian popula- ity is found in about 1 in 250 individuals of Northern
tions, with the genetic susceptibility for the disease being European descent, with the heterozygote frequency
identified in 1 in 250 individuals. Over the past 15 years, seen in approximately 1 in 10 individuals. It is impor-
it has become increasingly apparent that nonalcoholic tant to consider HH in patients who present with the
fatty liver disease (NAFLD) is the most common cause symptoms and signs known to occur in established HH.
of elevated liver enzymes found in the U.S. population. When confronted with abnormal serum iron studies,
With the obesity epidemic in the United States, it is esti-
mated that 20% of the population may have abnormal
Table 44-1
liver enzymes on the basis of NAFLD and 3% may have
nonalcoholic steatohepatitis (NASH). Infiltrative disor- ClassifiCation of iron overloaD sYnDroMes
ders of the liver are relatively rare. Hereditary Hemochromatosis (HH)
HFE-related (type 1)
C282Y/C282Y
GenetiC liver Diseases C282Y/H63D
Hereditary hemochromatosis Other HFE mutations
capacity (TIBC) or transferrin, times 100%] and ferritin appropriate clinical setting. The genetic diagnosis of
levels should be obtained. Both of these will be elevated Wilson’s disease is difficult because >200 mutations in
in a symptomatic patient. It must be remembered that ATP7B have been described with different degrees of
ferritin is an acute-phase reactant and can be elevated in frequency and penetration in certain populations.
a number of other inflammatory disorders, such as rheu-
matoid arthritis, or in various neoplastic diseases, such
as lymphoma or other cancers. Also, serum ferritin is
Disorders of the Liver and Biliary Tree
CHAPTER 44
In adults, the diagnosis often comes in the course of
evaluation of patients with abnormal liver test abnor- liver was characterized in a group of obese patients.
malities or in a work-up for cirrhosis. A hint to diagno- In 1980, Ludwig and colleagues at the Mayo Clinic
sis may be coexistent lung disease at a relatively young described 20 obese, diabetic, nonalcoholic patients who
age or a family history of liver and/or lung disease. had similar findings on liver biopsy to patients with
Patients may have symptoms of pulmonary disease with alcoholic liver disease, and the term nonalcoholic ste-
cough and dyspnea. Liver disease may be asymptomatic atohepatitis was introduced. The prevalence of NAFLD
CHAPTER 44
is present, this should be treated as well. Acute intermit-
as the principal hepatic manifestation of sarcoidosis,
tent porphyria presents with abdominal pain, with the
and this is the most common presentation of hepatic
diagnosis made by avoidance of certain precipitating
granulomas (Chap. 329). The vast majority of these
factors such as starvation or certain diets. Intravenous
patients do not require any specific treatment other
heme as hematin has been used for treatment.
than what would normally be used for treatment of
their sarcoidosis. A small subset, however, can develop
CHAPTER 45
sis or defects of biliary excretion. F1C1 is defective the entire gut. Quantitatively much more important
in progressive familial intrahepatic cholestasis type 1 for bile salt recirculation, however, is the active transport
(PFIC1) and benign recurrent intrahepatic cholesta- mechanism for conjugated bile acids in the distal ileum
sis type 1 (BRIC1) and results in ablation of all other (Chap. 294). The reabsorbed bile acids enter the por-
ATP-dependent transporter functions. BSEP is defective tal bloodstream and are taken up rapidly by hepatocytes,
in PFIC2 and BRIC2. Mutations of MRP2 (ABCC2) reconjugated, and resecreted into bile (enterohepatic
cause the Dubin-Johnson syndrome, an inherited form circulation).
fast for delivery into the duodenum with the first meal precipitate (Fig. 45-1).
of the day. The normal capacity of the gallbladder is There are several important mechanisms in the for-
∼30 mL of bile. mation of lithogenic (stone-forming) bile. The most
important is increased biliary secretion of cholesterol.
This may occur in association with obesity, the meta-
bolic syndrome, high-caloric and cholesterol-rich diets,
Diseases of the Gallbladder or drugs (e.g., clofibrate) and may result from increased
Disorders of the Liver and Biliary Tree
Congenital Anomalies
Anomalies of the biliary tract are not uncommon and
include abnormalities in number, size, and shape (e.g., ABCG5/G8 CYP7A1 MDR3 (ABCB4)
agenesis of the gallbladder, duplications, rudimentary or
oversized “giant” gallbladders, and diverticula). Phrygian cap
I.
is a clinically innocuous entity in which a partial or com-
plete septum (or fold) separates the fundus from the body.
Cholesterol Normal cholesterol Normal cholesterol
Anomalies of position or suspension are not uncommon Normal bile acids Bile acids Normal bile acids
and include left-sided gallbladder, intrahepatic gallbladder, Normal lecithin Normal lecithin Lecithin
retrodisplacement of the gallbladder, and “floating” gall-
bladder. The latter condition predisposes to acute torsion,
volvulus, or herniation of the gallbladder. II. Supersaturation
CHAPTER 45
large study of symptomatic gallstones in Swedish twins An important mechanism is nucleation of cholesterol
provided strong evidence for a role of genetic factors monohydrate crystals, which is greatly accelerated in
in gallstone pathogenesis. Genetic factors accounted for human lithogenic bile. Accelerated nucleation of cho-
25%, shared environmental factors for 13%, and indi- lesterol monohydrate in bile may be due to either an
vidual environmental factors for 62% of the phenotypic excess of pronucleating factors or a deficiency of antinucleating
variation among monozygotic twins. A single nucleo- factors. Mucin and certain non-mucin glycoproteins,
tide polymorphism of the gene encoding the hepatic principally immunoglobulins, appear to be pronucleat-
ter and (2) sluggish gallbladder contraction in response increase uptake of dietary cholesterol, and increase
to a standard meal, resulting in impaired gallbladder biliary cholesterol secretion
b. Natural estrogens, other estrogens, and oral
emptying. That these changes are related to pregnancy
contraceptives lead to decreased bile salt secretion
per se is supported by several studies that show reversal and decreased conversion of cholesterol to
of these abnormalities quite rapidly after delivery. Dur- cholesteryl esters
ing pregnancy, gallbladder sludge develops in 20–30% 5. Increasing age: Increased biliary secretion of
of women and gallstones in 5–12%. Although biliary cholesterol, decreased size of bile acid pool,
sludge is a common finding during pregnancy, it is usu- decreased secretion of bile salts
ally asymptomatic and often resolves spontaneously after 6. Gallbladder hypomotility leading to stasis and
formation of sludge
delivery. Gallstones, which are less common than sludge
a. Prolonged parenteral nutrition
and frequently associated with biliary colic, may also dis- b. Fasting
appear after delivery because of spontaneous dissolution c. Pregnancy
related to bile becoming unsaturated with cholesterol d. Drugs such as octreotide
postpartum. 7. Clofibrate therapy: Increased biliary secretion of
Approximately 10–20% of persons with rapid weight cholesterol
reduction achieved through very low calorie dieting 8. Decreased bile acid secretion
develop gallstones. In a study involving 600 patients a. Primary biliary cirrhosis
b. Genetic defect of the CYP7A1 gene
who completed a 16-week, 520-kcal/d diet, UDCA in 9. Decreased phospholipid secretion: Genetic defect of
a dosage of 600 mg/d proved highly effective in pre- the MDR3 gene
venting gallstone formation; gallstones developed in 10. Miscellaneous
only 3% of UDCA recipients, compared to 28% of a. High-calorie, high-fat diet
placebo-treated patients. b. Spinal cord injury
To summarize, cholesterol gallstone disease occurs Pigment Stones
because of several defects, which include (1) bile super- 1. Demographic/genetic factors: Asia, rural setting
saturation with cholesterol, (2) nucleation of cholesterol 2. Chronic hemolysis
monohydrate with subsequent crystal retention and 3. Alcoholic cirrhosis
stone growth, and (3) abnormal gallbladder motor func- 4. Pernicious anemia
tion with delayed emptying and stasis. Other important 5. Cystic fibrosis
factors known to predispose to cholesterol-stone forma- 6. Chronic biliary tract infection, parasite infections
tion are summarized in Table 45-1. 7. Increasing age
8. Ileal disease, ileal resection or bypass
Pigment stones
Black pigment stones are composed of either pure
calcium bilirubinate or polymer-like complexes with stones. Enterohepatic recycling of bilirubin in ileal dis-
calcium and mucin glycoproteins. They are more com- ease states contributes to their pathogenesis. Brown pig-
mon in patients who have chronic hemolytic states ment stones are composed of calcium salts of unconju-
(with increased conjugated bilirubin in bile), liver gated bilirubin with varying amounts of cholesterol and
cirrhosis, Gilbert’s syndrome, or cystic fibrosis. Gall- protein. They are caused by the presence of increased
bladder stones in patients with ileal diseases, ileal resec- amounts of unconjugated, insoluble bilirubin in bile
tion, or ileal bypass generally are also black pigment that precipitates to form stones. Deconjugation of an
excess of soluble bilirubin mono- and diglucuronides acoustic shadowing; these two characteristics distinguish 461
may be mediated by endogenous β-glucuronidase but sludges from gallstones. Ultrasound can also be used to
may also occur by spontaneous hydrolysis. Sometimes, assess the emptying function of the gallbladder.
the enzyme is also produced when bile is chronically The plain abdominal film may detect gallstones con-
infected by bacteria, and such stones are brown. Pig- taining sufficient calcium to be radiopaque (10–15% of
ment stone formation is especially prominent in Asians cholesterol and ∼50% of pigment stones). Plain radiog-
and is often associated with infections in the gallbladder raphy may also be of use in the diagnosis of emphyse-
and biliary tree (Table 45-1). matous cholecystitis, porcelain gallbladder, limey bile,
and gallstone ileus.
CHAPTER 45
Diagnosis Oral cholecystography (OCG) has historically been a
useful procedure for the diagnosis of gallstones but has
Procedures of potential use in the diagnosis of choleli- been replaced by ultrasound and is regarded as obsolete.
thiasis and other diseases of the gallbladder are detailed It may be used to assess the patency of the cystic duct
in Table 45-2. Ultrasonography of the gallbladder and gallbladder emptying function. Further, OCG can
is very accurate in the identification of cholelithiasis also delineate the size and number of gallstones and
and has replaced oral cholecystography (Fig. 45-2A). determine whether they are calcified.
Table 45-2
Diagnostic Evaluation of the Gallbladder
Diagnostic Advantages Diagnostic Limitations Comment
Gallbladder Ultrasound
Rapid Bowel gas Procedure of choice for detection
Accurate identification of gallstones (>95%) Massive obesity of stones
Simultaneous scanning of GB, liver, bile ducts, Ascites
pancreas
“Real-time” scanning allows assessment of GB
volume, contractility
Not limited by jaundice, pregnancy
May detect very small stones
Plain Abdominal x-ray
Low cost Relatively low yield Pathognomonic findings in: calcified
Readily available ? Contraindicated in pregnancy gallstones
Limey bile, porcelain GB
Emphysematous cholecystitis
Gallstone ileus
Radioisotope Scans (HIDA, DIDA, etc.)
Accurate identification of cystic duct obstruction ? Contraindicated in pregnancy Indicated for confirmation of
Simultaneous assessment of bile ducts Serum bilirubin >103–205 μmol/L suspected acute cholecystitis; less
(6–12 mg/dL) sensitive and less specific in chronic
Cholecystogram of low cholecystitis; useful in diagnosis of
resolution acalculous cholecystopathy, espe-
cially if given with CCK to assess
gallbladder emptying
Figure 45-2
Examples of ultrasound and radiologic studies of the duct (CHD), common bile duct (CBD), and pancreatic duct
biliary tract. A. An ultrasound study showing a distended (PD) are shown. The arrow points to the ampulla of Vater.
gallbladder containing a single large stone (arrow), which C. Endoscopic retrograde cholangiogram (ERC) showing
casts an acoustic shadow. B. Endoscopic retrograde chol- choledocholithiasis. The biliary tract is dilatated and con-
angiopancreatogram (ERCP) showing normal biliary tract tains multiple radiolucent calculi. D. ERCP showing scleros-
anatomy. In addition to the endoscope and large vertical ing cholangitis. The common bile duct shows areas that are
gallbladder filled with contrast dye, the common hepatic strictured and narrowed.
Symptoms of gallstone disease a fatty meal, should not be confused with biliary pain.
Such symptoms are frequently elicited from patients
Gallstones usually produce symptoms by causing inflam- with or without gallstone disease but are not specific for
mation or obstruction following their migration into biliary calculi. Biliary colic may be precipitated by eat-
the cystic duct or CBD. The most specific and charac- ing a fatty meal, by consumption of a large meal follow-
teristic symptom of gallstone disease is biliary colic that ing a period of prolonged fasting, or by eating a normal
is a constant and often long-lasting pain (see below). meal; it is frequently nocturnal, occurring within a few
Obstruction of the cystic duct or CBD by a stone pro- hours of retiring.
duces increased intraluminal pressure and distention of
the viscus that cannot be relieved by repetitive biliary
Natural history
contractions. The resultant visceral pain is characteristi-
cally a severe, steady ache or fullness in the epigastrium Gallstone disease discovered in an asymptomatic patient
or right upper quadrant (RUQ) of the abdomen with or in a patient whose symptoms are not referable to
frequent radiation to the interscapular area, right scapula, cholelithiasis is a common clinical problem. The natu-
or shoulder. ral history of “silent,” or asymptomatic, gallstones has
Biliary colic begins quite suddenly and may per- occasioned much debate. A study of predominantly
sist with severe intensity for 15 min to 5 h, subsiding male silent gallstone patients suggests that the cumula-
gradually or rapidly. It is steady rather than intermit- tive risk for the development of symptoms or complica-
tent as would be suggested by the word colic, which tions is relatively low—10% at 5 years, 15% at 10 years,
must be regarded as a misnomer, although it is in wide- and 18% at 15 years. Patients remaining asymptom-
spread use. An episode of biliary pain persisting beyond atic for 15 years were found to be unlikely to develop
5 h should raise the suspicion of acute cholecystitis (see symptoms during further follow-up, and most patients
below). Nausea and vomiting frequently accompany who did develop complications from their gallstones
episodes of biliary pain. An elevated level of serum bili- experienced prior warning symptoms. Similar conclu-
rubin and/or alkaline phosphatase suggests a common sions apply to diabetic patients with silent gallstones.
duct stone. Fever or chills (rigors) with biliary pain usu- Decision analysis has suggested that (1) the cumulative
ally imply a complication, i.e., cholecystitis, pancreatitis, risk of death due to gallstone disease while on expectant
or cholangitis. Complaints of vague epigastric fullness, management is small, and (2) prophylactic cholecystec-
dyspepsia, eructation, or flatulence, especially following tomy is not warranted.
Complications requiring cholecystectomy are much 463
dispersion of cholesterol from stones by physical-
more common in gallstone patients who have devel-
chemical means. UDCA may also retard cholesterol
oped symptoms of biliary pain. Patients found to have
crystal nucleation. In carefully selected patients with
gallstones at a young age are more likely to develop
a functioning gallbladder and with radiolucent stones
symptoms from cholelithiasis than are patients >60 years
<10 mm in diameter, complete dissolution can be
at the time of initial diagnosis. Patients with diabetes
achieved in ∼50% of patients within 6 months to 2 years.
mellitus and gallstones may be somewhat more sus-
For good results within a reasonable time period, this
ceptible to septic complications, but the magnitude of
therapy should be limited to radiolucent stones smaller
risk of septic biliary complications in diabetic patients is
than 5 mm in diameter. The dose of UDCA should be
CHAPTER 45
incompletely defined.
10–15 mg/kg per day. Stones larger than 15 mm in
size rarely dissolve. Pigment stones are not responsive
to UDCA therapy. The highest success rate (i.e., >70%)
Treatment Gallstones
occurs in patients with small (<5 mm) floating radiolu-
cent gallstones. Probably ≤10% of patients with symp-
Surgical Therapy In asymptomatic gallstone
tomatic cholelithiasis are candidates for such treatment.
patients, the risk of developing symptoms or complica-
The diagnosis of acute cholecystitis is usually made culitis, obstructing adenocarcinoma of the gallbladder,
on the basis of a characteristic history and physical diabetes mellitus, torsion of the gallbladder, “unusual”
examination. The triad of sudden onset of RUQ ten- bacterial infections of the gallbladder (e.g., Leptospira,
derness, fever, and leukocytosis is highly suggestive. Streptococcus, Salmonella, or Vibrio cholerae), and parasitic
Typically, leukocytosis in the range of 10,000–15,000 infestation of the gallbladder. Acalculous cholecystitis
cells per microliter with a left shift on differential may also be seen with a variety of other systemic disease
count is found. The serum bilirubin is mildly elevated processes (sarcoidosis, cardiovascular disease, tuberculo-
[<85.5 μmol/L (5 mg/dL)] in fewer than half of sis, syphilis, actinomycosis, etc.).
patients, while about one-fourth have modest eleva- Although the clinical manifestations of acalculous cho-
tions in serum aminotransferases (usually less than a lecystitis are indistinguishable from those of calculous
fivefold elevation). Ultrasound will demonstrate calculi cholecystitis, the setting of acute gallbladder inflamma-
in 90–95% of cases and is useful for detection of signs tion complicating severe underlying illness is characteristic
of gallbladder inflammation including thickening of the of acalculous disease. Ultrasound, CT, or radionuclide
wall, pericholecystic fluid, and dilation of the bile duct. examinations demonstrating a large, tense, static gall-
The radionuclide (e.g., HIDA) biliary scan may be con- bladder without stones and with evidence of poor emp-
firmatory if bile duct imaging is seen without visualiza- tying over a prolonged period may be diagnostically
tion of the gallbladder. useful in some cases. The complication rate for acalcu-
Approximately 75% of patients treated medically have lous cholecystitis exceeds that for calculous cholecystitis.
remission of acute symptoms within 2–7 days following Successful management of acute acalculous cholecystitis
hospitalization. In 25%, however, a complication of acute appears to depend primarily on early diagnosis and sur-
cholecystitis will occur despite conservative treatment (see gical intervention, with meticulous attention to postop-
below). In this setting, prompt surgical intervention is erative care.
required. Of the 75% of patients with acute cholecys- Acalculous cholecystopathy
titis who undergo remission of symptoms, ∼25% will Disordered motility of the gallbladder can produce
experience a recurrence of cholecystitis within 1 year, recurrent biliary pain in patients without gallstones. Infu-
and 60% will have at least one recurrent bout within sion of an octapeptide of CCK can be used to measure
6 years. In view of the natural history of the disease, the gallbladder ejection fraction during cholescintig-
acute cholecystitis is best treated by early surgery when- raphy. The surgical findings have included abnormali-
ever possible. ties such as chronic cholecystitis, gallbladder muscle
Mirizzi’s syndrome is a rare complication in which a hypertrophy, and/or a markedly narrowed cystic duct.
gallstone becomes impacted in the cystic duct or neck of Some of these patients may well have had antecedent
the gallbladder causing compression of the CBD, result- gallbladder disease. The following criteria can be used
ing in CBD obstruction and jaundice. Ultrasound shows to identify patients with acalculous cholecystopathy:
gallstone(s) lying outside the hepatic duct. Endoscopic ret- (1) recurrent episodes of typical RUQ pain character-
rograde cholangiopancreatography (ERCP) (Fig. 45-2B) istic of biliary tract pain, (2) abnormal CCK cholescin-
or percutaneous transhepatic cholangiography (PTC) or tigraphy demonstrating a gallbladder ejection fraction of
magnetic resonance cholangiopancreatography (MRCP) <40%, and (3) infusion of CCK reproduces the patient’s
will usually demonstrate the characteristic extrinsic pain. An additional clue would be the identification of
compression of the CBD. Surgery consists of removing a large gallbladder on ultrasound examination. Finally,
the cystic duct, diseased gallbladder, and the impacted it should be noted that sphincter of Oddi dysfunction
can also give rise to recurrent RUQ pain and CCK- epithelial cells. A visible, easily palpable, nontender 465
scintigraphic abnormalities. mass sometimes extending from the RUQ into the
right iliac fossa may be found on physical examination.
Emphysematous cholecystitis
The patient with hydrops of the gallbladder frequently
So-called emphysematous cholecystitis is thought to remains asymptomatic, although chronic RUQ pain
begin with acute cholecystitis (calculous or acalculous) may also occur. Cholecystectomy is indicated, because
followed by ischemia or gangrene of the gallbladder empyema, perforation, or gangrene may complicate the
wall and infection by gas-producing organisms. Bacteria condition.
most frequently cultured in this setting include anaer-
obes, such as C. welchii or C. perfringens, and aerobes, Gangrene and perforation
CHAPTER 45
such as E. coli. This condition occurs most frequently in Gangrene of the gallbladder results from ischemia of the
elderly men and in patients with diabetes mellitus. The wall and patchy or complete tissue necrosis. Underly-
clinical manifestations are essentially indistinguishable ing conditions often include marked distention of the
from those of nongaseous cholecystitis. The diagnosis gallbladder, vasculitis, diabetes mellitus, empyema, or tor-
is usually made on plain abdominal film by finding gas sion resulting in arterial occlusion. Gangrene usually pre-
within the gallbladder lumen, dissecting within the gall- disposes to perforation of the gallbladder, but perforation
Calcium salts in the lumen of the gallbladder in suffi- plication of acute cholecystitis such as empyema, emphy-
cient concentration may produce calcium precipitation sematous cholecystitis, or perforation is suspected or
and diffuse, hazy opacification of bile or a layering effect confirmed. Patients with uncomplicated acute cholecys-
on plain abdominal roentgenography. This so-called titis should undergo early elective laparoscopic chole-
limey bile, or milk of calcium bile, is usually clinically cystectomy, ideally within 72 hours after diagnosis. The
innocuous, but cholecystectomy is recommended, espe- complication rate is not increased in patients undergoing
cially when it occurs in a hydropic gallbladder. In the early as opposed to delayed (>6 weeks after diagnosis)
entity called porcelain gallbladder, calcium salt deposition cholecystectomy. Delayed surgical intervention is prob-
within the wall of a chronically inflamed gallbladder ably best reserved for (1) patients in whom the overall
may be detected on the plain abdominal film. Cho- medical condition imposes an unacceptable risk for early
lecystectomy is advised in all patients with porcelain surgery and (2) patients in whom the diagnosis of acute
gallbladder because in a high percentage of cases this cholecystitis is in doubt. Early cholecystectomy (within
finding appears to be associated with the development 72 hours) is the treatment of choice for most patients
of carcinoma of the gallbladder. with acute cholecystitis. Mortality figures for emergency
cholecystectomy in most centers approach 3%, while
Treatment Acute Cholecystitis the mortality risk for early elective cholecystectomy is
∼0.5% in patients under age 60. Of course, the opera-
Medical Therapy Although surgical interven-
tive risks increase with age-related diseases of other
tion remains the mainstay of therapy for acute chole- organ systems and with the presence of long- or short-
cystitis and its complications, a period of in-hospital term complications of gallbladder disease. Seriously ill or
stabilization may be required before cholecystectomy. debilitated patients with cholecystitis may be managed
Oral intake is eliminated, nasogastric suction may be with cholecystostomy and tube drainage of the gallblad-
indicated, and extracellular volume depletion and elec- der. Elective cholecystectomy may then be done at a
trolyte abnormalities are repaired. Meperidine or non- later date.
steroidal anti-inflammatory drugs (NSAIDs) are usually
employed for analgesia because they may produce
less spasm of the sphincter of Oddi than drugs such as Postcholecystectomy complications
morphine. Intravenous antibiotic therapy is usually indi-
Early complications following cholecystectomy include
cated in patients with severe acute cholecystitis, even
atelectasis and other pulmonary disorders, abscess for-
though bacterial superinfection of bile may not have
mation (often subphrenic), external or internal hem-
occurred in the early stages of the inflammatory pro-
orrhage, biliary-enteric fistula, and bile leaks. Jaundice
cess. Antibiotic therapy is guided by the most common
may indicate absorption of bile from an intraabdomi-
organisms likely to be present, which are E. coli, Klebsi-
nal collection following a biliary leak or mechanical
ella spp., and Streptococcus spp. Effective antibiotics
obstruction of the CBD by retained calculi, intraductal
include ureidopenicillins such as piperacillin or mezlo-
blood clots, or extrinsic compression.
cillin, ampicillin sulbactam, ciprofloxacin, moxifloxa-
Overall, cholecystectomy is a very successful opera-
cin, and third-generation cephalosporins. Anaerobic
tion that provides total or near-total relief of preopera-
coverage by a drug such as metronidazole should be
tive symptoms in 75–90% of patients. The most common
added if gangrenous or emphysematous cholecystitis is
cause of persistent postcholecystectomy symptoms
is an overlooked symptomatic nonbiliary disorder considered as indications for sphincterotomy include 467
(e.g., reflux esophagitis, peptic ulceration, pancreati- (1) prolonged duration of symptoms, (2) lack of
tis, or—most often—irritable bowel syndrome). In a response to symptomatic treatment, (3) presence of
small percentage of patients, however, a disorder of the severe disability, and (4) the patient’s choice of sphinc-
extrahepatic bile ducts may result in persistent symp- terotomy over surgery (given a clear understanding on
tomatology. These so-called postcholecystectomy syn- his or her part of the risks involved in both procedures).
dromes may be due to (1) biliary strictures, (2) retained Criteria for diagnosing dyskinesia of the sphincter of
biliary calculi, (3) cystic duct stump syndrome, (4) ste- Oddi are even more controversial than those for papil-
nosis or dyskinesia of the sphincter of Oddi, or (5) bile lary stenosis. Proposed mechanisms include spasm of the
CHAPTER 45
salt–induced diarrhea or gastritis. sphincter, denervation sensitivity resulting in hyperto-
nicity, and abnormalities of the sequencing or frequency
Cystic duct stump syndrome rates of sphincteric-contraction waves. When thorough
In the absence of cholangiographically demonstrable evaluation has failed to demonstrate another cause for
retained stones, symptoms resembling biliary pain or the pain, and when cholangiographic and manometric
cholecystitis in the postcholecystectomy patient have criteria suggest a diagnosis of biliary dyskinesia, medi-
frequently been attributed to disease in a long (>1 cm) cal treatment with nitrites or anticholinergics to attempt
both adenomyomatosis and cholesterolosis when symp- are at increased risk for the subsequent development of
tomatic or when cholelithiasis is present. cholangiocarcinoma.
The prevalence of gallbladder polyps in the adult
population is ∼5%, with a marked male predominance.
Few significant changes have been found over a 5-year Congenital biliary ectasia
period in asymptomatic patients with gallbladder polyps Dilatation of intrahepatic bile ducts may involve either
<10 mm in diameter. Cholecystectomy is recommended the major intrahepatic radicles (Caroli’s disease), the
Disorders of the Liver and Biliary Tree
in symptomatic patients, as well as in asymptomatic inter- and intralobular ducts (congenital hepatic fibro-
patients >50 years of age, or in those whose polyps are sis), or both. In Caroli’s disease, clinical manifestations
>10 mm in diameter or associated with gallstones or include recurrent cholangitis, abscess formation in and
polyp growth on serial ultrasonography. around the affected ducts, and, often, gallstone for-
mation within portions of ectatic intrahepatic biliary
radicles. Ultrasound, MRC, and CT are of great diag-
nostic value in demonstrating cystic dilatation of the
Diseases of the Bile Ducts intrahepatic bile ducts. Treatment with ongoing antibi-
otic therapy is usually undertaken in an effort to limit
Congenital Anomalies
the frequency and severity of recurrent bouts of chol-
Biliary atresia and hypoplasia angitis. Progression to secondary biliary cirrhosis with
Atretic and hypoplastic lesions of the extrahepatic and portal hypertension, extrahepatic biliary obstruction,
large intrahepatic bile ducts are the most common bili- cholangiocarcinoma, or recurrent episodes of sepsis with
ary anomalies of clinical relevance encountered in hepatic abscess formation is common.
infancy. The clinical picture is one of severe obstruc-
tive jaundice during the first month of life, with pale
Choledocholithiasis
stools. When biliary atresia is suspected on the basis of
clinical, laboratory, and imaging findings the diagnosis is Pathophysiology and clinical manifestations
confirmed by surgical exploration and operative cholan- Passage of gallstones into the CBD occurs in ∼10–15%
giography. Approximately 10% of cases of biliary atresia of patients with cholelithiasis. The incidence of com-
are treatable with roux-en-Y choledochojejunostomy, mon duct stones increases with increasing age of the
with the Kasai procedure (hepatic portoenterostomy) patient, so that up to 25% of elderly patients may have
being attempted in the remainder in an effort to restore calculi in the common duct at the time of cholecystec-
some bile flow. Most patients, even those having suc- tomy. Undetected duct stones are left behind in ∼1–5%
cessful biliary-enteric anastomoses, eventually develop of cholecystectomy patients. The overwhelming major-
chronic cholangitis, extensive hepatic fibrosis, and por- ity of bile duct stones are cholesterol stones formed
tal hypertension. in the gallbladder, which then migrate into the extra-
hepatic biliary tree through the cystic duct. Primary
calculi arising de novo in the ducts are usually pigment
Choledochal cysts
stones developing in patients with (1) hepatobiliary
Cystic dilatation may involve the free portion of the parasitism or chronic, recurrent cholangitis; (2) con-
CBD, i.e., choledochal cyst, or may present as diver- genital anomalies of the bile ducts (especially Caroli’s
ticulum formation in the intraduodenal segment. In disease); (3) dilated, sclerosed, or strictured ducts; or
the latter situation, chronic reflux of pancreatic juice (4) an MDR3 (ABCB4) gene defect leading to impaired
into the biliary tree can produce inflammation and ste- biliary phospholipids secretion (low phospholipid–
nosis of the extrahepatic bile ducts leading to cholan- associated cholelithiasis). Common duct stones may
gitis or biliary obstruction. Because the process may be remain asymptomatic for years, may pass spontaneously
gradual, ∼50% of patients present with onset of symp- into the duodenum, or (most often) may present with
toms after age 10. The diagnosis may be made by biliary colic or a complication.
Complications choledocholithiasis unless concomitant hepatic disease 469
Cholangitis
or another factor leading to marked hyperbilirubinemia
Cholangitis may be acute or chronic, and symptoms exists. Serum bilirubin levels ≥342.0 μmol/L (20 mg/
result from inflammation, which usually is caused by dL) should suggest the possibility of neoplastic obstruc-
at least partial obstruction to the flow of bile. Bacte- tion. The serum alkaline phosphatase level is almost
ria are present on bile culture in ∼75% of patients with always elevated in biliary obstruction. A rise in alkaline
acute cholangitis early in the symptomatic course. The phosphatase often precedes clinical jaundice and may
characteristic presentation of acute cholangitis involves be the only abnormality in routine liver function tests.
biliary pain, jaundice, and spiking fevers with chills There may be a two- to tenfold elevation of serum
CHAPTER 45
(Charcot’s triad). Blood cultures are frequently positive, aminotransferases, especially in association with acute
and leukocytosis is typical. Nonsuppurative acute cholangi- obstruction. Following relief of the obstructing process,
tis is most common and may respond relatively rapidly serum aminotransferase elevations usually return rap-
to supportive measures and to treatment with antibiot- idly to normal, while the serum bilirubin level may take
ics. In suppurative acute cholangitis, however, the presence 1–2 weeks to return to normal. The alkaline phos-
of pus under pressure in a completely obstructed duc- phatase level usually falls slowly, lagging behind the
decrease in serum bilirubin.
Hepatobiliary Ultrasound
Rapid Bowel gas None None Initial procedure of
Simultaneous scanning of GB, liver, Massive obesity choice in investigat-
bile ducts, pancreas Ascites ing possible biliary
Accurate identification of dilated bile Barium tract obstruction
SECTION VI
Abbreviations: CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; HBUS, hepatobiliary
ultrasound.
approach. It not only provides stone clearance but also of hemobilia may resolve without operative interven- 471
defines the anatomy of the biliary tree in relationship to the tion, surgical ligation of the bleeding vessel is frequently
cystic duct. CBD stones should be suspected in gallstone required.
patients who have any of the following risk factors: (1) a
history of jaundice or pancreatitis, (2) abnormal tests of
liver function, and (3) ultrasonographic or MRCP evi- Extrinsic Compression of
dence of a dilated CBD or stones in the duct. Alterna- the Bile Ducts
tively, if intraoperative cholangiography reveals retained Partial or complete biliary obstruction may be pro-
stones, postoperative ERCP can be carried out. The duced by extrinsic compression of the ducts. The most
CHAPTER 45
need for preoperative ERCP is expected to decrease common cause of this form of obstructive jaundice is
further as laparoscopic techniques for bile duct explora- carcinoma of the head of the pancreas. Biliary obstruc-
tion improve. tion may also occur as a complication of either acute
The widespread use of laparoscopic cholecystectomy or chronic pancreatitis or involvement of lymph nodes
and ERCP has decreased the incidence of complicated in the porta hepatis by lymphoma or metastatic carci-
biliary tract disease and the need for choledocholithot- noma. The latter should be distinguished from cholesta-
omy and T-tube drainage of the bile ducts. EBS fol- sis resulting from massive replacement of the liver by
mal strictures. Long-term treatment with glucocorti- creatic portion of the common bile duct, and (5) pancre-
coids and/or azathioprine may be needed after relapse atic duct involvement. Associated infectious organisms
or for inadequate response (Chap. 313). include Cryptosporidium, Mycobacterium avium-intracellulare,
Patients with primary sclerosing cholangitis often pres- cytomegalovirus, Microsporidia, and Isospora. In addition,
ent with signs and symptoms of chronic or intermittent acalculous cholecystitis occurs in up to 10% of patients.
biliary obstruction: RUQ abdominal pain, pruritus, jaun- ERCP sphincterotomy, while not without risk, pro-
dice, or acute cholangitis. Late in the course, complete vides significant pain reduction in patients with AIDS-
Disorders of the Liver and Biliary Tree
biliary obstruction, secondary biliary cirrhosis, hepatic associated papillary stenosis. Secondary sclerosing cholan-
failure, or portal hypertension with bleeding varices gitis may occur as a long-term complication of choledo-
may occur. The diagnosis is usually established by find- cholithiasis, cholangiocarcinoma, operative or traumatic
ing multifocal, diffusely distributed strictures with inter- biliary injury, or contiguous inflammatory processes.
vening segments of normal or dilated ducts, producing
a beaded appearance on cholangiography (Fig. 45-2D).
The cholangiographic techniques of choice in suspected Treatment Sclerosing Cholangitis
cases are MRCP and ERCP. When a diagnosis of scle-
rosing cholangitis has been established, a search for Therapy with cholestyramine may help control symp-
associated diseases, especially for chronic inflammatory toms of pruritus, and antibiotics are useful when chol-
bowel disease, should be carried out. angitis complicates the clinical picture. Vitamin D and
A recent study describes the natural history and out- calcium supplementation may help prevent the loss
come for 305 patients of Swedish descent with primary of bone mass frequently seen in patients with chronic
sclerosing cholangitis; 134 (44%) of the patients were cholestasis. Glucocorticoids, methotrexate, and cyclo-
asymptomatic at the time of diagnosis and, not surpris- sporine have not been shown to be efficacious in PSC.
ingly, had a significantly higher survival rate. The inde- UDCA in high dosage (20 mg/kg) improves serum
pendent predictors of a bad prognosis were age, serum liver tests, but an effect on survival has not been
bilirubin concentration, and liver histologic changes. documented. In cases where high-grade biliary obstruc-
Cholangiocarcinoma was found in 24 patients (8%). tion (dominant strictures) has occurred, balloon dila-
Inflammatory bowel disease was closely associated with tation or stenting may be appropriate. Only rarely is
primary sclerosing cholangitis and had a prevalence of surgical intervention indicated. Efforts at biliary-enteric
81% in this study population. anastomosis or stent placement may, however, be com-
Small duct PSC is defined by the presence of chronic plicated by recurrent cholangitis and further progres-
cholestasis and hepatic histology consistent with PSC sion of the stenosing process. The prognosis is unfavor-
but with normal findings on cholangiography. Small able, with a median survival of 9 to 12 years following
duct PSC is found in ∼5% of patients with PSC and the diagnosis, regardless of therapy. Four variables (age,
may represent an earlier stage of PSC associated with serum bilirubin level, histologic stage, and splenomeg-
a significantly better long-term prognosis. However, aly) predict survival in patients with PSC and serve as
such patients may progress to classic PSC and/or end- the basis for a risk score. PSC is one of the most com-
stage liver disease with consequent necessity of liver mon indications for liver transplantation.
transplantation.
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SECTION VII
Liver
Transplantation
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ChaPter 46
LIVER TRANSPLANTATION
476
Table 46-1 associated with inflammatory and fibrotic obstruction of 477
Indications for Liver Transplantation the biliary tree may be an indication for transplantation.
Because prior biliary surgery complicates and is a rela-
Children Adults
tive contraindication for liver transplantation, surgical
Biliary atresia Primary biliary cirrhosis diversion of the biliary tree has been all but abandoned
Neonatal hepatitis Secondary biliary cirrhosis for patients with sclerosing cholangitis. In patients who
Congenital hepatic fibrosis Primary sclerosing cholangitis undergo transplantation for hepatic vein thrombosis (Budd-
Alagille’s syndromea Autoimmune hepatitis
Byler’s diseaseb Caroli’s diseasec
Chiari syndrome), postoperative anticoagulation is essen-
α1-Antitrypsin deficiency Cryptogenic cirrhosis tial; underlying myeloproliferative disorders may have
Inherited disorders of Chronic hepatitis with to be treated but are not a contraindication to liver
metabolism cirrhosis transplantation. If a donor organ can be located quickly,
Wilson’s disease Hepatic vein thrombosis before life-threatening complications—including cere-
Tyrosinemia Fulminant hepatitis bral edema—set in, patients with acute liver failure are
Glycogen storage diseases Alcoholic cirrhosis candidates for liver transplantation. Routine candi-
Lysosomal storage Chronic viral hepatitis
dates for liver transplantation are patients with alcoholic
diseases
Protoporphyria Primary hepatocellular cirrhosis, chronic viral hepatitis, and primary hepatocellular
malignancies malignancies. Although all three of these categories are
CHAPTER 46
Crigler-Najjar disease Hepatic adenomas considered to be high risk, liver transplantation can be
type I offered to carefully selected patients. Currently, chronic
Familial hypercholester- Nonalcoholic hepatitis C and alcoholic liver disease are the most
olemia steatohepatitis common indications for liver transplantation, account-
Primary hyperoxaluria Familial amyloid
ing for over 40% of all adult candidates who undergo
type I polyneuropathy
Hemophilia
the procedure. Patients with alcoholic cirrhosis can
Liver Transplantation
be considered as candidates for transplantation if they
a
Arteriohepatic dysplasia, with paucity of bile ducts, and congenital
meet strict criteria for abstinence and reform; however,
malformations, including pulmonary stenosis. these criteria still do not prevent recidivism in up to a
b
Intrahepatic cholestasis, progressive liver failure, mental and growth quarter of cases. Patients with chronic hepatitis C have
retardation. early allograft and patient survival comparable to those
c
Multiple cystic dilatations of the intrahepatic biliary tree.
of other subsets of patients after transplantation; how-
ever, reinfection in the donor organ is universal, recur-
rent hepatitis C is insidiously progressive, the impact
Inherited or genetic disorders of metabolism associated with
of antiviral therapy is limited, allograft cirrhosis devel-
liver failure constitute another major indication for
ops in 20–30% at 5 years, and cirrhosis and late organ
transplantation in children and adolescents. In Crigler-
failure are being recognized with increasing frequency
Najjar disease type I and in certain hereditary disorders
beyond 5 years. In patients with chronic hepatitis B, in
of the urea cycle and of amino acid or lactate-pyruvate
the absence of measures to prevent recurrent hepatitis B,
metabolism, transplantation may be the only way
survival after transplantation is reduced by approxi-
to prevent impending deterioration of central ner-
mately 10–20%; however, prophylactic use of hepatitis B
vous system function, despite the fact that the native
immune globulin (HBIg) during and after transplanta-
liver is structurally normal. Combined heart and liver
tion increases the success of transplantation to a level
transplantation has yielded dramatic improvement in
comparable to that seen in patients with nonviral causes
cardiac function and in cholesterol levels in children
of liver decompensation. Specific oral antiviral drugs
with homozygous familial hypercholesterolemia; com-
(e.g., lamivudine, adefovir, entecavir, and tenofovir
bined liver and kidney transplantation has been suc-
disoproxil fumarate) (Chap. 40) can be used both for
cessful in patients with primary hyperoxaluria type I. In
prophylaxis against and for treatment of recurrent hepa-
hemophiliacs with transfusion-associated hepatitis and
titis B, facilitating further the management of patients
liver failure, liver transplantation has been associated
undergoing liver transplantation for end-stage hepatitis
with recovery of normal Factor VIII synthesis.
B; most transplantation centers rely on a combination
of HBIg and antiviral drugs to manage patients with
hepatitis B. Issues of disease recurrence are discussed in
Transplantation in Adults more detail later. Patients with nonmetastatic primary
Liver transplantation is indicated for end-stage cirrhosis hepatobiliary tumors—primary hepatocellular carcinoma
of all causes (Table 46-1). In sclerosing cholangitis and (HCC), cholangiocarcinoma, hepatoblastoma, angiosar-
Caroli’s disease (multiple cystic dilatations of the intra- coma, epithelioid hemangioendothelioma, and multiple
hepatic biliary tree), recurrent infections and sepsis or massive hepatic adenomata—have undergone liver
478 transplantation; however, for some hepatobiliary malig- Table 46-2
nancies, overall survival is significantly lower than that Contraindications to Liver Transplantation
for other categories of liver disease. Most transplanta-
Absolute Relative
tion centers have reported 5-year recurrence-free sur-
vival rates in patients with unresectable HCC for single Uncontrolled extrahepatobi- Age <70
tumors <5 cm in diameter or for three or fewer lesions liary infection
all <3 cm comparable to those seen in patients undergo- Active, untreated sepsis Prior extensive
hepatobiliary surgery
ing transplantation for nonmalignant indications. Con-
Uncorrectable, life-limiting Portal vein thrombosis
sequently, liver transplantation is currently restricted to congenital anomalies
patients whose hepatic malignancies meet these criteria. Active substance or alcohol Renal failure not attributable
Expanded criteria for patients with HCC are being abuse to liver disease
evaluated. Because the likelihood of recurrent cholan- Advanced cardiopulmonary Previous extrahepatic
giocarcinoma is very high, only highly selected patients disease malignancy (not including
with limited disease are being evaluated for transplanta- nonmelanoma skin cancer)
tion after intensive chemotherapy and radiation. Extrahepatobiliary Severe obesity
malignancy (not including
nonmelanoma skin cancer)
Metastatic malignancy to Severe malnutrition/
SECTION VII
CHAPTER 46
resources/professionalresources.asp?index=9.
liver histology preserved. Compatibility in ABO blood
group and organ size between donor and recipient are a
For children <18 years of age, status 1 includes acute or chronic
important considerations in donor selection; however, liver failure plus hospitalization in an intensive care unit or inborn
ABO-incompatible, split liver, or reduced-donor-organ errors of metabolism. Status 1 is retained for those persons with ful-
transplants can be performed in emergencies or marked minant hepatic failure and supersedes the MELD score.
b
The MELD scale is continuous, with 34 levels ranging between
donor scarcity. Tissue typing for human leukocyte 6 and 40. Donor organs usually do not become available unless the
Liver Transplantation
antigen (HLA) matching is not required, and preformed MELD score exceeds 20.
cytotoxic HLA antibodies do not preclude liver trans- c
Patients with stage T2 hepatocellular carcinoma receive 22 disease-
plantation. Following perfusion with cold electrolyte specific points. An α-fetoprotein level = 500 ng/mL is considered as
stage I hepatocellular carcinoma even without evidence for a tumor
solution, the donor liver is removed and packed in ice. on imaging.
The use of University of Wisconsin (UW) solution, rich d
Creatinine is included because renal function is a validated pre-
in lactobionate and raffinose, has permitted the exten- dictor of survival in patients with liver disease. For adults undergo-
sion of cold ischemic time up to 20 h; however, ing dialysis twice a week, the creatinine in the equation is set to
4 mg/100 mL.
12 h may be a more reasonable limit. Improved tech- e
For children <18 years of age, the Pediatric End-Stage Liver
niques for harvesting multiple organs from the same Disease (PELD) scale is used. This scale is based on albumin, bilirubin,
donor have increased the availability of donor livers, INR, growth failure, and age. Status 1 is retained.
but the availability of donor livers is far outstripped by
the demand. Currently in the United States, all donor
livers are distributed through a nationwide organ- mortality, to reduce waiting time prior to transplanta-
sharing network (United Network for Organ Sharing tion, to be the best predictor of pretransplantation mor-
[UNOS]) designed to allocate available organs based on tality, to satisfy the prevailing view that medical need
regional considerations and recipient acuity. Recipients should be the decisive determinant, and to eliminate
who have the highest disease severity generally have both the subjectivity inherent in the CTP scoring sys-
the highest priority, but allocation strategies that bal- tem (presence and degree of ascites and hepatic enceph-
ance highest urgency against best outcomes continue alopathy) and the differences in waiting times among
to evolve to distribute cadaver organs most effectively. different regions of the country. Recent data indicate
Allocation based on the Child-Turcotte-Pugh (CTP) that liver recipients with MELD scores <15 experienced
score, which uses five clinical variables (encephalopathy higher posttransplantation mortality rates than similarly
stage, ascites, bilirubin, albumin, and prothrombin time) classified patients who remained on the wait list. This
and waiting time, has been replaced by allocation based observation has led to the modification of UNOS pol-
on urgency alone, calculated by the Model for End- icy to allocate donor organs to candidates with MELD
Stage Liver Disease (MELD) score. The MELD score is scores exceeding 15 within the local or regional pro-
based on a mathematical model that includes bilirubin, curement organization before offering the organ to
creatinine, and prothrombin time expressed as interna- local patients whose scores are <15. In addition, serum
tional normalized ratio (INR) (Table 46-3). Neither sodium, another important predictor of survival in liver
waiting time (except as a tie breaker between two transplantation candidates, is taken into consideration in
potential recipients with the same MELD scores) nor allocating donor livers.
posttransplantation outcome is taken into account, but The highest priority (status 1) continues to be
the MELD score has been shown to reduce waiting list reserved for patients with fulminant hepatic failure
480 or primary graft nonfunction. Because candidates for Comprehensive outcome data on adult-to-adult living
liver transplantation who have HCC may not be suf- donor liver transplantation are being collected (www.
ficiently decompensated to compete for donor organs nih-a2all.org).
based on urgency criteria alone, and because pro-
tracted waiting for cadaver donor organs often results
in tumor growth beyond acceptable limits for trans-
Surgical Technique
plantation, such patients are assigned disease-specific
MELD points (Table 46-3). Removal of the recipient’s native liver is technically
difficult, particularly in the presence of portal hyper-
tension with its associated collateral circulation and
extensive varices and especially in the presence of
Living Donor Transplantation
scarring from previous abdominal operations. The
Occasionally, especially for liver transplantation in combination of portal hypertension and coagulopa-
children, one cadaver organ can be split between two thy (elevated prothrombin time and thrombocytope-
recipients (one adult and one child). A more viable nia) may translate into large blood product transfusion
alternative, transplantation of the right lobe of the liver requirements. After the portal vein and infrahepatic
from a healthy adult donor into an adult recipient, has and suprahepatic inferior vena cavae are dissected, the
SECTION VII
gained increased popularity. Living donor transplanta- hepatic artery and common bile duct are dissected.
tion of the left lobe (left lateral segment), introduced Then the native liver is removed and the donor organ
in the early 1990s to alleviate the extreme shortage of inserted. During the anhepatic phase, coagulopathy,
donor organs for small children, accounts currently for hypoglycemia, hypocalcemia, and hypothermia are
approximately one-third of all liver transplantation pro- encountered and must be managed by the anesthe-
cedures in children. Driven by the shortage of cadaver siology team. Caval, portal vein, hepatic artery, and
organs, living donor transplantation involving the more bile duct anastomoses are performed in succession, the
Liver Transplantation
sizable right lobe is being considered with increasing last by end-to-end suturing of the donor and recipient
frequency in adults; however, living donor liver trans- common bile ducts or by choledochojejunostomy to
plantation cannot be expected to solve the donor organ a Roux-en-Y loop if the recipient common bile duct
shortage; 219 such procedures were done in 2009, rep- cannot be used for reconstruction (e.g., in sclerosing
resenting only about 4% of all liver transplant operations cholangitis). A typical transplant operation lasts 8 h,
done in the United States. with a range of 6–18 h. Because of excessive bleed-
Living donor transplantation can reduce waiting ing, large volumes of blood, blood products, and
time and cold-ischemia time; is done under elective, volume expanders may be required during surgery;
rather than emergency, circumstances; and may be however, blood requirements have fallen sharply with
lifesaving in recipients who cannot afford to wait for improvements in surgical technique and experience.
a cadaver donor. The downside, of course, is the risk As noted earlier, emerging alternatives to ortho-
to the healthy donor (a mean of 10 weeks of medical topic liver transplantation include split-liver grafts, in
disability; biliary complications in ∼5%; postoperative which one donor organ is divided and inserted into two
complications such as wound infection, small-bowel recipients; and living donor procedures, in which part
obstruction, and incisional hernias in 9–19%; and of the left (for children), the left (for children or small
even, in 0.2–0.4%, death) as well as the increased fre- adults), or the right (for adults) lobe of the liver is har-
quency of biliary (15–32%) and vascular (10%) com- vested from a living donor for transplantation into the
plications in the recipient. Potential donors must recipient. In the adult procedure, once the right lobe is
participate voluntarily without coercion, and trans- removed from the donor, the donor right hepatic vein
plantation teams should go to great lengths to exclude is anastomosed to the recipient right hepatic vein rem-
subtle coercive or inappropriate psychological factors nant, followed by donor-to-recipient anastomoses of
as well as outline carefully to both donor and recipi- the portal vein and then the hepatic artery. Finally, the
ent the potential benefits and risks of the procedure. biliary anastomosis is performed, duct-to-duct if prac-
Donors for the procedure should be 18–60 years old; tical or via Roux-en-Y anastomosis. Heterotopic liver
have a compatible blood type with the recipient; have transplantation, in which the donor liver is inserted
no chronic medical problems or history of major without removal of the native liver, has met with very
abdominal surgery; be related genetically or emotion- limited success and acceptance, except in a very small
ally to the recipient; and pass an exhaustive series of number of centers. In attempts to support desperately
clinical, biochemical, and serologic evaluations to ill patients until a suitable donor organ can be identi-
unearth disqualifying medical disorders. The recipient fied, several transplantation centers are studying extra-
should meet the same UNOS criteria for liver trans- corporeal perfusion with bioartificial liver cartridges
plantation as recipients of a cadaver donor allograft. constructed from hepatocytes bound to hollow fiber
systems and used as temporary hepatic-assist devices, with the enterohepatic circulation of cyclosporine. As 481
but their efficacy remains to be established. Areas of a result, in most transplantation centers tacrolimus has
research with the potential to overcome the shortage now supplanted cyclosporine for primary immunosup-
of donor organs include hepatocyte transplantation and pression, and many centers rely on oral rather than IV
xenotransplantation with genetically modified organs of administration from the outset. For transplantation cen-
nonhuman origin (e.g., swine). ters that prefer cyclosporine, a better-absorbed micro-
emulsion preparation is now available.
Although more potent than cyclosporine, tacrolimus
is also more toxic and more likely to be discontinued
Postoperative Course for adverse events. The toxicity of tacrolimus is simi-
and Management lar to that of cyclosporine; nephrotoxicity and neuro-
toxicity are the most commonly encountered adverse
Immunosuppressive Therapy effects, and neurotoxicity (tremor, seizures, hallucina-
The introduction in 1980 of cyclosporine as an tions, psychoses, coma) is more likely and more severe
immunosuppressive agent contributed substantially to in tacrolimus-treated patients. Both drugs can cause
the improvement in survival after liver transplanta- diabetes mellitus, but tacrolimus does not cause hir-
tion. Cyclosporine, a calcineurin inhibitor (CNI), sutism or gingival hyperplasia. Because of overlapping
CHAPTER 46
blocks early activation of T cells and is specific for toxicity between cyclosporine and tacrolimus, especially
T cell functions that result from the interaction of the nephrotoxicity, and because tacrolimus reduces cyclo-
T cell with its receptor and that involve the calcium- sporine clearance, these two drugs should not be used
dependent signal transduction pathway. As a result, the together. Because 99% of tacrolimus is metabolized by
activity of cyclosporine leads to inhibition of lympho- the liver, hepatic dysfunction reduces its clearance; in
kine gene activation, blocking interleukins 2, 3, and primary graft nonfunction (when, for technical reasons
Liver Transplantation
4, tumor necrosis factor α, and other lymphokines. or because of ischemic damage prior to its insertion,
Cyclosporine also inhibits B cell functions. This pro- the allograft is defective and does not function normally
cess occurs without affecting rapidly dividing cells in from the outset), tacrolimus doses have to be reduced
the bone marrow, which may account for the reduced substantially, especially in children. Both cyclospo-
frequency of posttransplantation systemic infections. rine and tacrolimus are metabolized by the cytochrome
The most common and important side effect of cyclo- P450 IIIA system, and, therefore, drugs that induce
sporine therapy is nephrotoxicity. Cyclosporine causes cytochrome P450 (e.g., phenytoin, phenobarbital, car-
dose-dependent renal tubular injury and direct renal bamazepine, rifampin) reduce available levels of cyclo-
artery vasospasm. Following renal function is therefore sporine and tacrolimus; drugs that inhibit cytochrome
important in monitoring cyclosporine therapy, perhaps P450 (e.g., erythromycin, fluconazole, ketoconazole,
even a more reliable indicator than blood levels of the clotrimazole, itraconazole, verapamil, diltiazem, nicardip-
drug. Nephrotoxicity is reversible and can be man- ine, cimetidine, danazol, metoclopramide, bromocrip-
aged by dose reduction. Other adverse effects of cyclo- tine, and the HIV protease inhibitor ritonavir) increase
sporine therapy include hypertension, hyperkalemia, cyclosporine and tacrolimus blood levels. Indeed, itra-
tremor, hirsutism, glucose intolerance, and gingival conazole is used occasionally to help boost tacrolimus
hyperplasia. levels. Like azathioprine, cyclosporine and tacrolimus
Tacrolimus, a macrolide lactone antibiotic isolated appear to be associated with a risk of lymphoproliferative
from a Japanese soil fungus, Streptomyces tsukubaensis, malignancies (discussed later), which may occur earlier
has the same mechanism of action as cyclosporine but is after cyclosporine or tacrolimus than after azathioprine
10–100 times more potent. Initially applied as “rescue” therapy. Because of these side effects, combinations of
therapy for patients in whom rejection occurred despite cyclosporine or tacrolimus with prednisone and an anti-
the use of cyclosporine, tacrolimus was shown to be metabolite (azathioprine or mycophenolic acid, discussed
associated with a reduced frequency of acute, refrac- later)—all at reduced doses—are preferable regimens for
tory, and chronic rejection. Although patient and graft immunosuppressive therapy.
survival are the same with these two drugs, the advan- Mycophenolic acid, a nonnucleoside purine metab-
tage of tacrolimus in minimizing episodes of rejection, olism inhibitor derived as a fermentation product from
reducing the need for additional glucocorticoid doses, several Penicillium species, is another immunosuppressive
and reducing the likelihood of bacterial and cytomega- drug being used increasingly for patients undergoing
lovirus (CMV) infection has simplified the management liver transplantation. Mycophenolate has been shown
of patients undergoing liver transplantation. In addition, to be better than azathioprine, when used with other
the oral absorption of tacrolimus is more predictable standard immunosuppressive drugs, in preventing rejec-
than that of cyclosporine, especially during the early tion after renal transplantation and has been adopted
postoperative period when T-tube drainage interferes widely as well for use in liver transplantation. The most
482 common adverse effects of mycophenolate are bone with strict attention to the infectious consequences of
marrow suppression and gastrointestinal complaints. such therapy and careful confirmation of the diagno-
In patients with pretransplantation renal dysfunction sis of acute rejection. In this vein, efforts have been
or renal deterioration that occurs intraoperatively or made to minimize the use of glucocorticoids, a main-
immediately postoperatively, tacrolimus or cyclosporine stay of immunosuppressive regimens, and steroid-free
therapy may not be practical; under these circumstances, immunosuppression can be achieved in some instances.
induction or maintenance of immunosuppression with Patients who undergo liver transplantation for autoim-
antithymocyte globulin (ATG, thymoglobulin) or mune diseases such as primary biliary cirrhosis, autoim-
monoclonal antibodies to T cells, OKT3, may be appro- mune hepatitis, and primary sclerosing cholangitis are
priate. Therapy with these agents has been especially less likely to achieve freedom from glucocorticoids.
effective in reversing acute rejection in the posttransplant
period and is the standard treatment for acute rejec-
tion that fails to respond to methylprednisolone boluses. Postoperative Complications
Available data support the use of thymoglobulin induc- Complications of liver transplantation can be divided
tion to delay CNI use and its attendant nephrotoxicity. into nonhepatic and hepatic categories (Tables 46-4
IV infusions of thymoglobulin may be complicated by and 46-5). In addition, both immediate postop-
fever and chills, which can be ameliorated by premedi- erative and late complications are encountered. As a
SECTION VII
cation with antipyretics and a low dose of glucocorti- rule, patients who undergo liver transplantation have
coids. Infusions of OKT3 may be complicated by fever, been chronically ill for protracted periods and may be
chills, and diarrhea, or by pulmonary edema, which can
be fatal. Because OKT3 is such a potent immunosup-
pressive agent, its use is also more likely to be compli-
cated by opportunistic infection or lymphoproliferative Table 46-4
Liver Transplantation
CHAPTER 46
bilirubin (renal dysfunction) is mediated by donor intrahepatic lymphocytes that
Hepatic Dysfunction Unique to Liver Transplantation recognize red blood cell A or B antigens on recipient
Primary graft erythrocytes. Transient in nature, this process resolves
nonfunction once the donor liver is repopulated by recipient bone
Vascular Portal vein obstruction marrow–derived lymphocytes; the hemolysis can be
compromise Hepatic artery thrombosis treated by transfusing blood group O red blood cells
Anastomotic leak with
Liver Transplantation
and/or by administering higher doses of glucocorti-
intraabdominal bleeding coids. Transient thrombocytopenia is also commonly
Bile duct disorder Stenosis, obstruction, leak
Rejection
encountered. Aplastic anemia, a late occurrence, is rare
Recurrent primary but has been reported in almost 30% of patients who
hepatic disease underwent liver transplantation for acute, severe hepati-
tis of unknown cause.
Bacterial, fungal, or viral infections are common
and may be life-threatening postoperatively. Early after
malnourished and wasted. The impact of such chronic transplant surgery, common postoperative infections
illness and the multisystem failure that accompanies predominate—pneumonia, wound infections, infected
liver failure continue to require attention in the post- intraabdominal collections, urinary tract infections, and
operative period. Because of the massive fluid losses and IV line infections—rather than opportunistic infections;
fluid shifts that occur during the operation, patients these infections may involve the biliary tree and liver as
may remain fluid-overloaded during the immediate well. Beyond the first postoperative month, the toll of
postoperative period, straining cardiovascular reserve; immunosuppression becomes evident, and opportunis-
this effect can be amplified in the face of transient renal tic infections—CMV, herpes viruses, fungal infections
dysfunction and pulmonary capillary vascular permeability. (Aspergillus, Candida, cryptococcal disease), mycobacterial
Continuous monitoring of cardiovascular and pulmo- infections, parasitic infections (Pneumocystis, Toxoplasma),
nary function, measures to maintain the integrity of the bacterial infections (Nocardia, Legionella, and Listeria)—
intravascular compartment and to treat extravascular predominate. Rarely, early infections represent those
volume overload, and scrupulous attention to potential transmitted with the donor liver, either infections pres-
sources and sites of infection are of paramount impor- ent in the donor or infections acquired during pro-
tance. Cardiovascular instability may also result from the curement processing. De novo viral hepatitis infections
electrolyte imbalance that may accompany reperfusion acquired from the donor organ or, almost unheard of
of the donor liver as well as from restoration of systemic nowadays, from transfused blood products occur after
vascular resistance following implantation. Pulmonary typical incubation periods for these agents (well beyond
function may be compromised further by paralysis of the first month). Obviously, infections in an immuno-
the right hemidiaphragm associated with phrenic nerve suppressed host demand early recognition and prompt
injury. The hyperdynamic state with increased cardiac management; prophylactic antibiotic therapy is admin-
output that is characteristic of patients with liver failure istered routinely in the immediate postoperative period.
reverses rapidly after successful liver transplantation. Use of sulfamethoxazole with trimethoprim reduces the
Other immediate management issues include renal incidence of postoperative Pneumocystis carinii pneumo-
dysfunction. Prerenal azotemia, acute kidney injury nia. Antiviral prophylaxis for CMV with ganciclovir
484 should be administered in patients at high risk (e.g., anastomotic leak; stenosis, obstruction, or leakage of the
when a CMV-seropositive donor organ is implanted anastomosed common bile duct; recurrence of primary
into a CMV-seronegative recipient). hepatic disorder (discussed later); and rejection.
Neuropsychiatric complications include seizures
(commonly associated with cyclosporine and tacroli-
mus toxicity), metabolic encephalopathy, depression, Transplant Rejection
and difficult psychosocial adjustment. Rarely, diseases Despite the use of immunosuppressive drugs, rejection
are transmitted by the allograft from the donor to the of the transplanted liver still occurs in a proportion of
recipient. In addition to viral and bacterial infections, patients, beginning 1–2 weeks after surgery. Clinical
malignancies of donor origin have occurred. Posttrans- signs suggesting rejection are fever, right upper quad-
plantation lymphoproliferative disorders, especially B cell rant pain, and reduced bile pigment and volume.
lymphoma, are a recognized complication associated Leukocytosis may occur, but the most reliable indicators
with immunosuppressive drugs such as azathioprine, are increases in serum bilirubin and aminotransferase
tacrolimus, and cyclosporine (discussed earlier). Epstein- levels. Because these tests lack specificity, distinguish-
Barr virus has been shown to play a contributory role in ing among rejection, biliary obstruction, primary graft
some of these tumors, which may regress when immu- nonfunction, vascular compromise, viral hepatitis, CMV
nosuppressive therapy is reduced. De novo neoplasms infection, drug hepatotoxicity, and recurrent primary
SECTION VII
appear at increased frequency after liver transplanta- disease may be difficult. Radiographic visualization of
tion, particularly squamous cell carcinomas of the skin. the biliary tree and/or percutaneous liver biopsy often
Routine screening should be performed. help to establish the correct diagnosis. Morphologic fea-
Long-term complications after liver transplantation tures of acute rejection include a mixed portal cellular
attributable primarily to immunosuppressive medica- infiltrate, bile duct injury, and/or endothelial inflam-
tions include diabetes mellitus (associated with gluco- mation (“endothelialitis”); some of these findings are
Liver Transplantation
corticoids) as well as hypertension, hyperlipidemia, and reminiscent of graft-versus-host disease, primary biliary
chronic renal insufficiency (associated with cyclosporine cirrhosis, or recurrent allograft hepatitis C. As soon as
and tacrolimus). Monitoring and treating these disorders transplant rejection is suspected, treatment consists of
is a routine component of posttransplantation care; in IV methylprednisolone in repeated boluses; if this fails
some cases, they respond to changes in immunosuppres- to abort rejection, many centers use thymoglobulin or
sive regimen, while in others, specific treatment of the OKT3. Caution should be exercised when managing
disorder is introduced. acute rejection with pulse glucocorticoids or OKT3 in
patients with HCV infection, because of the high risk of
Hepatic Complications triggering recurrent allograft hepatitis C.
Chronic rejection is a relatively rare outcome that
Hepatic dysfunction after liver transplantation is similar can follow repeated bouts of acute rejection or that
to the hepatic complications encountered after major occurs unrelated to preceding rejection episodes. Mor-
abdominal and cardiothoracic surgery; however, in phologically, chronic rejection is characterized by
addition, hepatic complications include primary graft progressive cholestasis, focal parenchymal necrosis, mono-
failure, vascular compromise, failure or stricture of the nuclear infiltration, vascular lesions (intimal fibrosis,
biliary anastomoses, and rejection. As in nontransplant subintimal foam cells, fibrinoid necrosis), and fibrosis.
surgery, postoperative jaundice may result from pre This process may be reflected as ductopenia—the van-
hepatic, intrahepatic, and posthepatic sources. Prehepatic ishing bile duct syndrome. Reversibility of chronic
sources represent the massive hemoglobin pigment load rejection is limited; in patients with therapy-resistant
from transfusions, hemolysis, hematomas, ecchymoses, chronic rejection, retransplantation has yielded encour-
and other collections of blood. Early intrahepatic liver aging results.
injury includes effects of hepatotoxic drugs and anesthesia;
hypoperfusion injury associated with hypotension, sep-
sis, and shock; and benign postoperative cholestasis. Late
intrahepatic sources of liver injury include posttrans- Outcome
fusion hepatitis and exacerbation of primary disease.
Posthepatic sources of hepatic dysfunction include biliary Survival
obstruction and reduced renal clearance of conjugated The survival rate for patients undergoing liver trans-
bilirubin. Hepatic complications unique to liver trans- plantation has improved steadily since 1983. One-year
plantation include primary graft failure associated with survival rates have increased from ∼70% in the early
ischemic injury to the organ during harvesting; vascular 1980s to 85–90% from 2003 to 2009. Currently the
compromise associated with thrombosis or stenosis of 5-year survival rate exceeds 60%. An important obser-
the portal vein or hepatic artery anastomoses; vascular vation is the relationship between clinical status before
transplantation and outcome. For patients who undergo disordered iron metabolism has been observed in some 485
liver transplantation when their level of compensation patients with hemochromatosis. Hepatic vein throm-
is high (e.g., still working or only partially disabled), bosis (Budd-Chiari syndrome) may recur; this can be
a 1-year survival rate of >85% is common. For those minimized by treating underlying myeloproliferative
whose level of decompensation mandates continu- disorders and by anticoagulation. Because cholangiocar-
ous in-hospital care prior to transplantation, the 1-year cinoma recurs almost invariably, few centers now offer
survival rate is about 70%, while for those who are transplantation to such patients; however, a few highly
so decompensated that they require life support in an selected patients with operatively confirmed stage I or II
intensive care unit, the 1-year survival rate is ∼50%. cholangiocarcinoma who undergo liver transplantation
Since UNOS’s adoption in 2002 of the MELD sys- combined with neoadjuvant chemoradiation may expe-
tem for organ allocation, posttransplantation survival rience excellent outcomes. In patients with intrahepatic
has been found to be affected adversely for candidates hepatocellular carcinoma who meet criteria for trans-
with MELD scores >25, considered high disease severity. plantation, 1- and 5-year survivals are similar to those
Thus, irrespective of allocation scheme, high disease observed in patients undergoing liver transplantation
severity pretransplantation corresponds to diminished for nonmalignant disease. Finally, metabolic disorders
posttransplantation survival. Another important dis- such as nonalcoholic steatohepatitis recur frequently,
tinction in survival has been drawn between high- and especially if the underlying metabolic predisposition
CHAPTER 46
low-risk patient categories. For patients who do not fit is not altered. The metabolic syndrome occurs com-
any “high-risk” designations, 1-year and 5-year survival monly after liver transplantation as a result of recurrent
rates of 85 and 80%, respectively, have been recorded. nonalcoholic fatty liver, immunosuppressive medica-
In contrast, among patients in high-risk categories— tions, and/or, in patients with hepatitis C related to the
cancer, fulminant hepatitis, age >65, concurrent renal impact of HCV infection on insulin resistance, diabetes,
failure, respirator dependence, portal vein thrombosis, and fatty liver.
Liver Transplantation
and history of a portacaval shunt or multiple right upper Hepatitis A can recur after transplantation for ful-
quadrant operations—survival statistics fall into the minant hepatitis A, but such acute reinfection has
range of 60% at 1 year and 35% at 5 years. Survival after no serious clinical sequelae. In fulminant hepatitis B,
retransplantation for primary graft nonfunction is ∼50%. recurrence is not the rule; however, in the absence of
Causes of failure of liver transplantation vary with time. any prophylactic measures, hepatitis B usually recurs
Failures within the first 3 months result primarily from after transplantation for end-stage chronic hepatitis B.
technical complications, postoperative infections, and Before the introduction of prophylactic antiviral ther-
hemorrhage. Transplant failures after the first 3 months apy, immunosuppressive therapy sufficient to prevent
are more likely to result from infection, rejection, or allograft rejection led inevitably to marked increases
recurrent disease (such as malignancy or viral hepatitis). in hepatitis B viremia, regardless of pretransplantation
levels. Overall graft and patient survival were poor,
and some patients experienced a rapid recapitulation
Recurrence of Primary Disease of severe injury—severe chronic hepatitis or even ful-
Features of autoimmune hepatitis, primary sclerosing minant hepatitis—after transplantation. Also recog-
cholangitis, and primary biliary cirrhosis overlap with nized in the era before availability of antiviral regimens
those of rejection or posttransplantation bile duct injury. was fibrosing cholestatic hepatitis, rapidly progressive liver
Whether autoimmune hepatitis and sclerosing cho- injury associated with marked hyperbilirubinemia, sub-
angitis recur after liver transplantation is controversial; stantial prolongation of the prothrombin time (both
data supporting recurrent autoimmune hepatitis (in out of proportion to relatively modest elevations of
up to one-third of patients in some series) are more aminotransferase activity), and rapidly progressive liver
convincing than those supporting recurrent sclerosing failure. This lesion has been suggested to represent a
cholangitis. Similarly, reports of recurrent primary biliary “choking off” of the hepatocyte by an overwhelming
cirrhosis after liver transplantation have appeared; how- density of HBV proteins. Complications such as sep-
ever, the histologic features of primary biliary cirrhosis sis and pancreatitis were also observed more frequently
and chronic rejection are virtually indistinguishable and in patients undergoing liver transplantation for hepati-
occur as frequently in patients with primary biliary cir- tis B prior to the introduction of antiviral therapy. The
rhosis as in patients undergoing transplantation for other introduction of long-term prophylaxis with HBIg revo-
reasons. The presence of a florid inflammatory bile duct lutionized liver transplantation for chronic hepatitis B.
lesion is highly suggestive of the recurrence of primary Preoperative hepatitis B vaccination, preoperative or
biliary cirrhosis, but even this lesion can be observed in postoperative interferon (IFN) therapy, or short-term
acute rejection. Hereditary disorders such as Wilson’s (≤2 months) HBIg prophylaxis has not been shown
disease and α1-antitrypsin deficiency have not recurred to be effective, but a retrospective analysis of data
after liver transplantation; however, recurrence of from several hundred European patients followed for
486 3 years after transplantation has shown that long-term after lamivudine breakthrough. Currently, most liver
(≥6 months) prophylaxis with HBIg is associated with transplantation centers combine HBIg plus lamivu-
a lowering of the risk of HBV reinfection from ∼75% dine, adefovir, entecavir, or tenofovir disoproxil fuma-
to 35% and a reduction in mortality from ∼50% to 20%. rate. Clinical trials are underway to define the optimal
As a result of long-term HBIg use following liver application of these antiviral agents in the management
transplantation for chronic hepatitis B, similar improve- of patients undergoing liver transplantation for chronic
ments in outcome have been observed in the United hepatitis B; conceivably, in the future, combinations of
States, with 1-year survival rates between 75% and 90%. oral antiviral drugs may supplant HBIg.
Currently, with HBIg prophylaxis, the outcome of liver Prophylactic approaches applied to patients undergo-
transplantation for chronic hepatitis B is indistinguish- ing liver transplantation for chronic hepatitis B are being
able from that for chronic liver disease unassociated used as well for patients without hepatitis B who receive
with chronic hepatitis B; essentially, medical concerns organs from donors with anti-hepatitis B core (HBc).
regarding liver transplantation for chronic hepatitis B Patients who undergo liver transplantation for chronic
have been eliminated. Passive immunoprophylaxis with hepatitis B plus D are less likely to experience recurrent
HBIg is begun during the anhepatic stage of surgery, liver injury than patients undergoing liver transplanta-
repeated daily for the first 6 postoperative days, then tion for hepatitis B alone; still, such co-infected patients
continued with infusions that are given either at regu- would also be offered standard posttransplantation pro-
SECTION VII
lar intervals of 4–6 weeks or, alternatively, when anti- phylactic therapy for hepatitis B.
hepatitis B surface (HBs) levels fall below a threshold of Accounting for up to 40% of all liver transplanta-
100 mIU/mL. The current approach in most centers is tion procedures, the most common indication for liver
to continue HBIg indefinitely, which can add approxi- transplantation is end-stage liver disease resulting from
mately $20,000 per year to the cost of care; some cen- chronic hepatitis C. Recurrence of HCV infection
ters are evaluating regimens that shift to less frequent after liver transplantation can be documented in almost
Liver Transplantation
administration or to IM administration in the late post- every patient. The clinical consequences of recur-
transplantation period or, in low-risk patients, mainte- rent hepatitis C are limited during the first 5 years after
nance with antiviral therapy (discussed later) alone. Still, transplantation. Nonetheless, despite the relative clini-
“breakthrough” HBV infection occasionally occurs. cal benignity of recurrent hepatitis C in the early years
Further improving the outcome of liver transplanta- after liver transplantation, and despite the negligible
tion for chronic hepatitis B is the current availability of impact on patient survival during these early years,
such antiviral drugs as lamivudine, adefovir, entecavir, histologic studies have documented the presence of
and tenofovir disoproxil fumarate (Chap. 40). When moderate to severe chronic hepatitis in more than one-
these drugs are administered to patients with decom- half of all patients and bridging fibrosis or cirrhosis in
pensated liver disease, a proportion improve sufficiently ∼10%. Moreover, progression to cirrhosis within 5 years
to postpone imminent liver transplantation. In addi- is even more common, occurring in up to two-thirds
tion, lamivudine can be used to prevent recurrence of of patients if moderate hepatitis is detected in a 1-year
HBV infection when administered prior to transplan- biopsy. Not surprisingly, then, for patients undergo-
tation; to treat hepatitis B that recurs after transplanta- ing transplantation for hepatitis C, allograft and patient
tion, including in patients who break through HBIg survival are diminished substantially between 5 and
prophylaxis; and to reverse the course of otherwise fatal 10 years after transplantation. In a proportion of patients,
fibrosing cholestatic hepatitis. Clinical trials have shown even during the early posttransplantation period, recur-
that lamivudine antiviral therapy reduces the level of rent hepatitis C may be sufficiently severe biochemically
HBV replication substantially, sometimes even result- and histologically to merit antiviral therapy. Treatment
ing in clearance of hepatitis B surface antigen (HBsAg); with pegylated interferon (IFN) can suppress HCV-
reduces alanine aminotransferase (ALT) levels; and associated liver injury but rarely leads to sustained
improves histologic features of necrosis and inflam- benefit. Sustained virologic responses are the exception,
mation. Long-term use of lamivudine is safe and effec- and reduced tolerability is often dose-limiting. Preemp-
tive, but after several months a proportion of patients tive combination antiviral therapy with pegylated IFN
become resistant to lamivudine, resulting from YMDD and the nucleoside analogue ribavirin immediately after
(tyrosine-methionine-aspartate-aspartate) mutations in the transplantation does not appear to provide any advan-
HBV polymerase motif (Chap. 40). In approximately tage over therapy introduced after clinical hepatitis
one-half of such resistant patients, hepatic deterioration has occurred. Similarly, although IFN-based antiviral
may ensue. Fortunately, adefovir or tenofovir disoproxil therapy is not recommended for patients with decom-
fumarate are available as well and can be used to treat pensated liver disease, some centers have experimented
lamivudine-associated YMDD variants, effectively “res- with pretransplantation antiviral therapy in an attempt
cuing” patients experiencing hepatic decompensation to eradicate HCV replication prior to transplantation;
preliminary results are promising, but IFN treatment of liver transplantation procedures, and most transplanta- 487
patients with end-stage liver disease can lead to worsening tion centers screen candidates carefully for predictors
of hepatic decompensation, and HCV infection has of continued abstinence. Recidivism is more likely in
recurred after transplantation in some of these recipients. patients whose sobriety prior to transplantation was
Trials of hepatitis C immune globulin preparations to <6 months. For abstinent patients with alcoholic cir-
prevent recurrent hepatitis C after liver transplantation rhosis, liver transplantation can be undertaken success-
have not been successful. fully, with outcomes comparable to those for other
A small number succumb to early HCV-associated categories of patients with chronic liver disease, when
liver injury, and a syndrome reminiscent of fibrosing coordinated by a team approach that includes substance
cholestatic hepatitis (discussed earlier) has been observed abuse counseling.
rarely. Because patients with more episodes of rejection
receive more immunosuppressive therapy, and because
Posttransplantation Quality of Life
immunosuppressive therapy enhances HCV replication,
patients with severe or multiple episodes of rejection are Full rehabilitation is achieved in the majority of
more likely to experience early recurrence of hepatitis C patients who survive the early postoperative months
after transplantation. Both high viral levels and older and escape chronic rejection or unmanageable infec-
donor age have been linked to recurrent HCV-induced tion. Psychosocial maladjustment interferes with medi-
CHAPTER 46
liver disease and to earlier disease recurrence after cal compliance in a small number of patients, but
transplantation. most manage to adhere to immunosuppressive regi-
Patients who undergo liver transplantation for end- mens, which must be continued indefinitely. In one
stage alcoholic cirrhosis are at risk of resorting to drink- study, 85% of patients who survived their transplant
ing again after transplantation, a potential source of operations returned to gainful activities. In fact, some
recurrent alcoholic liver injury. Currently, alcoholic women have conceived and carried pregnancies to
Liver Transplantation
liver disease is one of the more common indications term after transplantation without demonstrable injury
for liver transplantation, accounting for 20–25% of all to their infants.
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SECTION VIII
Disorders of the
pancreas
CHAPTER 47
gENEral CONSIDEraTIONS More than 90% of the pancreas must be damaged before
maldigestion of fat and protein is manifested. Non-
As emphasized in Chap. 48, the etiologies as well as invasive, indirect tests of pancreatic exocrine function
the clinical manifestations of pancreatitis are quite varied. (fecal elastase) are much more likely to give abnormal
Although it is well-appreciated that pancreatitis is fre- results in patients with obvious pancreatic disease (i.e.,
quently secondary to biliary tract disease and alcohol pancreatic calcification, steatorrhea, or diabetes mellitus,
abuse, it can also be caused by drugs, trauma, and viral than in patients with occult disease). Thus, the number
infections and is associated with metabolic and connec- of patients who have subclinical exocrine dysfunction
tive tissue disorders. In ∼30% of patients with acute (<90% loss of function) is unknown.
pancreatitis and 25–40% of patients with chronic pan-
creatitis, the etiology initially can be obscure.
Although good data exist concerning the incidence TESTS USEfUl IN ThE DIagNOSIS Of
of acute pancreatitis (about 5–35/100,000 new cases PaNCrEaTIC DISEaSE
per year worldwide, with a mortality rate of about 3%),
Several tests have proved of value in the evaluation of
the number of patients who suffer with acute pancre-
pancreatic disease. Examples of specific tests and their
atitis is largely increasing and is now estimated to be
usefulness in the diagnosis of acute and chronic pan-
70 hospitalizations/100,000 persons annually, resulting
creatitis are summarized in Table 47-1 and Fig. 47-1.
in >200,000 new cases of acute pancreatitis per year in
At some institutions, pancreatic-function tests are available
the United States. Only one prospective study on the
and performed if the diagnosis of pancreatic disease remains
incidence of chronic pancreatitis is available; it showed
a possibility after noninvasive tests (ultrasound, CT, mag-
an incidence of 8.2 new cases per 100,000 per year and
netic resonance cholangiopancreatography [MRCP])
a prevalence of 26.4 cases per 100,000. These numbers
or invasive tests (endoscopic retrograde cholangiopancrea-
probably underestimate considerably the true incidence
tography [ERCP], endoscopic ultrasonography [EUS])
and prevalence, because non alcohol–induced pancreati-
have given normal or inconclusive results. In this
tis has been largely ignored. At autopsy, the prevalence
regard, tests employing direct stimulation of the pancreas
of chronic pancreatitis ranges from 0.04 to 5%. The
are the most sensitive.
relative inaccessibility of the pancreas to direct exami-
nation and the nonspecificity of the abdominal pain
associated with pancreatitis make the diagnosis of pan- Pancreatic enzymes in body fluids
creatitis difficult and usually dependent on elevation of The serum amylase and lipase levels are widely used
blood amylase and/or lipase levels. Many patients with as screening tests for acute pancreatitis in the patient
chronic pancreatitis do not have elevated blood amylase with acute abdominal pain or back pain. Values
or lipase levels. Some patients with chronic pancreati- greater than three times the upper limit of normal
tis develop signs and symptoms of pancreatic exocrine virtually clinch the diagnosis if gut perforation or
insufficiency, and, thus, objective evidence for pancre- infarction is excluded. In acute pancreatitis, the serum
atic disease can be demonstrated. However, there is a amylase and lipase are usually elevated within 24 h
very large reservoir of pancreatic exocrine function. of onset and remain so for 3–7 days. Levels usually
490
Table 47-1 491
Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Tumors
Test Principle Comment
CHAPTER 47
3. Ultrasonography (US) Can provide information on Simple, noninvasive; sequential studies quite
edema, inflammation, calcification, feasible; useful in diagnosis of pseudocyst
pseudocysts, and mass lesions limited by interference by bowel gas
4. CT scan Permits detailed visualization of Useful in the diagnosis of pancreatic calcifica-
pancreas and surrounding structures, tion, dilated pancreatic ducts, and pancreatic
pancreatic fluid collection, pseudo- tumors; may not be able to distinguish between
cyst, degree of necrosis inflammatory and neoplastic mass lesions
(continued)
492 Table 47-1
Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Tumors
(continued)
Test Principle Comment
2. Endoscopic secretin—CCK Replaces need for tube placement Sensitive enough to detect occult disease;
test duodenum avoids intubation and fluoroscopy; requires
sedation
Measurement of intraluminal digestion products
1. Microscopic examination Lack of proteolytic and lipolytic Simple, reliable; not sensitive enough to detect
of stool for undigested meat enzymes causes decreased digestion milder cases of pancreatic insufficiency
fibers and fat of meat fibers and triglycerides
2. Quantitative stool fat Lack of lipolytic enzymes brings about Reliable, reference standard for defining severity
determination impaired fat digestion of malabsorption; does not distinguish between
maldigestion and malabsorption
3. Fecal nitrogen Lack of proteolytic enzymes leads to Does not distinguish between maldigestion and
impaired protein digestion, resulting in malabsorption; low sensitivity
an increase in stool nitrogen
Measurement of pancreatic enzymes in feces
1. Elastase Pancreatic secretion of proteolytic Good sensitivity if stools not liquid
enzymes; not degraded in intestine
return to normal within 7 days unless there is pancre- a nonpancreatic source of amylase, especially when the
atic ductal disruption, ductal obstruction, or pseudo- blood amylase level is only moderately elevated.
cyst formation. Approximately 85% of patients with Elevation of ascitic fluid amylase occurs in acute pan-
acute pancreatitis have a threefold or greater elevated creatitis as well as in (1) pancreatogenous ascites due
Disorders of the Pancreas
serum amylase and lipase levels. The values may be to disruption of the main pancreatic duct or a leaking
normal if (1) there is a delay (of 2–5 days) before pseudocyst and (2) other abdominal disorders that sim-
blood samples are obtained, (2) the underlying disor- ulate pancreatitis (e.g., intestinal obstruction, intestinal
der is chronic pancreatitis rather than acute pancre- infarction, or perforated peptic ulcer). Elevation of pleu-
atitis, or (3) hypertriglyceridemia is present. Patients ral fluid amylase can occur in acute pancreatitis, chronic
with hypertriglyceridemia and proven pancreatitis have pancreatitis, carcinoma of the lung, and esophageal
been found to have spuriously low levels of amylase perforation.
and perhaps lipase activity. In the absence of objective Lipase may now be the single best enzyme to measure
evidence of pancreatitis by abdominal ultrasound, CT for the diagnosis of acute pancreatitis. Improvements
scan, MRCP, or EUS, mild to moderate elevations in substrates and technology offer clinicians improved
of amylase, and/or lipase are not helpful in making a options, especially when a turbidimetric assay is used.
diagnosis of chronic pancreatitis. The newer lipase assays have colipase as a cofactor and
The serum amylase can be elevated in other con- are fully automated.
ditions (Table 47-2), in part because the enzyme is No single blood test is reliable for the diagnosis
found in many organs. In addition to the pancreas and of acute pancreatitis in patients with renal failure.
salivary glands, small quantities of amylase are found Determining whether a patient with renal failure and
in the tissues of the fallopian tubes, lung, thyroid, abdominal pain has pancreatitis remains a difficult
and tonsils and can be produced by various tumors clinical problem. One study found that serum amylase
(carcinomas of the lung, esophagus, breast, and ovary). levels were elevated in patients with renal dysfunc-
Urinary amylase measurements, including the amylase/ tion only when creatinine clearance was <0.8 mL/s
creatinine clearance ratio, are no more sensitive or spe- (<50 mL/min). In such patients, the serum amylase
cific than blood amylase levels and are rarely employed. level was invariably <8.3 μkat/L (<500 IU/L) in the
Isoamylase determinations do not accurately distin- absence of objective evidence of acute pancreatitis. In
guish elevated blood amylase levels due to bona fide that study, serum lipase and trypsin levels paralleled
pancreatitis from elevated blood amylase levels due to serum amylase values. With these limitations in mind,
• Clinical signs and symptoms suggestive of chronic pancreatic disease: abdominal pain, weight loss, steatorrhea,
493
malabsorption, history of alcohol abuse, recurrent pancreatitis, fatty-food intolerance
• Perform history, physical exam, review of laboratory studies, consider fecal elastase measurement
• CT Scan
• CP Diagnostic criteria: calcifications in combination with atrophy and/or dilated duct
Step 1
• Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results; continue to Step 2
• Pancreas Function Test (with secretin)—gastroduodenal (SST) or endoscopic (ePFT) collection method
• CP Diagnostic criteria: peak [bicarbonate] <80 meq/L
Step 4 • Diagnostic criteria met; no further imaging needed
• Inconclusive or nondiagnostic results; continue to Step 5
CHAPTER 47
• Note: Consider combining ePFT with EUS
Chronic Pancreatitis
Figure 47-1
A step-wise diagnostic approach to the patient with sus- (sMRCP/MRCP) are appropriate diagnostic alternatives to
pected chronic pancreatitis (CP). Endoscopic ultrasonogra endoscopic retrograde cholangiopancreatography (ERCP).
phy (EUS) and magnetic resonance cholangiopancreatography
the recommended screening tests for acute pancreati- pseudocysts, and pancreatic carcinoma. Echographic
tis are serum lipase and serum amylase levels. Serum lipase appearances can indicate the presence of edema, inflam-
and amylase values greater than three times normal are mation, and calcification (not obvious on plain films of
highly specific. the abdomen), as well as pseudocysts, mass lesions, and
gallstones. In acute pancreatitis, the pancreas is charac-
teristically enlarged. In pancreatic pseudocyst, the usual
Studies pertaining to pancreatic structure appearance is primarily that of smooth, round fluid col-
Radiologic tests lection. Pancreatic carcinoma distorts the usual land-
Plain films of the abdomen, which once provided useful marks, and mass lesions >3.0 cm are usually detected
information in patients with acute and chronic pancre- as localized, solid lesions. Ultrasound is often the initial
atitis, have been superceded by other detailed imaging investigation for most patients with suspected pancreatic
procedures (US, EUS, CT, MRCP). disease. However, obesity and excess small- and large-
Ultrasonography can provide important information bowel gas can interfere with pancreatic imaging by
in patients with acute pancreatitis, chronic pancreatitis, ultrasound studies.
494 Table 47-2 contrast) is useful in estimating the extent of pancre-
Causes of Hyperamylasemia and atic necrosis and in predicting morbidity and mortality.
Hyperamylasuria Spiral (helical) CT provides clear images much more
Pancreatic Disease rapidly and essentially negates artifact caused by patient
I. Pancreatitis II. Pancreatic
movement.
A. Acute trauma EUS produces high-resolution images of the pancre-
B. Chronic: ductal III. Pancreatic atic parenchyma and pancreatic duct with a transducer
obstruction carcinoma fixed to an endoscope that can be directed onto the
C. Complications of surface of the pancreas through the stomach or duode-
pancreatitis num. EUS and MRCP have largely replaced ERCP for
1. Pancreatic pseudocyst diagnostic purposes in many centers. EUS allows one to
2. Pancreatogenous
ascites
obtain information about the pancreatic duct as well as
3. Pancreatic abscess the parenchyma and has few procedure-related compli-
4. Pancreatic necrosis cations associated with it, in contrast to the 5–20% of
Nonpancreatic Disorders
post-ERCP pancreatitis observed. EUS is also helpful in
detecting common bile duct stones. Pancreatic masses
I. Renal insufficiency IV. Macroamylasemia
can be biopsied via EUS and one can deliver nerve-
II. Salivary gland lesions V. Burns
A. Mumps VI. Diabetic
blocking agents through EUS fine-needle injection.
B. Calculus ketoacidosis Criteria for abnormalities on EUS in severe chronic
C. Irradiation sialadenitis VII. Pregnancy pancreatic disease have been developed. Currently,
D. Maxillofacial surgery VIII. Renal chronic pancreatitis is considered diagnosed by EUS if
III. “Tumor” hyperamylasemia transplantation five or more criteria listed in Table 47-3 are present.
A. Carcinoma of the lung IX. Cerebral trauma Recent studies comparing EUS and ERCP to the secre-
B. Carcinoma of the X. Drugs: morphine tin test in patients with unexplained abdominal pain
esophagus
suspected of having chronic pancreatitis show equiva-
SECTION VIII
C. Breast carcinoma,
ovarian carcinoma lent diagnostic accuracy in detecting early changes of
chronic pancreatitis. The exact role of EUS versus CT,
ERCP, or function testing in the early diagnosis of
Other Abdominal Disorders chronic pancreatitis has yet to be clearly defined.
I. Biliary tract disease: cholecystitis, choledocholithiasis MRCP/MRI is now being used to view the bile
II. Intraabdominal disease ducts, pancreatic duct, and the pancreas parenchyma.
Disorders of the Pancreas
A. Perforated or penetrating peptic ulcer Non breath–holding and three-dimensional turbo spin-
B. Intestinal obstruction or infarction echo techniques are being used to produce superb MRCP
C. Ruptured ectopic pregnancy images. The main pancreatic duct and common bile duct
D. Peritonitis
can be seen well, but there is still a question as to whether
E. Aortic aneurysm
F. Chronic liver disease
changes can be detected consistently in the secondary
G. Postoperative hyperamylasemia ducts. The secondary ducts are not visualized in a nor-
mal pancreas. MRCP may be particularly useful to eval-
uate the pancreatic duct in high-risk patients such as the
elderly because this is a noninvasive procedure. Secretin
CT is the best imaging study for initial evaluation of enhanced MRCP is currently under investigation but is
a suspected pancreatic disorder and for the complica- emerging as a method to better evaluate ductal changes.
tions of acute and chronic pancreatitis. It is especially
useful in the detection of pancreatic and peripancre- Table 47-3
atic acute fluid collections, fluid-containing lesions
Endoscopic Ultrasonographic Criteria for
such as pseudocysts, walled-off necrosis, calcium Chronic Pancreatitis
deposits (see Chap. 48, Figs. 48-1, 48-2, and 48-4),
and pancreatic neoplasms. Most lesions are charac- Ductal Parenchymal
terized by (1) enlargement of the pancreatic outline, Stones Echogenic strands
(2) distortion of the pancreatic contour, and/or (3) a Echogenic ductal walls Echogenic foci
fluid filling that has a different attenuation coefficient
Irregular ductal walls Calcifications
than normal pancreas. Oral, water-soluble contrast
agents are used to opacify the stomach and duode- Stricture Lobular contour
num during CT scans; this strategy permits more Visible side branches Cyst
precise delineation of various organs as well as mass Ductular dilatation
lesions. Dynamic CT (using rapid IV administration of
Both EUS and MRCP have largely replaced diag- Tests of Exocrine Pancreatic 495
nostic ERCP in most patients. As these techniques Function
become more refined, they may well be the diagnos-
tic tests of choice to evaluate the pancreatic duct. Pancreatic function tests (Table 47-1) can be divided
ERCP is still needed for treatment of bile duct and into the following:
pancreatic duct lesions. ERCP is primarily of thera- 1. Direct stimulation of the pancreas by IV infusion of
peutic value after CT, EUS, or MRCP have detected secretin or secretin plus cholecystokinin (CCK) fol-
abnormalities requiring invasive endoscopic treatment. lowed by collection and measurement of duodenal
ERCP can also be helpful at clarification of equivo- contents
cal findings discovered with other imaging techniques 2. Study of intraluminal digestion products, such as undi-
(see Chap. 48, Figs. 48-1C, 48-3D, and 48-4B). Pan- gested meat fibers, stool fat, and fecal nitrogen
creatic carcinoma is characterized by stenosis or 3. Measurement of fecal pancreatic enzymes such as elastase
obstruction of either the pancreatic duct or the com-
mon bile duct; both ductal systems are often abnormal. The secretin test, used to detect diffuse pancre-
In chronic pancreatitis, ERCP abnormalities include atic disease, is based on the physiologic principle that
(1) luminal narrowing; (2) irregularities in the ductal the pancreatic secretory response is directly related to
system with stenosis, dilation, sacculation, and ecta- the functional mass of pancreatic tissue. In the stan-
sia; and (3) blockage of the pancreatic duct by calcium dard assay, secretin is given IV in a dose of 0.2 μg/kg
deposits. The presence of ductal stenosis and irregularity of synthetic human secretin as a bolus. Normal values
can make it difficult to distinguish chronic pancre- for the standard secretin test are (1) volume output
atitis from carcinoma. It is important to be aware that >2 mL/kg per hour, (2) bicarbonate (HCO3–) con-
ERCP changes interpreted as indicating chronic pan- centration >80 mmol/L, and (3) HCO3– output
creatitis actually may be due to the effects of aging on >10 mmol/L in 1 h. The most reproducible mea-
the pancreatic duct or to the fact that the procedure surement, giving the highest level of discrimination
was performed within several weeks of an attack of between normal subjects and patients with chronic pan-
CHAPTER 47
acute pancreatitis. Although aging may cause impressive creatic exocrine insufficiency, appears to be the maxi-
ductal alterations, it does not affect the results of pan- mal bicarbonate concentration.
creatic function tests (i.e., the secretin test). Elevated There may be a dissociation between the results of
serum amylase levels after ERCP have been reported the secretin test and other tests of absorptive function.
in 25–75% of patients, and clinical pancreatitis in 5–20% For example, patients with chronic pancreatitis often
of patients. There are no satisfactory means to pharma- have abnormally low outputs of HCO3– after secretin
but have normal fecal fat excretion. Thus the secretin
BiocheMistry And PhysioLoGy of primarily on nerves outside the pancreas, somatostatin acts
PAncreAtic exocrine secretion at multiple sites. Nitric oxide (NO) is also an important
neurotransmitter. The mechanism of action of these vari-
GenerAl considerAtions ous factors has not been fully defined.
The pancreas secretes 1500–3000 mL of isosmotic alka-
line (pH >8) fluid per day containing about 20 enzymes.
WAter And electrolyte secretion
The pancreatic secretions provide the enzymes needed
to effect the major digestive activity of the gastrointesti- Bicarbonate is the ion of primary physiologic impor-
nal tract and provide an optimal pH for the function of tance within pancreatic secretion. The ductal cells
these enzymes. secrete bicarbonate predominantly derived from plasma
(93%) more than from intracellular metabolism (7%).
Bicarbonate enters through the sodium bicarbonate
reGulAtion of pAncreAtic secretion cotransporter with depolarization caused by chloride
efflux through the cystic fibrosis transmembrane con-
The exocrine pancreas is influenced by intimately inter- ductance regulator (CFTR). Secretin and VIP, both
acting hormonal and neural systems. Gastric acid is the of which increase intracellular cyclic AMP, act on the
stimulus for the release of secretin from the duodenum, ductal cells opening the CFTR in promoting secretion.
which stimulates the secretion of water and electrolytes CCK, acting as a neuromodulator, markedly potenti-
from pancreatic ductal cells. Release of cholecystoki- ates the stimulatory effects of secretin. Acetylcholine
nin (CCK) from the duodenum and proximal jejunum also plays an important role in ductal cell secretion.
is largely triggered by long-chain fatty acids, certain Bicarbonate helps neutralize gastric acid and creates the
essential amino acids (tryptophan, phenylalanine, valine, appropriate pH for the activity of pancreatic enzymes
methionine), and gastric acid itself. CCK evokes an and bile salts.
enzyme-rich secretion from acinar cells in the pancreas.
The parasympathetic nervous system (via the vagus nerve)
exerts significant control over pancreatic secretion.
enzyme secretion
Secretion evoked by secretin and CCK depends on
permissive roles of vagal afferent and efferent pathways. The acinar cell is highly compartmentalized and is
This is particularly true for enzyme secretion, whereas concerned with the secretion of pancreatic enzymes.
water and bicarbonate secretions are heavily depen- Proteins synthesized by the rough endoplasmic reticu-
dent on the hormonal effects of secretin and to a lesser lum are processed in the Golgi and then targeted to
extent CCK. Also, vagal stimulation effects the release the appropriate site, whether that be zymogen gran-
of vasoactive intestinal peptide (VIP), a secretin agonist. ules, lysosomes, or other cell compartments. The pan-
Pancreatic exocrine secretion is influenced by inhibitory creas secretes amylolytic, lipolytic, and proteolytic
neuropeptides such as somatostatin, pancreatic polypeptide, enzymes. Amylolytic enzymes such as amylase, hydro-
peptide YY, neuropeptide Y, enkephalin, pancreastatin, lyze starch to oligosaccharides and to the disaccharide
calcitonin gene–related peptides, glucagon, and galanin. maltose. The lipolytic enzymes include lipase, phospho-
Although pancreatic polypeptide and peptide YY may act lipase A2, and cholesterol esterase. Bile salts inhibit
496
lipase in isolation, but colipase, another constituent of Enteropancreatic Axis and 497
pancreatic secretion, binds to lipase and prevents this Feedback Inhibition
inhibition. Bile salts activate phospholipase A and cho-
lesterol esterase. Proteolytic enzymes include endopep- Pancreatic enzyme secretion is controlled, at least in
tidases (trypsin, chymotrypsin), which act on internal part, by a negative feedback mechanism induced by the
peptide bonds of proteins and polypeptides; exopep- presence of active serine proteases in the duodenum.
tidases (carboxypeptidases, aminopeptidases), which To illustrate, perfusion of the duodenal lumen with
act on the free carboxyl- and amino-terminal ends of phenylalanine causes a prompt result in increased plasma
peptides, respectively; and elastase. The proteolytic CCK levels as well as increased secretion of chymo-
enzymes are secreted as inactive precursors and pack- trypsin and other pancreatic enzymes. However, simul-
aged as zymogens. Ribonucleases (deoxyribonucle- taneous perfusion with trypsin blunts both responses.
ases, ribonuclease) are also secreted. Enterokinase, an Conversely, perfusion of the duodenal lumen with
enzyme found in the duodenal mucosa, cleaves the protease inhibitors actually leads to enzyme hypersecre-
lysine-isoleucine bond of trypsinogen to form trypsin. tion. The available evidence supports the concept that
Trypsin then activates the other proteolytic zymo- the duodenum contains a peptide called CCK-releasing
gens and phospholipase A2 in a cascade phenomenon. factor (CCK-RF) that is involved in stimulating CCK
All pancreatic enzymes have pH optima in the alka- release. It appears that serine proteases inhibit pancre-
line range. The nervous system initiates pancreatic atic secretion by inactivating a CCK-releasing peptide
enzyme secretion. The neurologic stimulation is cho- in the lumen of the small intestine. Thus, the integra-
linergic, involving extrinsic innervation by the vagus tive result of both bicarbonate and enzyme secretion
nerve and subsequent innervation by intrapancreatic depends on a feedback process for both bicarbonate
cholinergic nerves. The stimulatory neurotransmitters and pancreatic enzymes. Acidification of the duode-
are acetylcholine and gastrin-releasing peptides. These num releases secretin, which stimulates vagal and other
neurotransmitters activate calcium-dependent second neural pathways to activate pancreatic duct cells, which
messenger systems, resulting in the release of zymogen secrete bicarbonate. This bicarbonate then neutralizes
CHAPTER 48
granules. VIP is present in intrapancreatic nerves and the duodenal acid, and the feedback loop is completed.
potentiates the effect of acetylcholine. In contrast to Dietary proteins bind proteases, thereby leading to an
other species, there are no CCK receptors on acinar increase in free CCK-RF. CCK is then released into
cells in humans. CCK in physiologic concentrations the blood in physiologic concentrations, acting pri-
stimulates pancreatic secretion by stimulating afferent marily through the neural pathways (vagal-vagal). This
vagal and intrapancreatic nerves. leads to acetylcholine-mediated pancreatic enzyme
secretion. Proteases continue to be secreted from the
CHAPTER 48
the circulation. Jaundice occurs infrequently; when pres-
activated proteolytic enzymes and cytokines, released
ent, it usually is due to edema of the head of the pan-
by the inflamed pancreas, on distant organs. Activated
creas with compression of the intrapancreatic portion
proteolytic enzymes, especially trypsin, not only digest
pancreatic and peripancreatic tissues but also activate of the common bile duct. Erythematous skin nodules
other enzymes such as elastase and phospholipase A2. due to subcutaneous fat necrosis may occur. In 10–20%
of patients, there are pulmonary findings, including
The active enzymes and cytokines then digest cellu-
basilar rales, atelectasis, and pleural effusion, the lat-
Abbreviation: BISAP, Bedside Index of Severity in Acute Pancreatitis. demia occurs in 5–10% of patients, and serum amylase
levels in these individuals are often spuriously normal
(Chap. 47). Approximately 5–10% of patients have
hypoxemia (arterial Po2 ≤ 60 mmHg), which may her-
elevations. After 3 to 7 days, even with continuing evi- ald the onset of ARDS. Finally, the electrocardiogram
dence of pancreatitis, total serum amylase values tend to is occasionally abnormal in acute pancreatitis with
Disorders of the Pancreas
return toward normal. However, pancreatic isoamylase ST-segment and T-wave abnormalities simulating myo-
and lipase levels may remain elevated for 7 to 14 days. cardial ischemia.
It will be recalled that amylase elevations in serum and A CT scan can confirm the clinical impression
urine occur in many conditions other than pancreatitis of acute pancreatitis even with less than a threefold
(see Chap. 47, Table 47-2). Importantly, patients with increase in serum amylase and lipase levels. Importantly,
acidemia (arterial pH ≤7.32) may have spurious eleva- CT can be helpful in indicating the severity of acute
tions in serum amylase. In one study, 12 of 33 patients pancreatitis and the risk of morbidity and mortality
with acidemia had elevated serum amylase, but only 1 and in evaluating the complications of acute pancreati-
had an elevated lipase value; in 9, salivary-type amy- tis (Table 48-3). However, a CT scan obtained within
lase was the predominant serum isoamylase. This find- the first several days of symptom onset may underesti-
ing explains why patients with diabetic ketoacidosis may mate the extent of tissue injury. What may appear to be
have marked elevations in serum amylase without any intestinal pancreatitis on initial CT scan may evolve to
other evidence of acute pancreatitis. Serum lipase activ- pancreatic necrosis on repeat CT scan 3 to 5 days later
ity increases in parallel with amylase activity. A three- (Fig. 48-1). Sonography is useful in acute pancreatitis to
fold elevated serum lipase value is usually diagnostic of evaluate the gallbladder if gallstone disease is suspected.
acute pancreatitis; these tests are especially helpful in Radiologic studies useful in the diagnosis of acute
patients with nonpancreatic causes of hyperamylasemia pancreatitis are discussed in Chap. 47, and listed in
(see Chap. 47, Table 47-2). Table 47-1, and depicted in Figs. 48-1 to 48-3.
Leukocytosis (15,000–20,000 leukocytes per μL)
occurs frequently. Patients with more severe disease
Diagnosis
may show hemoconcentration with hematocrit val-
ues >44% and/or azotemia with a blood urea nitrogen Any severe acute pain in the abdomen or back should
(BUN) level >22 mg/dL because of loss of plasma into suggest the possibility acute pancreatitis. The diagno-
the retroperitoneal space and peritoneal cavity. Hemo- sis is usually entertained when a patient with a possible
concentration may be the harbinger of more severe predisposition to pancreatitis presents with severe and
Table 48-3 constant abdominal pain, frequently associated with nau- 501
CT Findings and Grading of Acute sea, emesis, fever, tachycardia, and abnormal findings on
Pancreatitis (CT Severity Index [CTSI]) abdominal examination. Laboratory studies may reveal
leukocytosis, hypocalcemia, and hyperglycemia. The diag-
Grade Findings Score
nosis of acute pancreatitis requires two of the following:
A Normal pancreas: normal size, 0 typical abdominal pain, threefold or greater elevation in
sharply defined, smooth contour, serum amylase and/or lipase level, and/or confirmatory
homogeneous enhancement, findings on cross-sectional abdominal imaging. Although
retroperitoneal peripancreatic fat
not required for diagnosis, markers of severity include
without enhancement
hemoconcentration (hematocrit >44%), azotemia (BUN
B Focal or diffuse enlargement of 1 >22 mg/dL), and signs of organ failure (Table 48-2).
the pancreas, contour may show
The differential diagnosis should include the following
irregularity, enhancement may be
inhomogeneous but there is no disorders: (1) perforated viscus, especially peptic ulcer;
peripancreatic inflammation (2) acute cholecystitis and biliary colic; (3) acute intestinal
obstruction; (4) mesenteric vascular occlusion; (5) renal
C Peripancreatic inflammation with 2
intrinsic pancreatic abnormalities colic; (6) myocardial infarction; (7) dissecting aortic
aneurysm; (8) connective tissue disorders with vasculitis;
D Intrapancreatic or extrapancreatic fluid 3
(9) pneumonia; and (10) diabetic ketoacidosis. A penetrat-
collections
ing duodenal ulcer can usually be identified by imag-
E Two or more large collections or gas in 4 ing studies or endoscopy. A perforated duodenal ulcer is
the pancreas or retroperitoneum
readily diagnosed by the presence of free intraperitoneal
Necrosis score based on contrast-enhanced CT air on abdominal imaging. It may be difficult to differen-
Necrosis, % Score tiate acute cholecystitis from acute pancreatitis, since an
0 0 elevated serum amylase may be found in both disorders.
<33 2 Pain of biliary tract origin is more right sided or epigastric
CHAPTER 48
33–50 4 than periumbilical and can be more severe; ileus is usually
≥50 6
absent. Sonography is helpful in establishing the diagno-
Note: CT severity index equals unenhanced CT score plus necrosis
sis of cholelithiasis and cholecystitis. Intestinal obstruc-
score: maximum = 10; ≥6 = severe disease. tion due to mechanical factors can be differentiated from
Source: Modified from EJ Balthazar et al: Radiology 1990;174:331. pancreatitis by the history of crescendo-decrescendo
A B C
Figure 48-1
Acute pancreatitis: CT evolution. A. Contrast-enhanced CT consistent with development of necrosis, particularly in the
scan of the abdomen performed on admission for a patient body and neck region (arrow). Note that an early CT scan
with clinical and biochemical parameters suggestive of acute obtained within the first 48 hours of hospitalization may
pancreatitis. Note the abnormal enhancement of the pancre- underestimate or miss necrosis. C. Contrast-enhanced
atic parenchyma (arrow) suggestive of interstitial pancreatitis. CT scan of the abdomen performed on the same patient
B. Contrast-enhanced CT scan of the abdomen performed 2 months after the initial episode of acute pancreatitis. CT
on the same patient 6 days later for persistent fever and now demonstrates evidence of a fluid collection consistent
systemic inflammatory response syndrome. The pancreas with walled-off pancreatic necrosis (arrow). (Courtesy of Dr. KJ
now demonstrates significant areas of nonenhancement Mortele, Brigham and Women’s Hospital; with permission.)
502
A B
C D
Figure 48-2
SECTION VIII
A. Acute necrotizing pancreatitis: CT scan. Contrast- necrosis of the pancreas and peripancreatic area (arrow) in
enhanced CT scan showing acute pancreatitis with necrosis. a patient with necrotizing pancreatitis. Addendum: In past
Arrow shows partially enhancing body/tail of pancreas sur- years, both of these CT findings (Figs. 48-2B and 48-2C)
rounded by fluid with decreased enhancement in the neck/ would have been misinterpreted as pseudocysts. D. Spiral
body of the pancreas. B. Acute fluid collection: CT scan. CT showing a pseudocyst (small arrow) with a pseudoan-
Contrast-enhanced CT scan showing fluid collection in the eurysm (light area in pseudocyst). Note the demonstration
retroperitoneum (arrow) compressing the air-filled stomach of the main pancreatic duct (big arrow), even though this
Disorders of the Pancreas
arising from the pancreas in a patient with asparaginase- duct is minimally dilated by ERCP. (A, B, C, courtesy of
induced acute necrotizing pancreatitis. C. Walled-off pancre- Dr. KJ Mortele, Brigham and Women’s Hospital; D, courtesy of
atic necrosis: CT scan. CT scan showing marked walled-off Dr. PR Ros, Brigham and Women’s Hospital; with permission.)
A B C
Figure 48-3
A. Pancreaticopleural fistula: pancreatic duct leak on pancreatic duct disruption in the pancreatic pleural fistula.
ERCP. Pancreatic duct leak demonstrated (arrow) at the time C. Pancreaticopleural fistula: Chest x-ray. Large pleural effu-
of retrograde pancreatogram in a patient with acute exac- sion in the left hemithorax from a disrupted pancreatic duct.
erbation of alcohol-induced acute or chronic pancreatitis. Analysis of pleural fluid revealed elevated amylase concen-
B. Pancreaticopleural fistula: CT scan. Contrast-enhanced tration. (Courtesy of Dr. KJ Mortele, Brigham and Women’s
CT scan (coronal view) with arrows showing fistula tract from Hospital; with permission.)
pain, findings on abdominal examination, and CT of the age (>60 years), obesity (BMI ≥30), and comorbid dis- 503
abdomen showing changes characteristic of mechanical ease. There is also evidence to support initial episode
obstruction. Acute mesenteric vascular occlusion is usu- and alcohol use as additional risk factors for severity. At
ally suspected in elderly debilitated patients with brisk admission and during the first 24 h, markers of sever-
leukocytosis, abdominal distention, and bloody diarrhea, ity in acute pancreatitis include scoring systems such as
confirmed by CT or MR angiography. Systemic lupus BISAP score and APACHE II, SIRS, azotemia, hemo-
erythematosus and polyarteritis nodosa may be confused concentration, and organ failure. During hospitalization,
with pancreatitis, especially since pancreatitis may develop markers of severity include persistent organ failure last-
as a complication of these diseases. Diabetic ketoaci- ing more than 48 h and pancreatic necrosis.
dosis is often accompanied by abdominal pain and ele- The course of acute pancreatitis is defined by two
vated total serum amylase levels, thus closely mimicking phases. In the first phase, which lasts 1 to 2 weeks,
acute pancreatitis. However, the serum lipase level is not severity is defined by clinical parameters rather than
elevated in diabetic ketoacidosis. morphologic findings. The most important clinical
parameter is persistent organ failure (i.e., lasting longer
Course of the Disease than 48 h), which is the usual cause of death. Severity
and Complications in the second phase is defined by both clinical param-
eters and morphologic criteria. The important clini-
The initial assessment of severity in acute pancreati- cal parameter of severity, as in the first phase, is persis-
tis is critical for the appropriate triage and management tent organ failure. The morphologic criteria of greatest
of patients. The basis for the classification, severity, and interest is the development of necrotizing pancreatitis,
complications of acute pancreatitis was initially established especially when it prolongs hospitalization and/or it
at the International Symposium held in Atlanta in 1992. requires active intervention such as operative, endo-
While the definitions have come under greater scrutiny scopic, or percutaneous therapy or requires supportive
in recent years, it still serves as the common language for measures such as renal dialysis, ventilator support, or
clinical care and research in acute pancreatitis. The crite- need for nasoenteric feeding.
CHAPTER 48
ria for severity in acute pancreatitis was defined as organ The importance of the recognition of interstitial
failure of at least one organ system (defined as a systolic versus necrotizing acute pancreatitis has lead to the
blood pressure <90 mmHg, Pao2 ≤60 mmHg, creatinine development of a CT severity index (Table 48-3) as
>2.0 mg/dL after rehydration, and gastrointestinal bleed- another measure of severity that is best evaluated 3 to 5
ing >500 mL/24 h) and the presence of a local complica- days into hospitalization because it may not be possible
tion such as necrosis, pseudocyst, and abscess. to distinguish interstitial from necrotizing pancreatitis
is recommended to ensure adequacy of fluid resuscita- overall rate of infected necrosis has been in decline over
tion. A decrease in hematocrit and BUN during the first the past 10–15 years and currently is found in 20% of
12 to 24 h is strong evidence that sufficient fluids are patients with necrotizing pancreatitis. It is reasonable
being administered. If the hematocrit remains elevated to start antibiotics in a patient who appears septic while
or increases further (particularly among those whose awaiting the results of cultures. If cultures are negative,
hematocrit on admission are >44), fluid resuscitation is the antibiotics should be discontinued to minimize the
Disorders of the Pancreas
CHAPTER 48
pancreatitis (Fig. 48-1). In particular, a CECT scan allows the attack. Studies indicate that only those patients with
estimation of the presence and extent of pancreatic gallstone pancreatitis who are in the very severe group
necrosis. Recent studies suggest that the likelihood of should be considered for urgent ERCP. Finally, the treat-
prolonged pancreatitis or a serious complication is neg- ment for patients with hypertriglyceridemia-associated
ligible when the CT severity index is 1 or 2 and low with pancreatitis includes (1) weight loss to ideal weight, (2) a
scores of 3–6. However, patients with scores of 7–10 had lipid-restricted diet, (3) exercise, (4) avoidance of alcohol
a 92% morbidity rate and a 17% mortality rate (Table and of drugs that can elevate serum triglycerides (i.e.,
termed walled-off necrosis that affects the posterior wall the body or tail of the pancreas and 15% in the head.
of the stomach; and, on occasion, radiologic catheter Some patients have two or more pseudocysts. Abdomi-
drainage with irrigation in an effort to eliminate at least nal pain, with or without radiation to the back, is the
some infected semisolid material as well as the infected usual presenting complaint. A palpable, tender mass may
liquid material. Radiologic approach is usually sug- be found in the middle or left upper abdomen.
gested to treat a patient who is too ill to undergo surgi- On imaging studies, 75% of pseudocysts can be seen
Disorders of the Pancreas
CHAPTER 48
Cardiovascular Hyperglycemia
be treated safely and drainage can be accomplished by Hypotension Hypertriglyceridemia
endoscopic, radiologic, or surgical means. Hypovolemia Hypocalcemia
Pseudoaneurysms develop in up to 10% of patients Sudden death Encephalopathy
with acute pancreatitis at sites reflecting the distribu- Nonspecific ST-T Sudden blindness
tion of pseudocysts and fluid collections (Fig. 48-2D). changes in (Purtscher’s retinopathy)
The splenic artery is most frequently involved, followed electrocardiogram Central nervous system
simulating myocardial Psychosis
duct scars
If the pancreatic duct disruption is posterior, an inter-
nal fistula may develop between the pancreatic duct Abbreviations: DBTC, dibutylin dichloride; TIGAR-O, toxic-metabolic,
and the pleural space, producing a pleural effusion idiopathic, genetic, autoimmune, recurrent and severe acute pancre-
(pancreaticopleural fistula) that is usually left-sided and atitis, obstructive.
often massive (Fig. 48-3). If the pancreatic duct disrup-
tion is anterior, amylase- and lipase-rich peritoneal fluid
Disorders of the Pancreas
accumulate (pancreatic ascites). A leaking, disrupted fibrosis, and progressive destruction of both exocrine
pancreatic duct is best treated by ERCP and “bridging” and eventually endocrine tissue. A number of etiolo-
stent placement and infrequently requires thoracentesis gies may result in chronic pancreatitis, and may result in
or chest tube drainage. the cardinal complications of chronic pancreatitis such
Treatment may also require enteral or parenteral ali- as abdominal pain, steatorrhea, weight loss, and diabetes
mentation to improve nutrition. If ascites or pleural fluid mellitus (Table 48-5).
persists after 2 to 3 weeks of medical management, The events that initiate the inflammatory process
and the disruption is unable to be stented, the patient in the pancreas are incompletely understood. Current
should be considered for surgical intervention after ret- experimental and clinical observations have shown
rograde pancreatography to define the anatomy of the that alcohol has a direct toxic effect on the pancreas.
disrupted duct. While patients with alcohol-induced pancreatitis gener-
ally consume large amounts of alcohol, some consume
as little as ≤50 g/d. Prolonged consumption of socially
acceptable amounts of alcohol is compatible with the
development of chronic pancreatitis. Findings of exten-
Chronic Pancreatitis sive pancreatic fibrosis in patients who died during their
and Pancreatic Exocrine first attack of clinical acute alcohol-induced pancreati-
Insufficiency tis support the concept that such patients already had
chronic pancreatitis.
Pathophysiology
There is a strong association of smoking and
Chronic pancreatitis is a disease process character- chronic pancreatitis. Cigarette smoke leads to an
ized by irreversible damage to the pancreas as distinct increased susceptibility to pancreatic self-digestion and
from the reversible changes noted in acute pancreatitis. predisposes to dysregulation of duct cell CFTR func-
The condition is best defined by the presence of his- tion. It has become increasingly apparent that smok-
tologic abnormalities, including chronic inflammation, ing is an independent, dose-dependent risk factor for
chronic pancreatitis and recurrent acute pancreatitis. with cystic fibrosis, the high concentration of macro- 509
Smoking is clearly associated with progression of dis- molecules can block the pancreatic ducts. It must be
ease in late-onset idiopathic chronic pancreatitis and appreciated, however, that there is a great deal of het-
with increased disease severity in alcohol-induced erogeneity in relationship to the CFTR gene defect.
chronic pancreatitis. More than 1000 putative mutations of the CFTR gene
Recent characterization of pancreatic stellate cells have been identified. Attempts to elucidate the relation-
(PSC) has added insight to the underlying cellular ship between the genotype and pancreatic manifesta-
responses behind development of chronic pancreatitis. tions have been hampered by the number of mutations.
Specifically, PSCs are believed to play a role in main- The ability to detect CFTR mutations has led to the
taining normal pancreatic architecture that can shift recognition that the clinical spectrum of the disease is
toward fibrogenesis in the case of chronic pancreatitis. broader than previously thought. Two recent stud-
The sentinel acute pancreatitis event (SAPE) hypothesis ies have clarified the association between mutations of
uniformly describes the events in the pathogenesis of the CFTR gene and another monosymptomatic form
chronic pancreatitis. It is believed that alcohol or addi- of cystic fibrosis (i.e., chronic pancreatitis). It is esti-
tional stimuli lead to matrix metalloproteinase–medi- mated that in patients with idiopathic pancreatitis, the
ated destruction of normal collagen in pancreatic paren- frequency of a single CFTR mutation is 11 times the
chyma, which later allows for pancreatic remodeling. expected frequency and the frequency of two mutant
Proinflammatory cytokines, tumor necrosis factor α alleles is 80 times the expected frequency. In these stud-
(TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6) as ies, the patients were adults when the diagnosis of pan-
well as oxidant complexes are able to induce PSC activ- creatitis was made; none had any clinical evidence of
ity with subsequent new collagen synthesis. In addition pulmonary disease, and sweat test results were not diag-
to being stimulated by cytokines, oxidants, or growth nostic of cystic fibrosis. The prevalence of such muta-
factors, PSCs also possess transforming growth factor β tions is unclear, and further studies are certainly needed.
(TGF-β)–mediated self-activating autocrine pathways In addition, the therapeutic and prognostic implication
that may explain disease progression in chronic pancreati- of these findings with respect to managing pancreati-
CHAPTER 48
tis even after removal of noxious stimuli. tis remains to be determined. Long-term follow-up of
affected patients is needed. CFTR mutations are com-
mon in the general population. It is unclear whether
Etiologic Considerations the CFTR mutation alone can lead to pancreatitis as
an autosomal recessive disease. A recent study evalu-
Among adults in the United States, alcoholism is the ated 39 patients with idiopathic chronic pancreatitis to
Weight loss and new onset of diabetes may also pain or maldigestion and weight loss. The abdominal
occur. An obstructive pattern on liver tests is com- pain may be quite variable in location, severity, and fre-
mon (i.e., disproportionately elevated serum alkaline quency. The pain can be constant or intermittent with
phosphatase and minimally elevated serum amino- frequent pain-free intervals. Eating may exacerbate the
transferases). Elevated serum levels of immunoglobulin pain, leading to a fear of eating with consequent weight
G4 (IgG4) provide a marker for the disease, particularly loss. The spectrum of abdominal pain ranges from mild
in Western populations. Serum IgG4 normally accounts to quite severe, with narcotic dependence as a frequent
for only 5–6% of the total IgG4 in healthy patients but consequence. Maldigestion is manifested as chronic
is elevated at least twofold higher than 135 mg/dL in diarrhea, steatorrhea, weight loss, and fatigue. Patients
those with AIP. CT scans reveal abnormalities in the with chronic abdominal pain may or may not prog-
majority of patients and include diffuse enlargement, ress to maldigestion, and ∼20% of patients will present
focal enlargement, and a distinct enlargement at the with symptoms of maldigestion without a history of
head of the pancreas. ERCP or MRCP reveals strictures abdominal pain. Patients with chronic pancreatitis have
in the bile duct in more than one-third of patients with significant morbidity and mortality and utilize appre-
AIP; these may be common bile duct strictures, intrahe- ciable amounts of societal resources. Despite the steat-
patic bile duct strictures, or proximal bile duct strictures, orrhea, clinically apparent deficiencies of fat-soluble
with accompanying narrowing of the pancreatic bile vitamins are surprisingly uncommon. Physical findings
duct. This has been termed autoimmune cholangitis. in these patients are usually unimpressive so that there
Characteristic histologic findings include extensive lym- is a disparity between the severity of abdominal pain
phoplasmacytic infiltrates with dense fibrosis around and the physical signs that usually consist of some mild
pancreatic ducts, as well as a lymphoplasmacytic infiltra- tenderness.
tion, resulting in an obliterative phlebitis. In contrast to acute pancreatitis, the serum amylase
The Mayo Clinic criteria indicate that AIP can and lipase levels are usually not strikingly elevated in
be diagnosed with at least one of three abnormalities: chronic pancreatitis. Elevation of serum bilirubin and
(1) diagnostic histology; (2) characteristic findings on alkaline phosphatase may indicate cholestasis secondary
to common bile duct stricture caused by chronic 511
inflammation. Many patients have impaired glucose tol-
erance with elevated fasting blood glucose levels. The
diagnostic test with the best sensitivity and specific-
ity is the hormone stimulation test utilizing secretin. It
becomes abnormal when ≥60% of the pancreatic exo-
crine function has been lost. This usually correlates well
with the onset of chronic abdominal pain. In earlier
studies, approximately 40% of patients with chronic
pancreatitis had cobalamin (vitamin B12) malabsorption.
This can be corrected by the administration of oral pan-
creatic enzymes. The fecal elastase-1 and small bowel
biopsy are useful in the evaluation of patients with sus-
pected pancreatic steatorrhea. The fecal elastase level A
will be abnormal and small bowel histology will be nor-
mal in such patients. A decrease of fecal elastase level
to <100 μg per gram of stool strongly suggests severe
pancreatic exocrine insufficiency.
Utilizing radiographic techniques (Fig. 48-4), it
can be shown that diffuse calcifications noted on plain
film of the abdomen usually indicate significant dam-
age to the pancreas. While alcohol is by far the most
common cause of pancreatic calcification such calci-
fication may also be noted in hereditary pancreatitis,
posttraumatic pancreatitis, hypercalcemic pancreati-
CHAPTER 48
tis, islet cell tumors, idiopathic chronic pancreatitis,
and tropical pancreatitis. Abdominal ultrasonography, B
CT scanning, and MRCP greatly aid in the diagno-
sis of pancreatic disease (Fig. 48-4). In addition to
excluding a pseudocyst and pancreatic cancer, CT
may show calcification, dilated ducts, or an atrophic
CHAPTER 48
Pancreacarb MS-8 8000 45,000 40,000
Nonenteric Coated
Viokase Axcan Scandipharm, Birmingham, AL
(pancrelipase, USP) Tablets, Powder
Viokase 8 8000 30,000 30,000
Viokase 16 16,000 60,000 60,000
a
United States Pharmacopeia (USP) units per tablet or capsule
Note: FDA has mandated all enzyme manufacturers to submit new drug applications (NDAs) for all pancreatic extract drug products after
reviewing data that showed substantial variations among currently marketed products. Numerous manufacturers have investigations underway
to seek FDA approval for the treatment of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF) or other conditions under the new
guidelines for this class of drugs (www.fda.gov).
used in selected patients with chronic pancreatitis and standard surgical procedures tend to decrease islet cell
abdominal pain refractory to conventional therapy. The yield. Celiac plexus block has not been demonstrated to
patients who have benefited the most from total pan- provide long-lasting pain relief.
createctomy have chronic pancreatitis without prior
pancreatic surgery or evidence of islet cell insufficiency.
The role of this procedure remains to be fully defined Hereditary Pancreatitis
but may be an option in lieu of ductal decompression
surgery or pancreatic resection in patients with intrac- Hereditary pancreatitis is a rare disease that is simi-
table, painful small-duct disease, particularly as the lar to chronic pancreatitis except for an early age of
onset and evidence of hereditary factors (involving an
514 autosomal dominant gene with incomplete penetrance). vomiting may be present for years before the diagnosis
A genomewide search using genetic linkage analysis is entertained. The radiographic findings are symmetric
identified the hereditary pancreatitis gene on chromo- dilation of the proximal duodenum with bulging of the
some 7. Mutations in ion codons 29 (exon 2) and 122 recesses on either side of the annular band, effacement
(exon 3) of the cationic trypsinogen gene cause auto- but not destruction of the duodenal mucosa, accentua-
somal dominant forms of hereditary pancreatitis. The tion of the findings in the right anterior oblique posi-
codon 122 mutations lead to a substitution of the tion, and lack of change on repeated examinations. The
corresponding arginine with another amino acid, usu- differential diagnosis should include duodenal webs,
ally histidine. This substitution, when it occurs, elimi- tumors of the pancreas or duodenum, postbulbar pep-
nates a fail-safe trypsin self-destruction site necessary to tic ulcer, regional enteritis, and adhesions. Patients with
eliminate trypsin that is prematurely activated within annular pancreas have an increased incidence of pan-
the acinar cell. These patients have recurring attacks of creatitis and peptic ulcer. Because of these and other
severe abdominal pain that may last from a few days to potential complications, the treatment is surgical even
a few weeks. The serum amylase and lipase levels may if the condition has been present for years. Retro-
be elevated during acute attacks but are usually normal. colic duodenojejunostomy is the procedure of choice,
Patients frequently develop pancreatic calcification, dia- although some surgeons advocate Billroth II gastrec-
betes mellitus, and steatorrhea; in addition, they have tomy, gastroenterostomy, and vagotomy.
an increased incidence of pancreatic carcinoma, with
the cumulative incidence being as high as 40% by
Pancreas Divisum
age 70 years. A recent natural history study of heredi-
tary pancreatitis in more than 200 patients from France Pancreas divisum occurs when the embryologic ven-
reported that abdominal pain started in childhood at tral and dorsal pancreatic anlagen fail to fuse, so that
age 10 years, steatorrhea developed at age 29 years, dia- pancreatic drainage is accomplished mainly through
betes at age 38 years, and pancreatic carcinoma at age the accessory papilla. Pancreas divisum is the most
55 years. Such patients often require surgical ductal common congenital anatomic variant of the human
SECTION VIII
decompression for pain relief. Abdominal complaints in pancreas. Current evidence indicates that this anomaly
relatives of patients with hereditary pancreatitis should does not predispose to the development of pancre-
raise the question of pancreatic disease. atitis in the great majority of patients who harbor it.
However, the combination of pancreas divisum and
a small accessory orifice could result in dorsal duct
Pancreatic secretory trypsin inhibitor (PSTI) obstruction. The challenge is to identify this subset
gene mutations
Disorders of the Pancreas
CHAPTER 48
Acute and Chronic Pancreatitis
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SECTION IX
Neoplastic Diseases
of the
Gastrointestinal
System
chaPTer 49
robert J. mayer
The gastrointestinal tract is the second most common as mucosal damage caused by such physical insults as
noncutaneous site for cancer and the second major long-term exposure to extremely hot tea, the ingestion
cause of cancer-related mortality in the United States. of lye, radiation-induced strictures, and chronic acha-
lasia. The presence of an esophageal web in association
with glossitis and iron deficiency (i.e., Plummer-Vinson
esoPhaGeal cancer or Paterson-Kelly syndrome) and congenital hyper-
keratosis and pitting of the palms and soles (i.e., tylosis
INCIDENCE aND ETIOlOgy palmaris et plantaris) have each been linked with squa-
Cancer of the esophagus is a relatively uncom- mous cell esophageal cancer, as have dietary deficien-
mon but extremely lethal malignancy. The diag- cies of molybdenum, zinc, selenium, and vitamin A.
nosis was made in 16,640 Americans in 2010 Bisphosphonates may increase the risk in patients with
and led to 14,500 deaths. Worldwide, the incidence, of Barrett’s esophagus. Patients with head and neck can-
esophageal cancer varies strikingly. It occurs frequently cer are at increased risk of squamous cell cancer of the
within a geographic region extending from the southern esophagus.
shore of the Caspian Sea on the west to northern China
on the east and encompassing parts of Iran, Central
Asia, Afghanistan, Siberia, and Mongolia. Familial Table 49-1
increased risk has been seen in regions with high inci- SOmE ETIOlOgIC FaCTOrS BElIEvED TO BE
dence, though gene associations are not yet defined. aSSOCIaTED wITh ESOPhagEal CaNCEr
High-incidence “pockets” of the disease are also present Excess alcohol consumption
in such disparate locations as Finland, Iceland, Curaçao, Cigarette smoking
southeastern Africa, and northwestern France. In North Other ingested carcinogens
America and western Europe, the disease is more com- Nitrates (converted to nitrites)
mon in blacks than whites and in males than females; it Smoked opiates
appears most often after age 50 and seems to be associ- Fungal toxins in pickled vegetables
ated with a lower socioeconomic status. Mucosal damage from physical agents
Hot tea
A variety of causative factors have been implicated Lye ingestion
in the development of the disease (Table 49-1). In the Radiation-induced strictures
United States, esophageal cancer cases are either squa- Chronic achalasia
mous cell carcinomas or adenocarcinomas. The etiol- Host susceptibility
ogy of squamous cell esophageal cancer is related to Esophageal web with glossitis and iron deficiency (i.e.,
excess alcohol consumption and/or cigarette smoking. Plummer-Vinson or Paterson-Kelly syndrome)
The relative risk increases with the amount of tobacco Congenital hyperkeratosis and pitting of the palms and
soles (i.e., tylosis palmaris et plantaris)
smoked or alcohol consumed, with these factors acting
? Dietary deficiencies of selenium, molybdenum, zinc, and
synergistically. The consumption of whiskey is linked vitamin A
to a higher incidence than the consumption of wine ? Celiac sprue
or beer. Squamous cell esophageal carcinoma has also Chronic gastric reflux (i.e., Barrett’s esophagus) for
been associated with the ingestion of nitrites, smoked adenocarcinoma
opiates, and fungal toxins in pickled vegetables, as well
518
For unclear reasons, the incidence of squamous cell producing a picture resembling achalasia. Smaller, 519
esophageal cancer has decreased somewhat in both the potentially resectable tumors are often poorly visualized
black and white population in the United States over despite technically adequate esophagograms. Because of
CHAPTER 49
the past 30 years, while the rate of adenocarcinoma has this, esophagoscopy should be performed in all patients
risen dramatically, particularly in white males (M:F 6:1). suspected of having an esophageal abnormality, to visu-
Adenocarcinomas arise in the distal esophagus in the alize the tumor and to obtain histopathologic confirma-
presence of chronic gastric reflux and gastric metapla- tion of the diagnosis. Because the population of persons
sia of the epithelium (Barrett’s esophagus), which is at risk for squamous cell carcinoma of the esophagus
more common in obese persons. Adenocarcinomas (i.e., smokers and drinkers) also has a high rate of
arise within dysplastic columnar epithelium in the dis- cancers of the lung and the head and neck region,
some reports suggest that no additional benefit accrues adhesion, mainly as a consequence of loss of expres-
when surgery is added if significant shrinkage of tumor sion of E-cadherin. Intestinal-type lesions are frequently
has been achieved by the chemoradiation combination. ulcerative, more commonly appear in the antrum and
For the incurable, surgically unresectable patient lesser curvature of the stomach, and are often preceded
with esophageal cancer, dysphagia, malnutrition, and by a prolonged precancerous process, often initiated by
the management of tracheoesophageal fistulas are Helicobacter pylori infection. While the incidence of
major issues. Approaches to palliation include repeated diffuse carcinomas is similar in most populations, the
endoscopic dilatation, the surgical placement of a gas- intestinal type tends to predominate in the high-risk
trostomy or jejunostomy for hydration and feeding, geographic regions and is less likely to be found in
and endoscopic placement of an expansive metal stent areas where the frequency of gastric cancer is declining.
to bypass the tumor. Endoscopic fulguration of the Thus, different etiologic factor(s) are likely involved in
obstructing tumor with lasers is the most promising of these two subtypes. In the United States, ∼30% of gas-
these techniques. tric cancers originate in the distal stomach, ∼20% arise
in the midportion of the stomach, and ∼37% originate
in the proximal third of the stomach. The remaining
Tumors of the Stomach 13% involve the entire stomach.
CHAPTER 49
gastritis, loss of gastric acidity, and bacterial growth in
the stomach. The effect of H. pylori eradication on the Clinical features
subsequent risk for gastric cancer in high-incidence
areas is under investigation. Loss of acidity may occur Gastric cancers, when superficial and surgically curable,
when acid-producing cells of the gastric antrum have usually produce no symptoms. As the tumor becomes
been removed surgically to control benign peptic ulcer more extensive, patients may complain of an insidious
disease or when achlorhydria, atrophic gastritis, and upper abdominal discomfort varying in intensity from
No. of 5-Year
Stage TNM Features Cases, % Survival, %
CHAPTER 49
not receiving radiotherapy; however, survival was pro- high-grade, large-cell lymphomas. Like gastric adeno-
longed slightly when 5-fluorouracil (5-FU) plus leucovorin carcinoma, infection with H. pylori increases the risk for
was given in combination with radiation therapy (3-year gastric lymphoma in general and MALT lymphomas in
survival 50% vs 41% for radiation therapy alone). In particular. Gastric lymphomas spread initially to regional
this clinical setting, the 5-FU may be functioning as a lymph nodes (often to Waldeyer’s ring) and may then
radiosensitizer. disseminate. Gastric lymphomas are staged like other
The administration of combinations of cytotoxic lymphomas.
become refractory to imatinib subsequently benefit genes that normally suppress tumorigenesis. It remains
from sunitinib (Sutent), another inhibitor of the c-kit uncertain whether the genetic aberrations always occur
tyrosine kinase. in a defined order. Based on this model, however, can-
cer is believed to develop only in those polyps in which
most (if not all) of these mutational events take place.
Clinically, the probability of an adenomatous polyp
Colorectal Cancer
becoming a cancer depends on the gross appearance
Neoplastic Diseases of the Gastrointestinal System
CHAPTER 49
Insulin resistance
disease occurs more often in upper socioeconomic The large number of calories in Western diets cou-
populations who live in urban areas. Mortality from pled with physical inactivity has been associated with
colorectal cancer is directly correlated with per capita a higher prevalence of obesity. Obese persons develop
consumption of calories, meat protein, and dietary fat insulin resistance with increased circulating levels of
and oil as well as elevations in the serum cholesterol insulin, leading to higher circulating concentrations of
concentration and mortality from coronary artery dis- insulin-like growth factor type I (IGF-I). This growth
Table 49-5
Hereditable (Autosomal Dominant) Gastrointestinal Polyposis Syndromes
Distribution Histologic Malignant
Syndrome of Polyps Type Potential Associated Lesions
polyposis coli] gene) in both neoplastic (somatic muta- than the median age for the general population. Despite
tion) and normal (germ-line mutation) cells. The loss having a poorly differentiated histologic appearance, the
of this genetic material (i.e., allelic loss) results in the proximal colon tumors in HNPCC have a better prog-
absence of tumor-suppressor genes whose protein prod- nosis than sporadic tumors from patients of similar age.
ucts would normally inhibit neoplastic growth. The Families with HNPCC often include individuals with
presence of soft tissue and bony tumors, congenital multiple primary cancers; the association of colorectal
hypertrophy of the retinal pigment epithelium, mesen- cancer with either ovarian or endometrial carcinomas
teric desmoid tumors, and ampullary cancers in addition is especially strong in women. It has been recom-
to the colonic polyps characterizes a subset of polypo- mended that members of such families undergo biennial
sis coli known as Gardner’s syndrome. The appearance of colonoscopy beginning at age 25 years, with intermit-
malignant tumors of the central nervous system accom- tent pelvic ultrasonography and endometrial biopsy
panying polyposis coli defines Turcot’s syndrome. The for afflicted women; such a screening strategy has not
colonic polyps in all these conditions are rarely present yet been validated. HNPCC is associated with germ-
before puberty but are generally evident in affected indi- line mutations of several genes, particularly hMSH2 on
viduals by age 25. If the polyposis is not treated surgi- chromosome 2 and hMLH1 on chromosome 3. These
cally, colorectal cancer will develop in almost all patients mutations lead to errors in DNA replication and are
before age 40. Polyposis coli results from a defect in the thought to result in DNA instability because of defec-
colonic mucosa, leading to an abnormal proliferative pat- tive repair of DNA mismatches resulting in abnormal
tern and impaired DNA repair mechanisms. Once the cell growth and tumor development. Testing tumor
multiple polyps are detected, patients should undergo cells through molecular analysis of DNA or immuno
a total colectomy. Medical therapy with nonsteroi- histochemical staining of paraffin-fixed tissue for
dal anti-inflammatory drugs (NSAIDs) such as sulindac “microsatellite instability” (sequence changes reflecting
and cyclooxygenase-2 inhibitors such as celecoxib can defective mismatch repair) in patients younger than age
decrease the number and size of polyps in patients with 50 with colorectal cancer and a positive family history
polyposis coli; however, this effect on polyps is only for colorectal or endometrial cancer may identify
temporary, and NSAIDs are not proven to reduce the probands with HNPCC.
risk of cancer. Colectomy remains the primary therapy/
prevention. The offspring of patients with polyposis coli,
who often are prepubertal when the diagnosis is made Inflammatory Bowel Disease
in the parent, have a 50% risk for developing this pre-
malignant disorder and should be carefully screened by (Chap. 17) Large-bowel cancer is increased in inci-
annual flexible sigmoidoscopy until age 35. Proctosig- dence in patients with long-standing inflammatory
moidoscopy is a sufficient screening procedure because bowel disease (IBD). Cancers develop more commonly
polyps tend to be evenly distributed from cecum to anus, in patients with ulcerative colitis than in those with
making more-invasive and expensive techniques such granulomatous colitis, but this impression may result
as colonoscopy or barium enema unnecessary. Testing in part from the occasional difficulty of differentiating
for occult blood in the stool is an inadequate screening these two conditions. The risk of colorectal cancer in
maneuver. An alternative method for identifying carriers a patient with IBD is relatively small during the initial
is testing DNA from peripheral blood mononuclear cells 10 years of the disease, but then it appears to increase
for the presence of a mutated APC gene. The detection at a rate of ∼0.5–1% per year. Cancer may develop in
of such a germ-line mutation can lead to a definitive 8–30% of patients after 25 years. The risk is higher in
diagnosis before the development of polyps. younger patients with pancolitis.
Cancer surveillance in patients with IBD is unsatis-
factory. Symptoms such as bloody diarrhea, abdomi-
Hereditary nonpolyposis colon cancer
nal cramping, and obstruction, which may signal the
Hereditary nonpolyposis colon cancer (HNPCC), appearance of a tumor, are similar to the complaints
also known as Lynch syndrome, is another autosomal caused by a flare-up of the underlying disease. In
patients with a history of IBD lasting ≥15 years who widespread use of estrogen replacement in postmeno- 527
continue to experience exacerbations, the surgical pausal individuals.
removal of the colon can significantly reduce the risk
CHAPTER 49
for cancer and also eliminate the target organ for the
underlying chronic gastrointestinal disorder. The value Screening
of such surveillance techniques as colonoscopy with The rationale for colorectal cancer screening pro-
mucosal biopsies and brushings for less-symptomatic grams is that earlier detection of localized, superficial
individuals with chronic IBD is uncertain. The lack of cancers in asymptomatic individuals will increase the
uniformity regarding the pathologic criteria that charac- surgical cure rate. Such screening programs are impor-
terize dysplasia and the absence of data that such sur-
CHAPTER 49
submucosa (T1) or the muscularis (T2) are designated
as stage I (T1–2N0M0) disease; tumors that penetrate
through the muscularis but have not spread to lymph
nodes are stage II disease (T3N0M0); regional lymph
node involvement defines stage III (TXN1M0) disease;
and metastatic spread to sites such as liver, lung, or bone
indicates stage IV (TXNXM1) disease. Unless gross evi-
Mucosa
Muscularis
mucosa
Submucosa
Muscularis
propria
Serosa
Fat
Lymph nodes
Figure 49-3
Staging and prognosis for patients with colorectal cancer.
530 Table 49-6 past from 6–9 months (hepatomegaly, abnormal liver
Predictors of Poor Outcome Following chemistries) to 24–30 months (small liver nodule ini-
Total Surgical Resection of Colorectal tially identified by elevated CEA level and subsequent
SECTION IX
Venous invasion
Preoperative elevation of CEA titer (>5 ng/mL) stage at diagnosis is the best predictor of long-term
Aneuploidy prognosis. Patients with lymphovascular invasion and
Specific chromosomal deletion (e.g., allelic loss on high preoperative CEA levels are likely to have a more
chromosome 18q) aggressive clinical course.
CHAPTER 49
Radiation therapy to the pelvis is recommended irinotecan. Oxaliplatin, a platinum analogue, also
for patients with rectal cancer because it reduces the improves the response rate when added to 5-FU and LV
20–25% probability of regional recurrences follow- as initial treatment of patients with metastatic disease.
ing complete surgical resection of stage II or III tumors, The FOLFOX regimen is the following: 2-h infusion
especially if they have penetrated through the serosa. of LV (400 mg/m2 per day) followed by a 5-FU bolus
This alarmingly high rate of local disease recurrence is (400 mg/m2 per day) and 22-h infusion (1200 mg/m2)
believed to be due to the fact that the contained ana- every 2 weeks, together with oxaliplatin, 85 mg/m2 as
as the addition of either bevacizumab or cetuximab to occasionally located outside the pancreas; the associated
FOLFOX did not enhance outcome. Patients with stage syndromes are discussed in Chap. 52. Brunner’s gland
II tumors do not appear to benefit applicably from adju- adenomas are not truly neoplastic but represent a hyper-
vant therapy with the use of such treatment generally trophy or hyperplasia of submucosal duodenal glands.
restricted to those patients having biologic character- These appear as small nodules in the duodenal mucosa
istics (e.g., perforated tumors, Ty lesions, lymphovascu- that secrete a highly viscous alkaline mucus. Most often,
Neoplastic Diseases of the Gastrointestinal System
lar invasion) that place them at higher than usual risk this is an incidental radiographic finding not associated
for recurrence. In rectal cancer, the delivery of preop- with any specific clinical disorder.
erative or postoperative combined modality therapy
(5-FU plus radiation therapy) reduces the risk of recur- Polypoid adenomas
rence and increases the chance of cure for patients with
About 25% of benign small-bowel tumors are polyp-
stages II and III tumors, with the preoperative approach
oid adenomas (Table 49-5). They may present as single
being better tolerated. The 5-FU acts as a radiosensi-
polypoid lesions or, less commonly, as papillary villous
tizer when delivered together with radiation therapy.
adenomas. As in the colon, the sessile or papillary form
Life-extending adjuvant therapy is used in only about
of the tumor is sometimes associated with a coexist-
half of patients older than age 65 years. This age bias is
ing carcinoma. Occasionally, patients with Gardner’s
completely inappropriate as the benefits and likely the
syndrome develop premalignant adenomas in the small
tolerance of adjuvant therapy in patients aged 65+ years
bowel; such lesions are generally in the duodenum.
appear similar to those seen in younger individuals.
Multiple polypoid tumors may occur throughout the
small bowel (and occasionally the stomach and col-
orectum) in the Peutz-Jeghers syndrome. The polyps
Tumors of the Small Intestine are usually hamartomas (juvenile polyps) having a low
potential for malignant degeneration. Mucocutaneous
Small-bowel tumors comprise <3% of gastrointestinal melanin deposits as well as tumors of the ovary, breast,
neoplasms. Because of their rarity, a correct diagnosis pancreas, and endometrium are also associated with this
is often delayed. Abdominal symptoms are usually vague autosomal dominant condition.
and poorly defined, and conventional radiographic studies
of the upper and lower intestinal tract often appear
normal. Small-bowel tumors should be considered Leiomyomas
in the differential diagnosis in the following situations: These neoplasms arise from smooth-muscle components
(1) recurrent, unexplained episodes of crampy abdomi- of the intestine and are usually intramural, affecting
nal pain; (2) intermittent bouts of intestinal obstruction, the overlying mucosa. Ulceration of the mucosa may
especially in the absence of IBD or prior abdominal sur- cause gastrointestinal hemorrhage of varying severity.
gery; (3) intussusception in the adult; and (4) evidence Cramping or intermittent abdominal pain is frequently
of chronic intestinal bleeding in the presence of nega- encountered.
tive conventional contrast radiographs. A careful small-
bowel barium study is the diagnostic procedure of
choice; the diagnostic accuracy may be improved by Lipomas
infusing barium through a nasogastric tube placed into These tumors occur with greatest frequency in the distal
the duodenum (enteroclysis). ileum and at the ileocecal valve. They have a character-
istic radiolucent appearance and are usually intramural
Benign Tumors and asymptomatic, but on occasion cause bleeding.
CHAPTER 49
and occasional intestinal obstruction. The diagnosis
of small-bowel lymphoma may be suspected from the
Malignant Tumors appearance on contrast radiographs of patterns such as
While rare, small-bowel malignancies occur in patients infiltration and thickening of mucosal folds, mucosal
with long-standing regional enteritis and celiac sprue nodules, areas of irregular ulceration, or stasis of contrast
as well as in individuals with AIDS. Malignant tumors material. The diagnosis can be confirmed by surgical
exploration and resection of involved segments. Intesti-
congregating close to the ileocecal valve. Most intesti- The development of anal cancer is associated with
nal carcinoids are asymptomatic and of low malignant infection by human papillomavirus, the same organ-
potential, but invasion and metastases may occur, lead- ism etiologically linked to cervical cancer. The virus
ing to the carcinoid syndrome (Chap. 52). is sexually transmitted. The infection may lead to anal
warts (condyloma acuminata), which may progress
Leiomyosarcomas to anal intraepithelial neoplasia and on to squamous
cell carcinoma. The risk for anal cancer is increased
Neoplastic Diseases of the Gastrointestinal System
Leiomyosarcomas often are >5 cm in diameter and among homosexual males, presumably related to anal
may be palpable on abdominal examination. Bleed- intercourse. Anal cancer risk is increased in both men
ing, obstruction, and perforation are common. Such and women with AIDS, possibly because their immu-
tumors should be analyzed for the expression of mutant nosuppressed state permits more severe papillomavirus
c-kit receptor (defining GIST), and in the presence of infection. Anal cancers occur most commonly in mid-
metastatic disease, justifying treatment with imatinib dle-aged persons and are more frequent in women than
mesylate (Gleevec) or, in imatinib-refractory patients, men. At diagnosis, patients may experience bleeding,
sunitinib (Sutent). pain, sensation of a perianal mass, and pruritus.
Radical surgery (abdominal-perineal resection with
lymph node sampling and a permanent colostomy) was
Cancers of the Anus once the treatment of choice for this tumor type. The
5-year survival rate after such a procedure was 55–70%
Cancers of the anus account for 1–2% of the malignant in the absence of spread to regional lymph nodes and
tumors of the large bowel. Most such lesions arise in the <20% if nodal involvement was present. An alterna-
anal canal, the anatomic area extending from the ano- tive therapeutic approach combining external beam
rectal ring to a zone approximately halfway between radiation therapy with concomitant chemotherapy has
the pectinate (or dentate) line and the anal verge. resulted in biopsy-proven disappearance of all tumor
Carcinomas arising proximal to the pectinate line (i.e., in >80% of patients whose initial lesion was <3 cm
in the transitional zone between the glandular mucosa in size. Tumor recurrences develop in <10% of these
of the rectum and the squamous epithelium of the dis- patients, meaning that ∼70% of patients with anal
tal anus) are known as basaloid, cuboidal, or cloacogenic cancers can be cured with nonoperative treatment.
tumors; about one-third of anal cancers have this histo- Surgery should be reserved for the minority of individ-
logic pattern. Malignancies arising distal to the pectinate uals who are found to have residual tumor after being
line have squamous histology, ulcerate more frequently, managed initially with radiation therapy combined
and constitute ∼55% of anal cancers. The prognosis for with chemotherapy.
ChaPter 50
Brian I. Carr
CHAPTER 50
Symptom Patient # (%)
No symptom 129(24)
Physical signs
Abdominal pain 219(40) Hepatomegaly is the most common physical sign,
Other (workup of anemia and various 64(12) occurring in 50–90% of the patients. Abdominal bruits
diseases)
are noted in 6–25%, and ascites occurs in 30–60% of
Routine physical exam finding, elevated LFTs 129(24)
patients. Ascites should be examined by cytology. Sple-
CHAPTER 50
should be performed to detect the vascular lesions typi- screening. Prevention strategies including universal vac-
cal of HCC. Portal vein invasion is normally detected as cination against hepatitis are more likely to be effective
an obstruction and expansion of the vessel. A chest than screening efforts. Despite absence of formal guide-
CT is used to exclude metastases. MRI can also pro- lines, most practitioners obtain 6-monthly AFP and CT
vide detailed information, especially with the newer (or ultrasound) when following high-risk patients (HBV
contrast agents. Ethiodol (Lipiodol) is an ethiodized oil carriers, HCV cirrhosis, family history of HCC).
emulsion retained by liver tumors that can be delivered
HCC diagnosed
SECTION IX
Figure 50-1
Hepatocellular carcinoma treatment algorithm. Treatment LN, lymph node; OLTX, orthotopic liver transplantation; PEI,
approach to patients with hepatocellular carcinoma. The percutaneous ethanol injection; RFA, radiofrequency abla-
initial clinical evaluation is aimed at assessing the extent of tion; TACE, transarterial chemoembolization; UNOS, United
the tumor and the underlying functional compromise of the Network for Organ Sharing. Child’s A/B/C refers to the Child-
liver by cirrhosis. Patients are classified as having resectable Pugh classification of liver failure.
disease, unresectable disease, or as transplantation candidates.
CHAPTER 50
Author Year Agents 1 Agents 2 Survival Effect
Local Ablation Strategies Radiofrequency due to high tumor recurrence rates. Priority scoring for
ablation (RFA) uses heat to ablate tumors. The maximum OLTX previously led to HCC patients waiting too long
size of the probe arrays allows for a 7-cm zone of necro- for their OLTX, resulting in some tumors becoming too
sis, which would be adequate for a 3- to 4-cm tumor. advanced during the patient’s wait for a donated liver.
The heat reliably kills cells within the zone of necrosis. A variety of therapies were used as a “bridge” to OLTX,
Treatment of tumors close to the main portal pedicles including RFA, polyethylenimine, and transcatheter arte-
can lead to bile duct injury and obstruction. This limits rial chemoembolization (TACE). It seems clear that these
the location of tumors that are anatomically suited for pretransplant treatments allow patients to remain on
this technique. RFA can be performed percutaneously the waiting list longer, giving them greater opportuni-
with CT or ultrasound guidance, or at the time of ties to be transplanted. What remains unclear, however,
laparoscopy with ultrasound guidance. is whether this translates into prolonged survival after
transplant. Further, it is not known whether patients
Local Injection Therapy Numerous agents have
who have had their tumor(s) treated preoperatively
been used for local injection into tumors, most com-
follow the recurrence pattern predicted by their tumor
monly, ethanol (PEI). The relatively soft HCC within the
status at the time of transplant (i.e., post–local ablative
hard background cirrhotic liver allows for injection of
therapy), or if they follow the course set by their tumor
large volumes of ethanol into the tumor without diffu-
parameters present before such treatment. The United
sion into the hepatic parenchyma or leakage out of the
Network for Organ Sharing (UNOS) point system for
liver. PEI causes direct destruction of cancer cells, but it
priority scoring of OLTX recipients now includes addi-
is not selective for cancer and will destroy normal cells
tional points for patients with HCC. The success of living
in the vicinity. However, it usually requires multiple
related donor liver transplantation programs has also
injections (average three), in contrast to one for RFA. The
led to patients receiving transplantation earlier for HCC
maximum size of tumor reliably treated is 3 cm, even
and often with greater than minimal tumors.
with multiple injections.
Current Directions Resection and RFA each obtain Current Directions Expanded criteria for larger
similar results. HCCs beyond the Milan criteria (one lesion <5 cm
or three lesions, each <3 cm) are being increasingly
Liver Transplantation (OLTX) A viable option accepted by various UNOS areas for OLTX with satisfac-
for stages I and II tumors in the setting of cirrhosis tory longer-term survival. Furthermore, downstaging
is OLTX, with survival approaching that for noncan- HCCs by medical therapy (TACE) is increasingly recog-
cer cases. OLTX for patients with a single lesion ≤5 cm nized as acceptable treatment before OLTX.
or three or fewer nodules, each ≤3 cm (Milan crite-
ria), resulted in excellent tumor-free survival (≥70% at Adjuvant Therapy The role of adjuvant chemo-
5 years). For advanced HCC, OLTX has been abandoned therapy for patients after resection or OLTX remains
542
unclear. Both adjuvant and neoadjuvant approaches pilot studies with cisplatin have shown encouraging
have been studied, but no clear advantage in disease- responses. Because the reports have not usually strati-
free or overall survival has been found. However, a fied responses or survival based on TNM staging, it is
SECTION IX
meta-analysis of several trials revealed a significant difficult to know long-term prognosis in relation to
improvement in disease-free and overall survival. tumor extent. Most of the studies on regional hepatic
Although analysis of postoperative adjuvant systemic arterial chemotherapy also use an embolizing agent
chemotherapy trials demonstrated no disease-free or such as Ethiodol, gelatin sponge particles (Gelfoam),
overall survival advantage, single studies of TACE and starch (Spherex), or microspheres. Two products are
neoadjuvant 131I-Ethiodol showed enhanced survival composed of microspheres of defined size ranges—
Neoplastic Diseases of the Gastrointestinal System
CHAPTER 50
Phase III Target Survival (mo)
EGF receptor antagonists: erlotinib, gefitinib, lapatinib,
Sorafenib vs placebo Raf, VEGFR, 10.7 vs. 7.9 cetuximab, brivanib
PDGFR Multikinase antagonists: sorafenib, sunitinib
Sorafenib vs placebo Raf, WGFR, 6.5 vs. 4.2 VEGF antagonist: bevacizumab
(Asians) PDGFR VEGFR antagonist: ABT-869 (linifanib)
Phase II mTOR antagonists: sirolimus, temsirolimus, everolimus
Proteasome inhibitors: bortezomib
Sorafenib 9
OLTX for patients with tumor response ing primary biliary cirrhosis. Nodular tumors arising
5. Extrahepatic HCC or elevated bilirubin: sorafenib or at the bifurcation of the common bile duct are called
bevacizumab plus erlotinib (combination agent trials Klatskin tumors and are often associated with a collapsed
are in progress) gallbladder, a finding that mandates visualization of the
entire biliary tree. The approach to management of
central and peripheral CCC is quite different. Incidence
is increasing. Although most CCCs have no obvious
Neoplastic Diseases of the Gastrointestinal System
CHAPTER 50
receive postoperative adjuvant radiotherapy. Its effect with an abdominal ultrasound to assess vascular involve-
on survival has not been assessed. Intraluminal brachy- ment, biliary dilation, and liver lesions. This is followed
radiotherapy has also shown some promise. However, by a CT scan, or MRI and especially MRCP. The most
photodynamic therapy enhanced survival in one study. effective therapy is resection by pylorus-sparing pancre-
In this technique, sodium porfimer is injected intrave- aticoduodenectomy, an aggressive procedure resulting
nously and then subjected to intraluminal red light laser in better survival rates than with local resection. Sur-
photoactivation. OLTX has been assessed for treatment vival rates are ∼25% at 5 years in operable patients with
ally occur. Adenomas can often be large masses ranging ever, adenomas have smooth, well-defined edges,
from 8–15 cm. Due to their size and definite, but low, and enhance homogeneously, especially in the portal
malignant potential and potential for bleeding, adeno- venous phase on delayed images, when HCCs no
mas are typically resected. The most useful diagnostic longer enhance. FNHs exhibit a characteristic cen-
differentiating tool is a triphasic CT scan performed tral scar that is hypovascular on the arterial-phase and
with HCC fast bolus protocol for arterial-phase imag- hypervascular on the delayed-phase CT images. MRI is
ing, together with subsequent delayed venous-phase even more sensitive in depicting the characteristic cen-
Neoplastic Diseases of the Gastrointestinal System
imaging. Adenomas usually do not appear on the basis tral scar of FNH.
cHaPter 51
PANCREATIC CANCER
Physical Signs
Patients can present with jaundice and cachexia, and
scratch marks may be present. Of patients with operable
tumors 25% have a palpable gallbladder (Courvoisier’s
sign). Physical signs related to the development of distant
metastases include hepatomegaly, ascites, left supracla-
vicular lymphadenopathy (Virchow’s node), and perium-
bilical lymphadenopathy (Sister Mary Joseph’s nodes).
Diagnosis
Diagnostic Imaging
Patients who present with clinical features suggestive Figure 51-2
of pancreatic cancer undergo imaging to confirm the ERCP showing contrast in dilated pancreatic duct (arrows).
cholangiopancreatography (MRCP) is a noninvasive 549
method for accurately depicting the level and degree of Treatment Pancreatic Cancer
bile and pancreatic duct dilatation. EUS is highly sensi-
Resectable Disease Approximately 10% of
CHAPTER 51
tive in detecting lesions less than 3 cm in size, and is
useful as a local staging tool for assessing vascular inva- patients present with localized nonmetastatic disease
sion and lymph node involvement. Fluorodeoxyglucose that is potentially suitable for surgical resection. Approx-
positron emission tomography (FDG-PET) should be imately 30% of patients have R1 resection (microscopic
considered before surgery or radical chemoradiother- residual disease) following surgery. Those who undergo
apy (CRT), as it is superior to conventional imaging in R0 resection (no microscopic or macroscopic residual
detecting distant metastases. tumor), and who receive adjuvant treatment have the
Pancreatic Cancer
best chance of cure, with an estimated median survival
of 20–23 months and a 5-year survival of approximately
20%. Outcomes are more favorable in patients with
Tissue Diagnosis and Cytology small (<3 cm), well-differentiated tumors, and lymph
Preoperative confirmation of malignancy is not always node-negative disease.
necessary in patients with radiological appearances con- Patients should have surgery in dedicated pancre-
sistent with operable pancreatic cancer. However, EUS- atic centers that have lower postoperative morbidity
guided fine-needle aspiration is the technique of choice and mortality rates. The standard surgical procedure for
when there is any doubt, and also for use in patients patients with tumors of the pancreatic head or uncinate
who require neoadjuvant treatment. It has an accuracy process is a pylorus-preserving pancreaticoduodenec-
of approximately 90% and has a smaller risk of intraperi- tomy (modified Whipple’s procedure). The procedure
toneal dissemination compared with the percutaneous of choice for tumors of the pancreatic body and tail
route. Percutaneous biopsy of the pancreatic primary or is a distal pancreatectomy, which routinely includes
liver metastases is only acceptable in patients with inop- splenectomy.
erable or metastatic disease. ERCP is a useful method for Postoperative treatment, either chemotherapy or
obtaining ductal brushings, but the diagnostic value of CRT, improves long-term outcomes in this group of
pancreatic juice sampling is only in the order of 25–30%. patients. Adjuvant chemotherapy, comprising six cycles
of fluorouracil (5FU) and folinic acid (FA) or gemcitabine,
is common practice in Europe based on data from three
Serum Markers randomized controlled trials (Table 51-1): Results from
the European Study Group for Pancreatic Cancer 1 trial
Tumor-associated carbohydrate antigen 19-9 (CA 19-9) (ESPAC-1) revealed a median survival improvement from
is elevated in approximately 70–80% of patients with 14.7 months with surgery alone to 20.1 months with
pancreatic carcinoma, but is not recommended as a surgery plus adjuvant 5FU/FA, and patients did not ben-
routine diagnostic or screening test as its sensitivity and efit from CRT in this study. The Charité Onkologie trial
specificity are inadequate for accurate diagnosis. Pre- (CONKO 001) found that the use of gemcitabine after
operative CA 19-9 levels correlate with tumor stage, complete resection significantly delayed the develop-
and postresection CA 19-9 level has prognostic value. ment of recurrent disease compared with surgery alone.
It is an indicator of asymptomatic recurrence in patients The ESPAC-3 trial, which investigated the benefit of
with completely resected tumors and is used as a bio- adjuvant 5FU/FA versus gemcitabine, revealed no sur-
marker of response in patients with advanced disease vival difference between the two drugs. However, the
undergoing chemotherapy. A number of studies have safety profile of adjuvant gemcitabine, with respect to
established a high pretreatment CA 19-9 level as an the incidence of stomatitis and diarrhea, was superior to
independent prognostic factor. 5FU/FA.
A different treatment strategy using adjuvant 5FU
based CRT following gemcitabine as advocated by the
Staging Radiation Therapy Oncology Group (RTOG) 97-04 trial
is preferred in the United States. This approach may be
The American Joint Committee on Cancer (AJCC) most beneficial in patients with bulky tumors involving
tumor-node-metastasis (TNM) staging of pancre- the pancreatic head and in patients with R1 resection.
atic cancer takes into account the location and size of
the tumor, the involvement of lymph nodes, and dis- Inoperable Locally Advanced Disease
tant metastasis. This information is then combined to Approximately 30% of patients present with locally
assign a stage (Fig. 51-3). From a practical standpoint, advanced unresectable but nonmetastatic pancreatic
patients are grouped according to whether the cancer is carcinoma. The median survival with gemcitabine is
resectable, locally advanced (unresectable, but without 9 months, and patients who respond to or achieve
distant spread), or metastatic.
550
SECTION IX
Neoplastic Diseases of the Gastrointestinal System
Figure 51-3
Staging of pancreatic cancer, and survival according to stage. (Illustration by Stephen Millward.)
Table 51-1 551
Phase III Studies of Adjuvant Chemotherapy in Resected Pancreatic Cancer
CHAPTER 51
Survival
Study Comparator Arm Patient Number PFS/DFS (months) Median survival (months)
ESPAC 1 Neoptolemos Chemotherapy (Folinic 550 PFS 15.3 vs 9.4. 20.1 vs 14.7 (HR 0.71, 95%
et al. (2004) acid + bolus 5FU) vs No (p = 0.02) CI 0.55 to 0.92, p = 0.009)
chemotherapy
CONKO 001 Gemcitabine vs 368 Median DFS 13.4 vs 22.1 vs 20.2 (p = 0.06)
Pancreatic Cancer
Oettle et al. (2007) Observation 6.9 (p < 0.001)
ESPAC 3 Neoptolemos 5FU/LV vs Gemcitabine 1088 23 vs 23.6 (HR 0.94, 95% CI
et al. (2010) 0.81 to 1.08, p = 0.39)
Abbreviations: CI, confidence interval; CONKO, Charite ONKOlogie; DFS, disease-free survival; ESPAC, European Study Group for Pancreatic
Cancer; 5FU, fluorouracil; HR, hazard ratio; LV, leucovorin; PFS, progression-free survival.
Table 51-2
Selected Phase III Studies Evaluating Chemotherapy Treatment in Advanced Pancreatic Cancer
Survival
Patient
Study Comparator Arm Number PFS (months) Median survival (months)
Moore M et al. (2007) Gemcitabine vs 569 3.55 vs 3.75 (HR 0.77, 5.91 vs 6.24 (HR 0.82, 95% CI
Gemcitabine + erlotinib 95% CI 0.64 to 0.92, 0.69 to 0.99, p = 0.038)
p = 0.004)
GEM-CAP Cunningham Gemcitabine vs 533 3.8 vs 5.3 (HR 0.78, 6.2 vs 7.1 (HR 0.86, 95% CI
et al. (2009) Gemcitabine + 95% CI 0.66 to 0.93, 0.72 to 1.02, p = 0.08)
capecitabine (GEM-CAP) p = 0.004)
GEM-CAP meta-analysis Gemcitabine vs GEM-CAP 935 Overall survival in favor of
Cunningham et al. GEM-CAP (HR 0.86, 95% CI
(2009) 0.75 to 0.98, p = 0.02)
stable disease after 3–6 months of gemcitabine may gemcitabine, but no survival benefit. However, pooling
derive benefit from consolidation radiotherapy. of two other randomized controlled trials with this trial
in a meta-analysis resulted in a survival advantage with
Metastatic Disease Approximately 60% of
GEM-CAP.
patients with pancreatic cancer present with metastatic
A trial in good performance status patients with
disease. Patients with poor performance status do not
metastatic pancreatic cancer showed improved survival
benefit from chemotherapy. Gemcitabine is the stan-
with the combination of 5FU/FA, irinotecan and
dard treatment with a median survival of 6 months and
oxaliplatin (FOLFIRINOX) compared with gemcitabine,
a 1-year survival rate of only 20%. The toxicities associ-
but with increased toxicity. Nab-paclitaxel (Abraxane), an
ated with gemcitabine need to be weighed against the
albumin bound nano-particle formulation of paclitaxel,
potential benefits of treatment.
given with gemcitabine also shows promising activity.
Adding other drugs to gemcitabine to improve out-
come has been generally unsuccessful with the exception
of erlotinib, an oral HER1/EGFR tyrosine kinase
inhibitor. The combination of erlotinib with gemcitabine Future Directions
resulted in an improved 1-year survival compared The early detection and future treatment of pancreatic
with gemcitabine alone (23% versus 17%, p = 0.023) cancer relies on an improved understanding of molec-
(Table 51-2). Capecitabine, an oral fluoropyrimidine, ular pathways involved in the development of this
has been combined with gemcitabine (GEM-CAP) in a disease. This will ultimately lead to the discovery of
phase III trial that showed an improvement in response novel agents, and the identification of patient groups
rate and progression-free survival over single-agent who are likely to benefit most from targeted therapy.
CHaPTer 52
Robert T. Jensen
CHAPTER 52
A. Share general neuroendocrine cell markers (identification used for diagnosis)
1. Chromogranins (A, B, C) are acidic monomeric soluble proteins found in the large secretory granules. Chromogranin
A is the most widely used.
2. Neuron-specific enolase (NSE) is the γ-γ dimer of the enzyme enolase and is a cytosolic marker of neuroendocrine
differentiation.
3. Synaptophysin is an integral membrane glycoprotein of 38,000 molecular weight found in small vesicles of neurons and
neuroendocrine tumors.
Midgut carcinoids are argentaffin-positive, have a high (usually intraabdominal in location) have been described
serotonin content, most frequently cause the typical car- only rarely and are not included in Table 52-2. They
cinoid syndrome when they metastasize (Table 52-3, include secretion of glucagon-like peptide-2 (GLP-2)
Fig. 52-1), release serotonin and tachykinins (substance P, that causes intestinal villus hypertrophy (enterogluca-
neuropeptide K, substance K), rarely secrete 5-HTP or gonomas), secretion of GLP-1 that causes hypoglycemia
ACTH, and less commonly metastasize to bone. Hind- and delayed transit, and intestinal and ovarian tumors
gut carcinoids (rectum, transverse and descending colon) secreting peptide tyrosine tyrosine (PYY) that result in
are argentaffin-negative, are often argyrophilic, rarely altered motility and constipation. Each of the functional
contain serotonin or cause the carcinoid syndrome syndromes listed in Table 52-2 is associated with symp-
(Fig. 52-1, Table 52-3), rarely secrete 5-HTP or ACTH, toms due to the specific hormone released. In contrast,
contain numerous peptides, and may metastasize to bone. nonfunctional PETs release no products that cause a
Pancreatic endocrine tumors can be classified into specific clinical syndrome. “Nonfunctional” is a misno-
nine well-established specific functional syndromes mer in the strict sense because those tumors frequently
(Table 52-2), five possible specific functional syn- ectopically secrete a number of peptides (pancreatic
dromes (PETs secreting calcitonin, renin, luteinizing polypeptide [PP], chromogranin A, ghrelin, neurotensin,
hormone, erythropoietin, or insulin-like growth factor α subunits of human chorionic gonadotropin, neuron-
II) (Table 52-2), and nonfunctional PETs (pancreatic specific enolase); however, they cause no specific clini-
polypeptide-secreting tumors; PPomas). Other func- cal syndrome. The symptoms caused by nonfunctional
tional hormonal syndromes due to nonpancreatic tumors PETs are entirely due to the tumor per se.
554 Table 52-2
Gastrointestinal Neuroendocrine Tumor Syndrome
Incidence
SECTION IX
Biologically (New
Active Cases/106 Associated
Peptide(s) Population/ Tumor with MEN Main Symptoms/
Name Secreted Year) Location Malignant, % 1, % Signs
CHAPTER 52
Incidence
Biologically (New
Active Cases/106 Associated
Peptide(s) Population/ Tumor with MEN Main Symptoms/
Name Secreted Year) Location Malignant, % 1, % Signs
Abbreviations: ACTH, adrenocorticotropic hormone; GRFoma, growth hormone-releasing factor secreting pancreatic endocrine tumor;
IF-II, insulin-like growth factor 2; MEN, multiple endocrine neoplasia; PET, pancreatic endocrine tumor; PPoma, tumor secreting pancreatic
polypeptide; PTHrP, parathyroid hormone–related peptide; VIPoma, tumor secreting vasoactive intestinal peptide; WDHA, watery diarrhea,
hypokalemia, and achlorhydria syndrome.
Carcinoid tumors can occur in almost any GI tissue Health Organization (WHO) classification it has been
(Table 52-3); however, at present most (70%) have their proposed that these tumors all be classified as GI neu-
origin in one of three sites: bronchus, jejunoileum, or roendocrine tumors (including carcinoids and PETs),
colon/rectum. In the past, carcinoid tumors most fre- which divides them into three general categories:
quently were reported in the appendix (i.e., 40%); how- (1a) well-differentiated NETs, (1b) well-differentiated
ever, the bronchus/lung, rectum, and small intestine neuroendocrine carcinomas that have low-grade malig-
are now the most common sites. Overall, the GI tract nancy, and (2) poorly differentiated neuroendocrine
is the most common site for these tumors, accounting carcinomas that are usually small cell neuroendocrine
for 64%, with the respiratory tract a distant second at carcinomas of high-grade malignancy. The term
28%. Both race and sex can affect the frequency as well as carcinoid is synonymous with well-differentiated NETs
the distribution of carcinoid tumors. African Americans (1a). This classification is further divided on the basis
have a high incidence of carcinoids, and rectal carci- of tumor location and biology. In addition, for the first
noids are the most common. Females have a lower inci- time a standard TNM (tumor, node, metastasis) classi-
dence of small-intestinal and pancreatic carcinoids. fication and grading system has been proposed for GI
The term pancreatic endocrine tumor, although widely neuroendocrine tumors. The new WHO classification
used and therefore retained here, is also a misnomer, and the TNM classification and grading system were
strictly speaking, because these tumors can occur either proposed to facilitate the comparison and evaluation of
almost entirely in the pancreas (insulinomas, gluca- clinical, pathologic, and prognostic features and results
gonomas, nonfunctional PETs, PETs causing hypercal- of treatment in GI NETs from different studies. These
cemia) or at both pancreatic and extrapancreatic sites classification systems may provide important prognostic
(gastrinomas, VIPomas [vasoactive intestinal peptide], information that can guide treatment (Table 52-4).
somatostatinomas, GRFomas [growth hormone–releasing The exact incidence of carcinoid tumors or PETs var-
factor]). PETs are also called islet cell tumors; how- ies according to whether only symptomatic tumors or all
ever, the use of this term is discouraged because it is not tumors are considered. The incidence of clinically sig-
established that they originate from the islets and many nificant carcinoids is 7–13 cases/million population per
can occur at extrapancreatic sites. year, whereas any malignant carcinoids at autopsy are
A number of new classification systems have been reported in 21–84 cases/million population per year.
proposed for both carcinoids and PETs. In the World The incidence of GI NETs is approximately 25–50 cases
556 Table 52-3 Carcinoid tumor cell
Carcinoid Tumor Location, Frequency Tryptophan
of Metastases, and Association With the Tryptophan hydroxylase
SECTION IX
Carcinoid Syndrome
Hydroxytryptophan
Incidence (5-HTP)
of Aromatic L-amino acid
Location Incidence of Carcinoid decarboxylase
(% of Total) Metastases Syndrome Serotonin
(5-HT)
Foregut
5-HT stored in
Neoplastic Diseases of the Gastrointestinal System
CHAPTER 52
Presence of liver metastases (p < .001) Presence of carcinoid syndrome
Extent of liver metastases (p < .001) Laboratory results (urinary 5-HIAA levels [p < .01], plasma
Presence of lymph node metastases (p < .001) neuropeptide K [p < .05], serum chromogranin A [p < .01])
Depth of invasion (p < .001) Presence of a second malignancy
Rapid rate of tumor growth Male sex (p < .001)
Elevated serum alkaline phosphatase levels (p = .003) Mode of discovery (incidental > symptomatic)
Primary tumor site (p < .001) Molecular findings (TGF-α expression [p < .05], chr 16q
Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; chr, chromosome; EGF, epidermal growth factor; Ki-67, proliferation-associated nuclear
antigen recognized by Ki-67 monoclonal antibody; LOH, loss of heterozygosity; MEN, multiple endocrine neoplasia; NET, neuroendocrine
tumors; PCNA, proliferating cell nuclear antigen; PET, pancreatic endocrine tumor; TGF-α, transforming growth factor α; TNM, tumor, node,
metastasis; VEGF, vascular endothelial growth factor; WHO, World Health Organization.
metalloproteinase expression); necrosis; presence of cyto- important is MEN 1, which is an autosomal dominant
keratin; elevated serum alkaline phosphatase levels; older disorder due to a defect in a 10-exon gene on 11q13,
age; advanced stages in WHO, TNM, or grading which encodes for a 610-amino-acid nuclear protein,
classification systems; and flow cytometric results such menin. Patients with MEN 1 develop hyperparathy-
as the presence of aneuploidy are all important prog- roidism due to parathyroid hyperplasia in 95–100% of
nostic factors for the development of metastatic disease cases, PETs in 80–100%, pituitary adenomas in 54–80%,
(Table 52-4). For patients with carcinoid tumors, addi- adrenal adenomas in 27–36%, bronchial carcinoids
tional associations with a worse prognosis include the in 8%, thymic carcinoids in 8%, gastric carcinoids in
development of the carcinoid syndrome (especially the 13–30% of patients with Zollinger-Ellison syndrome,
development of carcinoid heart disease), male sex, the skin tumors (angiofibromas [88%], collagenomas [72%]),
presence of a symptomatic tumor or greater increases central nervous system (CNS) tumors (meningiomas
in a number of tumor markers (5-hydroxyindolacetic [<8%]), and smooth-muscle tumors (leiomyomas, leio-
acid [5-HIAA], neuropeptide K, chromogranin A), and myosarcomas [1–7%]). Among patients with MEN 1,
the presence of various molecular features. With PETs 80–100% develop nonfunctional PETs (most are micro-
or gastrinomas, which have been the best studied PET scopic with 0–13% large/symptomatic), functional
long-term, a worse prognosis is associated with female PETs occur in 20–80% in different series with a mean
sex, overexpression of the Ha-ras oncogene or p53, the of 54% developing Zollinger-Ellison syndrome, 18%
absence of multiple endocrine neoplasia type 1 (MEN 1), insulinomas, 3% glucagonomas, 3% VIPomas, and <1%
higher levels of various tumor markers (i.e., chromogranin GRFomas or somatostatinomas. MEN 1 is present in
A, gastrin), and various molecular features (Table 52-4). 20–25% of all patients with Zollinger-Ellison syndrome,
A number of diseases due to various genetic disor- 4% of patients with insulinomas, and a low percentage
ders are associated with an increased incidence of neu- (<5%) of patients with the other PETs.
roendocrine tumors (Table 52-5). Each one is caused Three phacomatoses associated with neuroendo-
by a loss of a possible tumor-suppressor gene. The most crine tumors are von Hippel–Lindau disease (VHL),
558 Table 52-5
Genetic Syndromes Associated With an Increased Incidence of Neuroendocrine Tumors (NETs)
(Carcinoids or Pancreatic Endocrine Tumors [PETs])
SECTION IX
Multiple endocrine 11q13 (encodes 610-amino-acid 80–100% develop PETs (microscopic), 20–80%
neoplasia type 1 protein, menin) (clinical): (nonfunctional > gastrinoma > insulinoma)
(MEN 1) Carcinoids: gastric (13–30%), bronchial/thymic (8%)
von Hippel–Lindau 3q25 (encodes 213-amino-acid protein) 12–17% develop PETs (almost always nonfunctional)
Neoplastic Diseases of the Gastrointestinal System
disease
von Recklinghausen’s 17q11.2 (encodes 2485-amino-acid 0–10% develop PETs, primarily duodenal
disease (neurofibro- protein, neurofibromin) somatostatinomas (usually nonfunctional)
matosis 1 [NF-1]) Rarely insulinoma, gastrinoma
Tuberous sclerosis 9q34 (TSCI) (encodes 1164-amino-acid Uncommonly develop PETs (nonfunctional and
protein, hamartin) 16p13 (TSC2) (encodes functional [insulinoma, gastrinoma])
1807-amino-acid protein, tuberin)
von Recklinghausen’s disease (neurofibromatosis type 1 susceptibility gene) been found to be generally impor-
[NF-1]), and tuberous sclerosis (Bourneville’s disease) tant in their molecular pathogenesis (Table 52-1).
(Table 52-5). VHL is an autosomal dominant disorder Alterations that may be important in their pathogenesis
due to defects on chromosome 3p25, which encodes include changes in the MEN 1 gene, p16/MTS1 tumor-
for a 213-amino-acid protein that interacts with the suppressor gene, and DPC 4/Smad 4 gene; amplification
elongin family of proteins as a transcriptional regula- of the HER-2/neu protooncogene; alterations in tran-
tor. In addition to cerebellar hemangioblastomas, renal scription factors (Hoxc6 [GI carcinoids]), growth factors,
cancer, and pheochromocytomas, 10–17% develop and their receptor expression; methylation of a number
a PET. Most are nonfunctional, although insulino- of genes that probably results in their inactivation; and
mas and VIPomas have been reported. Patients with deletions of unknown tumor-suppressor genes as well as
NF-1 (von Recklinghausen’s disease) have defects gains in other unknown genes (Table 52-1). Compara-
in a gene on chromosome 17q11.2 that encodes for tive genomic hybridization, genome-wide allelotyping
a 2845-amino-acid protein, neurofibromin, which studies, and genome-wide single-nucleotide polymor-
functions in normal cells as a suppressor of the ras sig- phism analyses have shown that chromosomal losses and
naling cascade. Up to 10% of these patients develop gains are common in PETs and carcinoids, but they dif-
an upper GI carcinoid tumor, characteristically in fer between these two NETs and some have prognostic
the periampullary region (54%). Many are classified significance (Table 52-4). Mutations in the MEN 1 gene
as somatostatinomas because they contain somatosta- are probably particularly important. There is loss of het-
tin immunocytochemically; however, they uncom- erozygosity at the MEN 1 locus on chromosome 11q13 in
monly secrete somatostatin and rarely produce a clinical 93% of sporadic PETs (i.e., in patients without MEN 1)
somatostatinoma syndrome. NF-1 has rarely been asso- and in 26–75% of sporadic carcinoid tumors. Mutations
ciated with insulinomas and Zollinger-Ellison syndrome. in the MEN 1 gene are reported in 31–34% of sporadic
NF-1 accounts for 48% of all duodenal somatostastino- gastrinomas. The presence of a number of these molecu-
mas and 23% of all ampullary carcinoid tumors. Tuberous lar alterations (PET or carcinoid) correlates with tumor
sclerosis is caused by mutations that alter either the growth, tumor size, and disease extent or invasiveness
1164-amino-acid protein hamartin (TSC1) or the and may have prognostic significance.
1807-amino-acid protein tuberin (TSC2). Both hamartin
and tuberin interact in a pathway related to phosphati-
dylinositol 3-kinases and mTor signaling cascades. A Carcinoid Tumors and Carcinoid
few cases including nonfunctional and functional PETs Syndrome
(insulinomas and gastrinomas) have been reported in
these patients (Table 52-5). Characteristics of the Most
In contrast to most common nonendocrine tumors, Common GI Carcinoid Tumors
such as carcinoma of the breast, colon, lung, or stom-
Appendiceal carcinoids
ach, in neither PETs nor carcinoid tumors have alter-
ations in common oncogenes (ras, myc, fos, src, jun) or Appendiceal carcinoids occur in 1 in every 200–300
common tumor-suppressor genes (p53, retinoblastoma appendectomies, usually in the appendiceal tip. Most
(i.e., >90%) are <1 cm in diameter without metas- Table 52-6 559
tases in older studies, but more recently 2–35% have Clinical Characteristics in Patients With
had metastases (Table 52-3). In the SEER data of Carcinoid Syndrome
CHAPTER 52
1570 appendiceal carcinoids, 62% were localized, 27% At During Course
had regional metastases, and 8% had distant metastases. Presentation of Disease
Approximately 50% between 1 and 2 cm metastasized
Symptoms/signs
to lymph nodes. Their percentage of the total number Diarrhea 32–73% 68–84%
of carcinoids decreased from 43.9% (1950–1969) to Flushing 23–65% 63–74%
2.4% (1992–1999). Pain 10% 34%
tiple and small and infiltrate only to the submucosa. symptoms. In various studies of patients with carcinoid
The third subtype of gastric carcinoid (type III) tumors, elevated serum levels of PP were found in 43%,
(sporadic) occurs without hypergastrinemia (14–25% of motilin in 14%, gastrin in 15%, and VIP in 6%. Foregut
all gastric carcinoids) and has an aggressive course, with carcinoids are more likely to produce various GI pep-
54–66% developing metastases. Sporadic carcinoids are tides than are midgut carcinoids. Ectopic ACTH pro-
usually single, large tumors; 50% have atypical histol- duction causing Cushing’s syndrome is seen increas-
ogy, and they can be a cause of the carcinoid syndrome. ingly with foregut carcinoids (respiratory tract
Neoplastic Diseases of the Gastrointestinal System
Gastric carcinoids as a percentage of all carcinoids are primarily) and in some series has been the most com-
increasing in frequency (1.96% [1969–1971], 3.6% mon cause of the ectopic ACTH syndrome, account-
[1973–1991], 5.8% [1991–1999]). ing for 64% of all cases. Acromegaly due to growth
hormone–releasing factor release occurs with foregut
carcinoids, as does the somatostatinoma syndrome,
Carcinoid Tumors without the but rarely occurs with duodenal carcinoids. The most
Carcinoid Syndrome common systemic syndrome with carcinoid tumors is
The age of patients at diagnosis ranges from 10 to the carcinoid syndrome, which is discussed in detail in
93 years, with a mean age of 63 years for the small the next section.
intestine and 66 years for the rectum. The presenta-
tion is diverse and is related to the site of origin and the
extent of malignant spread. In the appendix, carcinoid Carcinoid Syndrome
tumors usually are found incidentally during surgery Clinical features
for suspected appendicitis. Small-intestinal carcinoids in
The cardinal features from a number of series at pre-
the jejunoileum present with periodic abdominal pain
sentation as well as during the disease course are shown
(51%), intestinal obstruction with ileus/invagination
in Table 52-6. Flushing and diarrhea are the two most
(31%), an abdominal tumor (17%), or GI bleeding
common symptoms, occurring in up to 73% initially
(11%). Because of the vagueness of the symptoms,
and in up to 89% during the course of the disease. The
the diagnosis usually is delayed approximately 2 years
characteristic flush is of sudden onset; it is a deep red or
from onset of the symptoms, with a range up to
violaceous erythema of the upper body, especially the
20 years. Duodenal, gastric, and rectal carcinoids are
neck and face, often associated with a feeling of warmth
most frequently found by chance at endoscopy. The
and occasionally associated with pruritus, lacrimation,
most common symptoms of rectal carcinoids are
diarrhea, or facial edema. Flushes may be precipitated
melena/bleeding (39%), constipation (17%), and diar-
by stress; alcohol; exercise; certain foods, such as cheese;
rhea (12%). Bronchial carcinoids frequently are discov-
or certain agents, such as catecholamines, pentagastrin,
ered as a lesion on a chest radiograph, and 31% of the
and serotonin reuptake inhibitors. Flushing episodes
patients are asymptomatic. Thymic carcinoids present as
may be brief, lasting 2 to 5 min, especially initially, or
anterior mediastinal masses, usually on chest radiograph
may last hours, especially later in the disease course.
or CT scan. Ovarian and testicular carcinoids usually
Flushing usually is associated with metastastic midgut
present as masses discovered on physical examination or
carcinoids but can also occur with foregut carcinoids.
ultrasound. Metastatic carcinoid tumor in the liver fre-
With bronchial carcinoids the flushes frequently are
quently presents as hepatomegaly in a patient who may
prolonged for hours to days, reddish in color, and asso-
have minimal symptoms and nearly normal liver func-
ciated with salivation, lacrimation, diaphoresis, diarrhea,
tion test results.
and hypotension. The flush associated with gastric car-
cinoids can also be reddish in color, but with a patchy
distribution over the face and neck, although the classic
Carcinoid Tumors with Systemic
flush seen with midgut carcinoids can also be seen with
Symptoms Due to Secreted
gastric carcinoids. It may be provoked by food and have
Products
accompanying pruritus.
Carcinoid tumors immunocytochemically can contain Diarrhea is present in 32–73% initially and 68–84% at
numerous GI peptides: gastrin, insulin, somatostatin, some time in the disease course. Diarrhea usually occurs
motilin, neurotensin, tachykinins (substance K, substance with flushing (85% of cases). The diarrhea usually
P, neuropeptide K), glucagon, gastrin-releasing peptide, is described as watery, with 60% of patients having
vasoactive intestinal peptide (VIP), pancreatic polypep- <1 L/d of diarrhea. Steatorrhea is present in 67%,
tide (PP), ghrelin, other biologically active peptides and in 46% it is greater than 15 g/d (normal <7 g).
Abdominal pain may be present with the diarrhea or tumor cells, and this can result in inadequate supplies 561
independently in 10–34% of cases. for conversion to niacin; hence, some patients (2.5%)
Cardiac manifestations occur in 11–20% initially of develop pellagra-like lesions. Serotonin has numerous
CHAPTER 52
patients with carcinoid syndrome and in 17–56% (mean biologic effects, including stimulating intestinal secre-
40%) at some time in the disease course. The cardiac tion with inhibition of absorption, stimulating increases
disease is due to the formation of fibrotic plaques in intestinal motility, and stimulating fibrogenesis. In
(composed of smooth-muscle cells, myofibroblasts, and various studies 56–88% of all carcinoid tumors were
elastic tissue) involving the endocardium, primarily on associated with serotonin overproduction; however,
the right side, although lesions on the left side also occur 12–26% of the patients did not have the carcinoid
occasionally, especially if a patent foramen ovale exists. syndrome. In one study platelet serotonin was ele-
in the endocardium. Both the magnitude of serotonin frequently. False-positive elevations may occur if the
overproduction and prior chemotherapy are important patient is eating serotonin-rich foods such as bananas,
predictors of progression of the heart disease. Atrial pineapples, walnuts, pecans, avocados, or hickory nuts
natriuretic peptide (ANP) overproduction also has or is taking certain medications (cough syrup contain-
been reported in patients with cardiac disease, but its ing guaifenesin, acetaminophen, salicylates, serotonin
role in the pathogenesis is unknown. However, high reuptake inhibitors, or l-dopa). The normal range in
plasma levels of ANP have a worse prognosis. Plasma daily urinary 5-HIAA excretion is 2–8 mg/d. Serotonin
connective tissue growth factor levels are elevated overproduction was noted in 92% of patients with car-
in many fibrotic conditions; elevated levels occur in cinoid syndrome in one study, and in another study,
patients with carcinoid heart disease and correlate with 5-HIAA had 73% sensitivity and 100% specificity for
the presence of right-ventricular dysfunction and the carcinoid syndrome.
extent of valvular regurgitation in patients with carci- Most physicians use only the urinary 5-HIAA excre-
noid tumors. tion rate; however, plasma and platelet serotonin levels,
Patients may develop either a typical or, rarely, an if available, may provide additional information. Platelet
atypical carcinoid syndrome. In patients with the typi- serotonin levels are more sensitive than urinary 5-HIAA
cal form, which characteristically is caused by a mid- but are not generally available. Because patients with
gut carcinoid tumor, the conversion of tryptophan foregut carcinoids may produce an atypical carcinoid
to 5-HTP is the rate-limiting step (Fig. 52-1). Once syndrome, if this syndrome is suspected and the urinary
5-HTP is formed, it is rapidly converted to 5-HT 5-HIAA is minimally elevated or normal, other urinary
and stored in secretory granules of the tumor or in metabolites of tryptophan, such as 5-HTP and 5-HT,
platelets. A small amount remains in plasma and is should be measured (Fig. 52-1).
converted to 5-HIAA, which appears in large amounts Flushing occurs in a number of other diseases,
in the urine. These patients have an expanded sero- including systemic mastocytosis, chronic myeloid leu-
tonin pool size, increased blood and platelet sero- kemia with increased histamine release, menopause,
tonin, and increased urinary 5-hydroxyindolacetic reactions to alcohol or glutamate, side effects of chlor-
acid (5-HIAA). Some carcinoid tumors cause an atypi- propamide, calcium channel blockers, and nicotinic
cal carcinoid syndrome that is thought to be due to acid. None of these conditions cause increased urinary
a deficiency in the enzyme dopa decarboxylase; thus, 5-HIAA.
5-HTP cannot be converted to 5-HT (serotonin), and The diagnosis of carcinoid tumor can be suggested
5-HTP is secreted into the bloodstream (Fig. 52-1). In by the carcinoid syndrome, recurrent abdominal symp-
these patients, plasma serotonin levels are normal but toms in a healthy-appearing individual, or the discov-
urinary levels may be increased because some 5-HTP ery of hepatomegaly or hepatic metastases associated
is converted to 5-HT in the kidney. Characteristically, with minimal symptoms. Ileal carcinoids, which make
urinary 5-HTP and 5-HT are increased, but urinary up 25% of all clinically detected carcinoids, should be
5-HIAA levels are only slightly elevated. Foregut car- suspected in patients with bowel obstruction, abdominal
cinoids are the most likely to cause an atypical carci- pain, flushing, or diarrhea.
noid syndrome. Serum chromogranin A levels are elevated in
One of the most immediate life-threatening compli- 56–100% of patients with carcinoid tumors, and the
cations of the carcinoid syndrome is the development level correlates with tumor bulk. Serum chromogranin
of a carcinoid crisis. This is more common in patients A levels are not specific for carcinoid tumors because
who have intense symptoms or have greatly increased they are also elevated in patients with PETs and other
urinary 5-HIAA levels (i.e., >200 mg/d). The crises neuroendocrine tumors. Plasma neuron-specific enolase
may occur spontaneously or be provoked by stress, levels are also used as a marker of carcinoid tumors but
anesthesia, chemotherapy, or a biopsy. Patients develop are less sensitive than chromogranin A, being increased
intense flushing, diarrhea, abdominal pain, cardiac in only 17–47% of patients.
arcinoid Syndrome and Nonmetastatic
C 563
Treatment the diarrhea but usually do not decrease flushing.
Carcinoid Tumors The use of methylsergide is limited because it can
CHAPTER 52
Carcinoid Syndrome Treatment includes cause or enhance retroperitoneal fibrosis. Ketanserin
avoiding conditions that precipitate flushing, dietary diminishes diarrhea in 30–100% of patients. 5-HT3
supplementation with nicotinamide, treatment of heart receptor antagonists (ondansetron, tropisetron, alos
failure with diuretics, treatment of wheezing with oral etron) can control diarrhea and nausea in up to 100%
bronchodilators, and control of the diarrhea with anti of patients and occasionally ameliorate the flush
diarrheal agents such as loperamide and diphenoxyl ing. A combination of histamine H1- and H2-receptor
ate. If patients still have symptoms, serotonin receptor antagonists (i.e., diphenhydramine and cimetidine
is given every 4–6 weeks. carcinomas, a full cancer operation should be done.
Short-term side effects occur in up to one-half of This includes a right hemicolectomy for appendiceal
patients. Pain at the injection site and side effects related carcinoid, an abdominoperineal resection or low
to the GI tract (59% discomfort, 15% nausea, diarrhea) are anterior resection for rectal carcinoids, and an en bloc
the most common. They are usually short-lived and do resection of adjacent lymph nodes for small-intestinal
not interrupt treatment. Important long-term side effects carcinoids. For carcinoids 1–2 cm in diameter for appen
Neoplastic Diseases of the Gastrointestinal System
include gallstone formation, steatorrhea, and deterioration diceal tumors, a simple appendectomy is proposed by
in glucose tolerance. The overall incidence of gallstones/ some, whereas others favor a formal right hemicolec
biliary sludge in one study was 52%, with 7% having symp tomy. For rectal carcinoids 1–2 cm, it is recommended
tomatic disease that required surgical treatment. that a wide local full-thickness excision be performed.
Interferon α is reported to be effective in controlling With type I or II gastric carcinoids, which are usually
symptoms of the carcinoid syndrome either alone or com <1 cm, endoscopic removal is recommended. In type I
bined with hepatic artery embolization. With interferon α or II gastric carcinoids, if the tumor is >2 cm or if there
alone the response rate is 42%, and with interferon α with is local invasion, some recommend total gastrectomy,
hepatic artery embolization, diarrhea was controlled for whereas others recommend antrectomy in type I to
1 year in 43% and flushing was controlled in 86%. reduce the hypergastrinemia, which led to regression of
Hepatic artery embolization alone or with chemo the carcinoids in a number of studies. For types I and II
therapy (chemoembolization) has been used to control gastric carcinoids of 1–2 cm, there is no agreement, with
the symptoms of carcinoid syndrome. Embolization some recommending endoscopic treatment followed
alone is reported to control symptoms in up to 76% of by chronic somatostatin treatment and careful follow-
patients, and chemoembolization (5-fluorouracil, doxo up and others recommending surgical treatment. With
rubicin, cisplatin, mitomycin) in 60–75% of patients. type III gastric carcinoids >2 cm, excision and regional
Hepatic artery embolization can have major side effects, lymph node clearance are recommended. Most tumors
including nausea, vomiting, pain, and fever. In two stud <1 cm are treated endoscopically.
ies 5–7% of patients died from complications of hepatic Resection of isolated or limited hepatic metastases
artery occlusion. may be beneficial and will be discussed in a later section
Other drugs have been used successfully in small on treatment of advanced disease.
numbers of patients to control the symptoms of car
cinoid syndrome. Parachlorophenylanine can inhibit
tryptophan hydroxylase and therefore the conversion
Pancreatic Endocrine Tumors
of tryptophan to 5-HTP. However, its severe side effects,
including psychiatric disturbances, make it intolerable Functional PETs usually present clinically with symp-
for long-term use. α-Methyldopa inhibits the conversion toms due to the hormone-excess state. Only late in
of 5-HTP to 5-HT, but its effects are only partial. the course of the disease does the tumor per se cause
Peptide radioreceptor therapy (using radiotherapy prominent symptoms such as abdominal pain. In con-
with radiolabeled somatostatin analogues), the use of trast, all the symptoms due to nonfunctional PETs
radiolabeled microspheres, and other methods for treat are due to the tumor per se. The overall result of this
ment of advanced metastatic disease may facilitate con is that some functional PETs may present with severe
trol of the carcinoid syndrome and are discussed in a symptoms with a small or undetectable primary tumor,
later section dealing with treatment of advanced disease. whereas nonfunctional tumors usually present late in the
Carcinoid Tumors (Nonmetastatic) disease course with large tumors, which are frequently
Surgery is the only potentially curative therapy. Because metastatic. The mean delay between onset of continu-
with most carcinoids the probability of metastatic dis ous symptoms and diagnosis of a functional PET syn-
ease increases with increasing size, the extent of surgical drome is 4–7 years. Therefore, the diagnoses frequently
resection is determined accordingly. With appendiceal are missed for extended periods.
carcinoids <1 cm, simple appendectomy was curative
in 103 patients followed for up to 35 years. With rec
tal carcinoids <1 cm, local resection is curative. With Treatment Pancreatic Endocrine Tumor
small-intestinal carcinoids <1 cm, there is not complete
agreement. Because 15–69% of small-intestinal carci Treatment of PETs requires two different strategies. First,
noids this size have metastases in different studies, some treatment must be directed at the hormone-excess
multiple. About 60–90% of gastrinomas are malignant 565
state such as the gastric acid hypersecretion in gastri (Table 52-2) with metastatic spread to lymph nodes and
nomas or the hypoglycemia in insulinomas. Ectopic liver. Distant metastases to bone occur in 12–30% of
CHAPTER 52
hormone secretion usually causes the presenting symp patients with liver metastases.
toms and can cause life-threatening complications.
Second, with all the tumors except insulinomas, >50%
Diagnosis
are malignant (Table 52-2); therefore, treatment must
also be directed against the tumor per se. Because in The diagnosis of ZES requires the demonstration of
many patients these tumors are not surgically curable inappropriate fasting hypergastrinemia, usually by dem-
due to the presence of advanced disease at diagnosis, onstrating hypergastrinemia occurring with an increased
CHAPTER 52
insulin and C-peptide levels at the time of hypoglycemia raised, and bullae form; when the bullae rupture,
is particularly helpful for establishing the correct eroded areas form. The lesions can wax and wane.
diagnosis. An elevated proinsulin level when the fasting The development of a similar rash in patients receiv-
glucose level is <45 mg/dL is sensitive and specific. ing glucagon therapy suggests that the rash is a direct
effect of the hyperglucagonemia. A characteristic labo-
ratory finding is hypoaminoacidemia, which occurs in
26–100% of patients.
toms and occurrence of the somatostatinoma syndrome diarrhea, hypokalemia, and dehydration. This syndrome
differ in each. Each of the usual symptoms is more com- also is called Verner-Morrison syndrome, pancreatic
mon in pancreatic than in intestinal somatostatinomas: cholera, and WDHA syndrome for watery diarrhea,
diabetes mellitus (95% vs. 21%), gallbladder disease (94% hypokalemia, and achlorhydria, which some patients
vs. 43%), diarrhea (92% vs. 38%), steatorrhea (83% vs. develop. The mean age of patients with this syndrome
12%), hypochlorhydria (86% vs. 12%), and weight loss is 49 years; however, it can occur in children, and when
(90% vs. 69%). The somatostatinoma syndrome occurs it does, it is usually caused by a ganglioneuroma or
in 30–90% of pancreatic and 0–5% of small-intestinal ganglioneuroblastoma.
somatostatinomas. In various series 43% of all duodenal The principal symptoms are large-volume diarrhea
NETs contain somatostatin; however, the somatostati- (100%) severe enough to cause hypokalemia (80–100%),
noma syndrome is rarely present (<2%). Somatostatino- dehydration (83%), hypochlorhydria (54–76%), and flush-
mas occur in the pancreas in 56–74% of cases, with the ing (20%). The diarrhea is secretory in nature, persisting
primary location being the pancreatic head. The tumors during fasting, and is almost always >1 L/d and in 70%
are usually solitary (90%) and large (mean size 4.5 cm). is >3 L/d. In a number of studies, the diarrhea was inter-
Liver metastases are common, being present in 69–84% mittent initially in up to half the patients. Most patients
of patients. Somatostatinomas are rare in patients with do not have accompanying steatorrhea (16%), and the
MEN 1, occurring in only 0.65%. increased stool volume is due to increased excretion of
Somatostatin is a tetradecapeptide that is widely sodium and potassium, which, with the anions, accounts
distributed in the CNS and GI tract, where it func- for the osmolality of the stool. Patients frequently have
tions as a neurotransmitter or has paracrine and auto- hyperglycemia (25–50%) and hypercalcemia (25–50%).
crine actions. It is a potent inhibitor of many processes, VIP is a 28-amino-acid peptide that is an important
including release of almost all hormones, acid secre- neurotransmitter, ubiquitously present in the CNS and
tion, intestinal and pancreatic secretion, and intesti- GI tract. Its known actions include stimulation of small-
nal absorption. Most of the clinical manifestations are intestinal chloride secretion as well as effects on smooth
directly related to these inhibitory actions. muscle contractility, inhibition of acid secretion, and
vasodilatory effects, which explain most features of the
clinical syndrome.
Diagnosis
In adults 80–90% of VIPomas are pancreatic in
In most cases somatostatinomas have been found by location, with the rest due to VIP-secreting pheochro-
accident either at the time of cholecystectomy or during mocytomas, intestinal carcinoids, and rarely ganglioneu-
endoscopy. The presence of psammoma bodies in romas. These tumors are usually solitary, 50–75% are in
a duodenal tumor should particularly raise suspicion. the pancreatic tail, and 37–68% have hepatic metastases
Duodenal somatostatin-containing tumors are increas- at diagnosis. In children <10 years old, the syndrome is
ingly associated with von Recklinghausen’s disease. Most usually due to ganglioneuromas or ganglioblastomas and
of these tumors (>98%) do not cause the somatostati- is less often malignant (10%).
noma syndrome. The diagnosis of the somatostatinoma
syndrome requires the demonstration of elevated plasma Diagnosis
somatostatin levels.
The diagnosis requires the demonstration of an
elevated plasma VIP level and the presence of large-
Treatment Somatostatinomas volume diarrhea. A stool volume <700 mL/d is pro-
posed to exclude the diagnosis of VIPoma. When the
Pancreatic tumors are frequently (70–92%) metastatic patient fasts, a number of diseases can be excluded that can
at presentation, whereas 30–69% of small-intestinal cause marked diarrhea. Other diseases that can produce
somatostatinomas have metastases. Surgery is the a secretory large-volume diarrhea include gastrinomas,
chronic laxative abuse, carcinoid syndrome, systemic
mastocytosis, rarely medullary thyroid cancer, diabetic microscopic NF-PETs, but they become large or symp- 569
diarrhea, sprue, and AIDS. Among these conditions, tomatic in only a minority (0–13%) of cases. In VHL
only VIPomas caused a marked increase in plasma VIP. 12–17% develop NF-PETs, and in 4% they are ≥3 cm
CHAPTER 52
Chronic surreptitious use of laxatives/diuretics can be in diameter.
particularly difficult to detect clinically. Hence, in a The most common symptoms are abdominal pain
patient with unexplained chronic diarrhea, screens for (30–80%), jaundice (20–35%), and weight loss, fatigue,
laxatives should be performed; they will detect many, or bleeding; 10–30% are found incidentally. The aver-
but not all, laxative abusers. age time from the beginning of symptoms to diagnosis
is 5 years.
The most important initial treatment in these patients is The diagnosis is established by histologic confirmation
to correct their dehydration, hypokalemia, and electro in a patient without either the clinical symptoms or the
lyte losses with fluid and electrolyte replacement. These elevated plasma hormone levels of one of the established
patients may require 5 L/d of fluid and >350 meq/d of syndromes. The principal difficulty in diagnosis is to
potassium. Because 37–68% of adults with VIPomas have distinguish an NF-PET from a nonendocrine pancre-
metastatic disease in the liver at presentation, a signifi atic tumor, which is more common. Even though chro-
cant number of patients cannot be cured surgically. In mogranin A levels are elevated in almost every patient,
these patients long-acting somatostatin analogues such this is not specific for this disease as it can be found in
as octreotide and lanreotide are the drugs of choice. functional PETs, carcinoids, and other neuroendocrine
Octreotide/lanreotide will control the diarrhea short- disorders. Plasma pancreatic polypeptide is increased
and long-term in 75–100% of patients. In nonresponsive in 22–71% of patients and should strongly suggest the
patients the combination of glucocorticoids and diagnosis in a patient with a pancreatic mass because it
octreotide/lanreotide has proved helpful in a small is usually normal in patients with pancreatic adenocar-
number of patients. Other drugs reported to be help cinomas. Elevated plasma PP is not diagnostic of this
ful in small numbers of patients include prednisone tumor because it is elevated in a number of other con-
(60–100 mg/d), clonidine, indomethacin, phenothi ditions, such as chronic renal failure, old age, inflamma-
azines, loperamide, lidamidine, lithium, propranolol, tory conditions, and diabetes. A positive somatostatin
and metoclopramide. Treatment of advanced disease receptor scan in a patient with a pancreatic mass should
with embolization, chemoembolization, chemotherapy, suggest the presence of PET/NF-PET rather than a
radiotherapy, radiofrequency ablation, and peptide nonendocrine tumor.
receptor radiotherapy may be helpful (discussed later).
sites. Patients have a mean age of 38 years, and the though it is detectable immunohistochemically in most
symptoms usually are due to either acromegaly or the PETs, no specific syndrome is associated with release of
tumor per se. The acromegaly caused by GRFomas is ghrelin by the PET.
indistinguishable from classic acromegaly. The pancre-
atic tumors are usually large (>6 cm), and liver metas-
tases are present in 39%. They should be suspected in Tumor Localization
any patient with acromegaly and an abdominal tumor,
Neoplastic Diseases of the Gastrointestinal System
a patient with MEN 1 with acromegaly, or a patient Localization of the primary tumor and knowledge of
without a pituitary adenoma with acromegaly or asso- the extent of the disease are essential to the proper man-
ciated with hyperprolactinemia, which occurs in 70% agement of all carcinoids and PETs. Without proper
of GRFomas. GRFomas are an uncommon cause localization studies it is not possible to determine
of acromegaly. GRFomas occur in <1% of MEN 1 whether the patient is a candidate for curative resection
patients. The diagnosis is established by performing or cytoreductive surgery or requires antitumor treat-
plasma assays for GRF and growth hormone. Most ment or to predict the patient’s prognosis reliably.
GRFomas have a plasma GRF level >300 pg/mL (nor- Numerous tumor localization methods are used in
mal <5 pg/mL men, <10 pg/mL women). Patients both types of NETs, including conventional imag-
with GRFomas also have increased plasma levels of ing studies (computed tomographic scanning, magnetic
insulin-like growth factor type I (IGF-I) levels similar to resonance imaging, transabdominal ultrasound, selective
those in classic acromegaly. Surgery is the treatment of angiography), somatostatin receptor scintigraphy (SRS),
choice if diffuse metastases are not present. Long-acting and positron emission tomographic scanning. In PETs,
somatostatin analogues such as octreotide and lanreo- endoscopic ultrasound (EUS) and functional localiza-
tide are the agents of choice, with 75–100% of patients tion by measuring venous hormonal gradients are also
responding. reported to be useful. Bronchial carcinoids are usually
detected by standard chest radiography and assessed by
CT. Rectal, duodenal, colonic, and gastric carcinoids
are usually detected by GI endoscopy.
Other Rare Pancreatic Endocrine
PETs, as well as carcinoid tumors, frequently overex-
Tumor Syndromes
press high-affinity somatostatin receptors in both their
Cushing’s syndrome (ACTHoma) due to a PET occurs primary tumors and their metastases. Of the five types
in 4–16% of all ectopic Cushing’s syndrome cases. It of somatostatin receptors (sst1–5), radiolabeled octreo-
occurs in 5% of cases of sporadic gastrinomas, almost tide binds with high affinity to sst2 and sst5, has a lower
invariably in patients with hepatic metastases, and is affinity for sst3, and has a very low affinity for sst1 and
an independent poor prognostic factor. Paraneoplastic sst4. Between 90 and 100% of carcinoid tumors and
hypercalcemia due to PETs releasing parathyroid hor- PETs possess sst2, and many also have the other four
mone–related peptide (PTHrP), a PTH-like material, or sst subtypes. Interaction with these receptors can be
unknown factor, is rarely reported. The tumors are usu- used to localize NETs by using [111In-DTPA-d-Phe1]
ally large, and liver metastases are usually present. Most octreotide and radionuclide scanning (SRS) as well as
(88%) appear to be due to release of PTHrP. PETs for treatment of the hormone-excess state with octreo-
occasionally can cause the carcinoid syndrome. PETs tide or lanreotide, as discussed earlier. Because of its
secreting calcitonin have been proposed as a specific sensitivity and ability to localize tumor throughout the
clinical syndrome. One-half of the patients have diar- body, SRS is the initial imaging modality of choice for
rhea, which disappears with resection of the tumor. localizing both the primary and metastatic NETs. SRS
The proposal that this could be a discrete syndrome localizes tumor in 73–89% of patients with carcinoids
is supported by the finding that 25–42% of patients and in 56–100% of patients with PETs, except insulino-
with medullary thyroid cancer with hypercalcitonemia mas. Insulinomas are usually small and have low densi-
develop diarrhea, probably secondary to a motility ties of sst receptors, resulting in SRS being positive in
disorder. This is classified in Table 52-2 as a possible spe- only 12–50% of patients with insulinomas. Figure 52-3
cific disorder because so few cases have been described. shows an example of the increased sensitivity of SRS in
Similarly classified with only a few cases described are a patient with a carcinoid tumor. The CT scan showed
a renin-producing PET in a patient presenting with a single liver metastasis, whereas the SRS demonstrated
hypertension; PETs secreting luteinizing hormone, three metastases in the liver in multiple locations. Occa-
resulting in masculinization or decreased libido; a PET- sional false-positive responses with SRS can occur (12%
secreting erythropoietin resulting in polycythemia; and in one study) because numerous other normal tissues
intraarterial secretin injections) but is still frequently 571
used in insulinoma patients in whom other imaging
studies are negative (assessing hepatic vein insulin con-
CHAPTER 52
centrations post-intraarterial calcium injections). The
intraarterial calcium test may also allow differentiation
of the cause of the hypoglycemia and indicate whether
it is due to an insulinoma or a nesidioblastosis. The
latter entity is becoming increasingly important because
hypoglycemia after gastric bypass surgery for obesity is
increasing in frequency, and it is primarily due to nesid-
p < .028
70 Chemotherapy for metastatic carcinoid tumors has
60 Single liver generally been disappointing, with response rates of
50 lobe metastases 0–40% with various two- and three-drug combinations.
(n = 14)
40
p = .0004 Chemotherapy for PETs has been more successful, with
30 tumor shrinkage reported in 30–70% of patients.
20 The current regimen of choice is streptozotocin and
Neoplastic Diseases of the Gastrointestinal System
Probability of survival, %
CHAPTER 52
are all in clinical studies. 111Indium-, 90yttrium-, and liver failure occurred and the most common side effect
177
lutetium-labeled compounds caused tumor stabiliza was fatigue (6.5%).
tion in 41–81%, 44–88%, and 23–40%, respectively, and The use of liver transplantation has been abandoned
a decrease in tumor size in 8–30%, 6–37%, and 38%, for treatment of most metastatic tumors to the liver.
respectively, of patients with advanced metastatic NETs. However, for metastatic NETs, it is still a consideration.
Use of 177Lu-labeled analogues to treat 504 patients with In a review of 103 cases of malignant NETs (48 PETs,
malignant NETs produced a reduction of tumor size of 43 carcinoids) the 2- and 5-year survival rates were
Nutrition
cHaPter 53
NUTRIENT REQUIREMENTS
AND DIETARY ASSESSMENT
Johanna Dwyer
Nutrients are substances that are not synthesized in REE are useful for assessing the energy needs of an indi-
sufficient amounts in the body and therefore must be vidual whose weight is stable. Thus, for males, REE =
supplied by the diet. Nutrient requirements for groups 900 + 10m, and for females, REE = 700 + 7m, where
of healthy persons have been determined experimentally. m is mass in kilograms. The calculated REE is then
For good health, we require energy-providing nutrients adjusted for physical activity level by multiplying by 1.2
(protein, fat, and carbohydrate), vitamins, minerals, and for sedentary, 1.4 for moderately active, or 1.8 for very
water. Human requirements for organic nutrients include active individuals. The final figure provides an estimate
9 essential amino acids, several fatty acids, glucose, 4 fat- of total caloric needs in a state of energy balance. For
soluble vitamins, 10 water-soluble vitamins, dietary fiber, further discussion of energy balance in health and
and choline. Several inorganic substances, including disease, see Chap. 55.
4 minerals, 7 trace minerals, 3 electrolytes, and the ultra
trace elements, must also be supplied by diet.
The required amounts of the essential nutrients dif- prOTEIN
fer by age and physiologic state. Conditionally essential Dietary protein consists of both essential and nonessential
nutrients are not required in the diet but must be sup- amino acids that are required for protein synthesis. The
plied to individuals who do not synthesize them in ade- nine essential amino acids are histidine, isoleucine, leu-
quate amounts, such as those with genetic defects, those cine, lysine, methionine/cystine, phenylalanine/tyrosine,
having pathologic states with nutritional implications, threonine, tryptophan, and valine. Certain amino acids,
and developmentally immature infants. Many other such as alanine, can also be used for energy and gluco-
organic and inorganic compounds present in foods have neogenesis. When energy intake is inadequate, protein
health effects. For example, lead and pesticide residues intake must be increased, because ingested amino acids
may have toxic effects. are diverted into pathways of glucose synthesis and oxi-
dation. In extreme energy deprivation, protein-calorie
malnutrition may ensue (Chap. 55).
essential nutrient reQuirements For adults, the recommended dietary allowance
(RDA) for protein is about 0.6 g/kg desirable body
ENErgy
mass per day, assuming that energy needs are met and
For weight to remain stable, energy intake must match that the protein is of relatively high biologic value.
energy output. The major components of energy output Current recommendations for a healthy diet call for at
are resting energy expenditure (REE) and physical activ- least 10 to 14% of calories from protein. Most American
ity; minor sources include the energy cost of metabo- diets provide at least those amounts. Biologic value
lizing food (thermic effect of food or specific dynamic tends to be highest for animal proteins, followed by
action) and shivering thermogenesis (e.g., cold-induced proteins from legumes (beans), cereals (rice, wheat,
thermogenesis). The average energy intake is about corn), and roots. Combinations of plant proteins that
2600 kcal/d for American men and about 1900 kcal/d complement one another in biologic value, or com-
for American women, though these estimates vary with binations of animal and plant proteins, can increase
body size and activity level. Formulas for estimating biologic value and lower total protein requirements.
576
Protein needs increase during growth, pregnancy, Other Nutrients 577
lactation, and rehabilitation after injury or malnutri-
tion. Tolerance to dietary protein is decreased in renal See Chap. 54 for detailed descriptions of vitamins and
insufficiency (causing uremia) and in liver failure. trace minerals.
Normal protein intake can precipitate encephalopathy
in patients with cirrhosis of the liver.
Dietary Reference Intakes
Fat and Carbohydrate and Recommended Dietary
Allowances
CHAPTER 53
Fats are a concentrated source of energy and constitute,
on average, 34% of calories in U.S. diets. However, for Fortunately, human life and well-being can be main-
optimal health, fat intake should total no more than tained within a fairly wide range for most nutrients.
30% of calories. Saturated fat and trans-fat should be However, the capacity for adaptation is not infinite—
limited to <10% of calories, and polyunsaturated fats to too much, as well as too little, intake of a nutrient could
<10% of calories, with monounsaturated fats comprising have adverse effects or alter the health benefits con-
the remainder of fat intake. At least 45–55% of total cal- ferred by another nutrient. Therefore, benchmark rec-
Infants
0–6 mo 400 40 5 4 2.0 0.2 0.3 2 0.1 65 0.4 1.7 5 125
7–12 mo 500 50 5 5 2.5 0.3 0.4 4 0.3 80 0.5 1.8 6 150
Children
1–3 y 300 15 5 6 30 0.5 0.5 6 0.5 150 0.9 2 8 200
4–8 y 400 25 5 7 55 0.6 0.6 8 0.6 200 1.2 3 12 250
Males
9–13 y 600 45 5 11 60 0.9 0.9 12 1.0 300 1.8 4 20 375
14–18 y 900 75 5 15 75 1.2 1.3 16 1.3 400 2.4 5 25 550
19–30 y 900 90 5 15 120 1.2 1.3 16 1.3 400 2.4 5 30 550
31–50 y 900 90 5 15 120 1.2 1.3 16 1.3 400 2.4 5 30 550
51–70 y 900 90 10 15 120 1.2 1.3 16 1.7 400 2.4h 5 30 550
>70 y 900 90 15 15 120 1.2 1.3 16 1.7 400 2.4h 5 30 550
Females
9–13 y 600 45 5 11 60 0.9 0.9 12 1.0 300 1.8 4 20 375
14–18 y 700 65 5 15 75 1.0 1.0 14 1.2 400i 2.4 5 25 400
19–30 y 700 75 5 15 90 1.1 1.1 14 1.3 400i 2.4 5 30 425
31–50 y 700 75 5 15 90 1.1 1.1 14 1.3 400i 2.4 5 30 425
51–70 y 700 75 10 15 90 1.1 1.1 14 1.5 400 2.4h 5 30 425
>70 y 700 75 15 15 90 1.1 1.1 14 1.5 400 2.4h 5 30 425
Pregnancy
≤18 y 750 80 5 15 75 1.4 1.4 18 1.6 600j 2.6 6 30 450
19–30 y 770 85 5 15 90 1.4 1.4 18 1.9 600j 2.6 6 30 450
31–50 y 770 85 5 15 90 1.4 1.4 18 1.9 600j 2.6 6 30 450
Lactation
≤18 y 1200 115 5 19 75 1.4 1.6 17 2.0 500 2.8 7 35 550
19–30 y 1300 120 5 19 90 1.4 1.6 17 2.0 500 2.8 7 35 550
31–50 y 1300 120 5 19 90 1.4 1.6 17 2.0 500 2.8 7 35 550
Note: This table presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type. RDAs and AIs may both be used as goals for individual intake. RDAs are
set to meet the needs of almost all individuals (97–98%) in a group. For healthy breastfed infants, the AI is the mean intake. The AI for other life stage and gender groups is believed to cover needs of all
individuals in the group, but lack of data or uncertainty in the data prevent being able 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. To calculate RAEs from retinol equivalents (REs) of provitamin A carotenoids
in foods, divide the REs by 2. For preformed vitamin A in foods or supplements and for provitamin A carotenoids in supplements, 1 RE = 1 RAE.
b
As calciferol. 1 μg calciferol = 40 IU vitamin D.
c
In the absence of adequate exposure to sunlight.
d
As 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.
e
As niacin equivalents (NE). 1 mg of niacin = 60 mg of tryptophan; 0–6 months = preformed niacin (not NE).
f
As 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.
g
Although 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.
h
Because 10 to 30% of older people may malabsorb food-bound B12, it is advisable for those >50 years to meet their RDA mainly by consuming foods fortified with B12 or a supplement containing B12.
i
In 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 from supplements or forti-
fied 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 Academy of Sciences Dietary Reference Intakes, 2000, 2002, reprinted with permission. Courtesy of the National Academy Press,
Washington, DC. http://www.nap.edu.
579
580
Nutrition SECTION X
Table 53-2
Dietary Reference Intakes: Recommended Intakes for Individuals—Elements
Life-Stage Calcium, Chromium, Copper, Fluoride, Iodine, Iron, Magnesium, Manganese, Molybdenum, Phosphorus Selenium, Zinc,
Group mg/d μg/d μg/d mg/d μg/d mg/d mg/d mg/d μg/d mg/d μg/d mg/d
Infants
0–6 mo 210 0.2 200 0.01 110 0.27 30 0.003 2 100 15 2
7–12 mo 270 5.5 220 0.5 130 11 75 0.6 3 275 20 3
Children
1–3 y 500 11 340 0.7 90 7 80 1.2 17 460 20 3
4–8 y 800 15 440 1 90 10 130 1.5 22 500 30 5
Males
9–13 y 1300 25 700 2 120 8 240 1.9 34 1250 40 8
14–18 y 1300 35 890 3 150 11 410 2.2 43 1250 55 11
19–30 y 1000 35 900 4 150 8 400 2.3 45 700 55 11
31–50 y 1000 35 900 4 150 8 420 2.3 45 700 55 11
51–70 y 1200 30 900 4 150 8 420 2.3 45 700 55 11
>70 y 1200 30 900 4 150 8 420 2.3 45 700 55 11
Females
9–13 y 1300 21 700 2 120 8 240 1.6 34 1250 40 8
14–18 y 1300 24 890 3 150 15 360 1.6 43 1250 55 9
19–30 y 1000 25 900 3 150 18 310 1.8 45 700 55 8
31–50 y 1000 25 900 3 150 18 320 1.8 45 700 55 8
51–70 y 1200 20 900 3 150 8 320 1.8 45 700 55 8
>70 y 1200 20 900 3 150 8 320 1.8 45 700 55 8
Pregnancy
≤18 y 1300 29 1000 3 220 27 400 2.0 50 1250 60 12
19–30 y 1000 30 1000 3 220 27 350 2.0 50 700 60 11
31–50 y 1000 30 1000 3 220 27 360 2.0 50 700 60 11
Lactation
≤18 y 1300 44 1300 3 290 10 360 2.6 50 1250 70 13
19–30 y 1000 45 1300 3 290 9 310 2.6 50 700 70 12
31–50 y 1000 45 1300 3 290 9 320 2.6 50 700 70 12
Note: This table presents recommended dietary allowances (RDAs) in bold type and adequate intakes (AIs) in ordinary type. RDAs and AIs may both be used as goals for individual intake. RDAs
are set to meet the needs of almost all individuals (97–98%) in a group. For healthy breastfed infants, the AI is the mean intake. The AI for other life stage and gender groups is believed to cover
needs of all individuals in the group, but lack of data or uncertainty in the data prevent being able to specify with confidence the percentage of individuals covered by this intake.
Source: Food and Nutrition Board, Institute of Medicine—National Academy of Sciences Dietary Reference Intakes, 2000, 2002, reprinted with permission. Courtesy of the National Academy
Press, Washington, DC. http://www.nap.edu.
is a median requirement for a group; 50% of individu- Tolerable Upper Levels of 581
als in a group fall below the requirement and 50% fall Nutrient Intake
above it. Thus, a person with a usual intake at the EAR
has a 50% risk of an inadequate intake. For these rea- Excessive nutrient intake can disturb body functions
sons, other standards, described later, are more useful for and cause acute, progressive, or permanent disabilities.
clinical purposes. The tolerable UL is the highest level of chronic nutri-
ent intake (usually daily) that is unlikely to pose a risk
of adverse health effects for most of the population.
Recommended Dietary Allowances Data on the adverse effects of large amounts of many
nutrients are unavailable or too limited to establish a
CHAPTER 53
The RDA is the average daily dietary intake level that
meets the nutrient requirements of nearly all healthy UL. Therefore, the lack of a UL does not mean that the
persons of a specific sex, age, life stage, or physi- risk of adverse effects from high intake is nonexistent.
ologic condition (such as pregnancy or lactation). The Healthy individuals derive no established benefit from
RDA is the nutrient-intake goal for planning diets of consuming nutrient levels above the RDA or AI.
individuals. Nutrients in commonly eaten foods rarely exceed the
The RDA is defined statistically as two standard UL. However, highly fortified foods and dietary supple-
Dietary Composition
Dietary Assessment
Dietary composition affects the biologic availability
and use of nutrients. For example, the absorption of In clinical situations, nutritional assessment is an itera-
iron may be impaired by high amounts of calcium or tive process that involves: (1) screening for malnutrition,
lead; also, non-heme iron uptake may be impaired by (2) assessing the diet and other data to establish either
SECTION X
the lack of ascorbic acid and amino acids in the meal. the absence or presence of malnutrition and its possible
Protein use by the body may be decreased when essen- causes, (3) planning and implementing the most appro-
tial amino acids are not present in sufficient amounts. priate nutritional therapy, and (4) reassessing intakes to
Animal foods, such as milk, eggs, and meat, have high make sure that they were consumed. Some disease states
biologic values with most of the needed amino acids affect the bioavailability, requirement, use, or excretion
present in adequate amounts. Plant proteins in corn of specific nutrients. In these circumstances, specific mea-
(maize), soy, and wheat have lower biologic values and surements of various nutrients or their biomarkers may be
Nutrition
must be combined with other plant or animal proteins required to ensure adequate replacement.
to achieve optimal use by the body. Most health care facilities have nutrition-screening
processes in place for identifying possible malnutri-
tion after hospital admission. Nutritional screening is
Route of Administration required by the Joint Commission on Accreditation of
The RDAs apply only to oral intakes. When nutrients Healthcare Organizations (JCAHO), but there are no
are administered parenterally, similar values can some- universally recognized or validated standards. The fac-
times be used for amino acids, carbohydrates, fats, sodium, tors that are usually assessed include: abnormal weight
chloride, potassium, and most of the vitamins, because for height or body mass index (e.g., BMI <19 or >25);
their intestinal absorption is nearly 100%. However, the reported weight change (involuntary loss or gain of
oral bioavailability of most mineral elements may be only >5 kg in the past 6 months) (Chap. 10); diagnoses with
half that obtained by parenteral administration. For some known nutritional implications (metabolic disease, any
nutrients that are not readily stored in the body or cannot disease affecting the gastrointestinal tract, alcoholism,
be stored in large amounts, timing of administration may and others); present therapeutic dietary prescription;
also be important. For example, amino acids cannot be chronic poor appetite; presence of chewing and swal-
used for protein synthesis if they are not supplied together; lowing problems or major food intolerances; need for
instead, they will be used for energy production. assistance with preparing or shopping for food, eating,
or other aspects of self-care; and social isolation. Reas-
sessment of nutrition status should occur periodically in
Disease hospitalized patients—at least once every week.
A more complete dietary assessment is indicated for
Specific dietary deficiency diseases include: protein- patients who exhibit a high risk of or frank malnutri-
calorie malnutrition; iron, iodine, and vitamin A defi- tion on nutrition screening. The type of assessment var-
ciency; megaloblastic anemia due to vitamin B12 or folic ies based on the clinical setting, severity of the patient’s
acid deficiency; vitamin D–deficiency rickets and osteo- illness, and stability of his or her condition.
malacia; and scurvy, beriberi, and pellagra (Chaps. 54
and 55). Each deficiency disease is characterized by
imbalances at the cellular level between the supply of
Acute Care Settings
nutrients or energy and the body’s nutritional needs for
growth, maintenance, and other functions. Imbalances In acute care settings, anorexia, various diseases, test pro-
and excess in nutrient intakes are recognized as risk fac- cedures, and medications can compromise dietary intake.
tors for certain chronic degenerative diseases, such as Under such circumstances, the goal is to identify and avoid
saturated fat and cholesterol in coronary artery disease; inadequate intake and assure appropriate alimentation.
sodium in hypertension; obesity in hormone-dependent Dietary assessment focuses on what patients are cur-
endometrial and breast cancers; and ethanol in alcoholism. rently eating, whether or not they are able and willing
Because the etiology and pathogenesis of these disorders to eat, and whether or not they experience any problems
are multifactorial, diet is only one of many risk factors. with eating. Dietary intake assessment is based on infor-
Osteoporosis, for example, is associated with calcium defi- mation from observed intakes; medical record; history;
ciency, as well as risk factors related to environment (e.g., clinical examination; and anthropometric, biochemical,
smoking, sedentary lifestyle), physiology (e.g., estrogen and functional status. The objective is to gather enough
information to establish the likelihood of malnutri- Nutritional monitoring is especially important for 583
tion due to poor dietary intake or other causes to assess patients who are very ill and who have extended lengths
whether nutritional therapy is indicated (Chap. 56). of stay. Patients who are fed by special enteral and par-
Simple observations may suffice to suggest inade- enteral routes also require special nutritional assessment
quate oral intake. These include dietitians’ and nurses’ and monitoring by physicians and/or dietitians with
notes, the amount of food eaten on trays, frequent certification in nutrition support (Chap. 56).
tests and procedures that are likely to cause meals to
be skipped, nutritionally inadequate diet orders such
as clear liquids or full liquids for more than a few days, Ambulatory Settings
CHAPTER 53
fever, gastrointestinal distress, vomiting, diarrhea, a The aim of dietary assessment in the outpatient setting is
comatose state, and diseases or treatments that involve to determine whether or not the patient’s usual diet is a
any part of the alimentary tract. Acutely ill patients with health risk in itself or if it contributes to existing chronic
diet-related diseases such as diabetes need assessment disease-related problems. Dietary assessment also pro-
because an inappropriate diet may exacerbate these vides the basis for planning a diet that fulfills therapeutic
conditions and adversely affect other therapies. Abnor- goals while ensuring patient adherence. The outpatient
mal biochemical values (serum albumin levels <35 g/L dietary assessment should review the adequacy of pres-
Table 53-3
My Pyramid: The USDA Food Guide Pyramid for Healthy Persons
Servings and Examples of Lower: Moderate: Higher:
Standard Portion Sizes 1600 kcal 2200 kcal 2800 kcal
Nutritional Status Assessment Nutrient-based standards like the DRI have also been
developed by the World Health Organization/Food
Full nutritional status assessment is reserved for seriously and Agricultural Organization of the United Nations
ill patients and those at very high nutritional risk when (WHO/FAO) and are available at their Web site:
the cause of malnutrition is still uncertain after initial http://wwww.who.int/nutrition/topics/nutrecomm/en/index.
clinical evaluation and dietary assessment. It involves html. The different standards have many similarities
multiple dimensions, including documentation of dietary in their basic concepts, definitions, and nutrient-
intake, anthropometric measurements, biochemical measure recommendation levels, but there are some differences
ments of blood and urine, clinical examination, health from the DRI, due to the functional criteria chosen,
history, and functional status. Therapeutic dietary pre- environmental differences, the timeliness of the evi-
scriptions and menu plans for most diseases are available dence reviewed, and expert judgment.
from most hospitals and from the American Dietetic
Association. For further discussion of nutritional assess-
ment, see Chap. 55.
CHaPTer 54
Vitamins and trace minerals are required constituents hypercholesterolemia). The hematologic-related vitamins
of the human diet since they are inadequately syn- and minerals either are not considered or are consid-
thesized or not synthesized in the human body. Only ered only briefly in this chapter, as are the bone-related
small amounts of these substances are needed to carry vitamins and minerals (vitamin D, calcium, phospho-
out essential biochemical reactions (e.g., by acting as rus, since they are covered elsewhere (Tables 54-1 and
coenzymes or prosthetic groups). Overt vitamin or 54-2 and Fig. 54-1).
trace mineral deficiencies are rare in Western countries
due to a plentiful, varied, and inexpensive food supply;
however, multiple nutrient deficiencies may appear
together in persons who are chronically ill or alcoholic. ViTaMins
After gastric bypass surgery, patients are at high risk
for multiple nutrient deficiencies. Moreover, subclini- thiamine (Vitamin b1)
cal vitamin and trace mineral deficiencies, as diagnosed Thiamine was the first B vitamin to be identified and
by laboratory testing, are quite common in the normal therefore is referred to as vitamin B1. Thiamine func-
population, especially in the geriatric age group. tions in the decarboxylation of α-ketoacids, such as
Victims of famine, emergency-affected and dis- pyruvate α-ketoglutarate, and branched-chain amino
placed populations, and refugees are at increased acids and thus is essential for energy generation. In addi-
risk for protein-energy malnutrition and classic tion, thiamine pyrophosphate acts as a coenzyme for a
micronutrient deficiencies (vitamin A, iron, iodine) as transketolase reaction that mediates the conversion of
well as for thiamine (beriberi), riboflavin, vitamin C hexose and pentose phosphates. It has been postulated
(scurvy), and niacin (pellagra) overt deficiencies. that thiamine plays a role in peripheral nerve conduc-
Body stores of vitamins and minerals vary tremendously. tion, although the exact chemical reactions underlying
For example, vitamin B12 and vitamin A stores are this function are not known.
large, and an adult may not become deficient for 1 or
more years after being on a deficient diet. However,
Food sources
folate and thiamine may become depleted within weeks
among those eating a deficient diet. Therapeutic modal- The median intake of thiamine in the United States
ities can deplete essential nutrients from the body; for from food alone is 2 mg/d. Primary food sources for
example, hemodialysis removes water-soluble vitamins, thiamine include yeast, organ meat, pork, legumes,
which must be replaced by supplementation. beef, whole grains, and nuts. Milled rice and grains
There are several roles for vitamins and trace miner- contain little thiamine, if any. Thiamine deficiency is
als in diseases: (1) deficiencies of vitamins and minerals therefore more common in cultures that rely heavily
may be caused by disease states such as malabsorption; on a rice-based diet. Tea, coffee (regular and decaffein-
(2) both deficiency and excess of vitamins and minerals ated), raw fish, and shellfish contain thiaminases, which
can cause disease in and of themselves (e.g., vitamin A can destroy the vitamin. Thus, drinking large amounts
intoxication and liver disease); and (3) vitamins and min- of tea or coffee can theoretically lower thiamine body
erals in high doses may be used as drugs (e.g., niacin for stores.
585
586 Table 54-1
Principal Clinical Findings of Vitamin Malnutrition
Dietary Level per Day
Associated with Overt Contributing Factors to
Nutrient Clinical Finding Deficiency in Adults Deficiency
Thiamine Beriberi: neuropathy, muscle weakness <0.3 mg/1000 kcal Alcoholism, chronic diuretic use,
and wasting, cardiomegaly, edema, hyperemesis
ophthalmoplegia, confabulation
Riboflavin Magenta tongue, angular stomatitis, <0.6 mg —
Section X
seborrhea, cheilosis
Niacin Pellagra: pigmented rash of sun- <9.0 niacin equivalents Alcoholism, vitamin B6 deficiency,
exposed areas, bright red tongue, riboflavin deficiency, tryptophan
diarrhea, apathy, memory loss, deficiency
disorientation
Vitamin B6 Seborrhea, glossitis, convulsions, <0.2 mg Alcoholism, isoniazid
neuropathy, depression, confusion,
Nutrition
microcytic anemia
Folate Megaloblastic anemia, atrophic glossitis, <100 μg/d Alcoholism, sulfasalazine,
depression, ↑ homocysteine pyrimethamine, triamterene
Vitamin B12 Megaloblastic anemia, loss of vibratory <1.0 μg/d Gastric atrophy (pernicious anemia),
and position sense, abnormal gait, terminal ileal disease, strict
dementia, impotence, loss of bladder vegetarianism, acid-reducing drugs
and bowel control, ↑ homocysteine, (e.g., H2 blockers)
↑ methylmalonic acid
Vitamin C Scurvy: petechiae, ecchymosis, coiled <10 mg/d Smoking, alcoholism
hairs, inflamed and bleeding gums, joint
effusion, poor wound healing, fatigue
Vitamin A Xerophthalmia, night blindness, Bitot’s <300 μg/d Fat malabsorption, infection, measles,
spots, follicular hyperkeratosis, alcoholism, protein-energy
impaired embryonic development, malnutrition
immune dysfunction
Vitamin D Rickets: skeletal deformation, rachitic <2.0 μg/d Aging, lack of sunlight exposure, fat
rosary, bowed legs; osteomalacia malabsorption, deeply pigmented
skin
Vitamin E Peripheral neuropathy, spinocerebellar Not described unless Occurs only with fat malabsorption
ataxia, skeletal muscle atrophy, underlying contributing or genetic abnormalities of vitamin E
retinopathy factor is present metabolism/transport
Vitamin K Elevated prothrombin time, bleeding <10 μg/d Fat malabsorption, liver disease,
antibiotic use
Boron No biologic function determined Developmental defects, male sterility, 20 mg/d (extrapolated
testicular atrophy from animal data)
Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syn- 2500 mg/d (milk-alkali)
drome), nephrolithiasis, impaired iron
absorption
CHAPTER 54
Copper Anemia, growth retardation, defective Nausea, vomiting, diarrhea, hepatic 10 mg/d (liver toxicity)
keratinization and pigmentation of hair, failure, tremor, mental deterioration,
hypothermia, degenerative changes hemolytic anemia, renal dysfunction
in aortic elastin, osteopenia, mental
deterioration
Chromium Impaired glucose tolerance Occupational: renal failure, dermatitis, ND
form of beriberi, patients may complain of pain and neuritis. Patients with dry beriberi present with a sym-
paresthesia. Wet beriberi presents primarily with cardio- metric peripheral neuropathy of the motor and sen-
vascular symptoms, due to impaired myocardial energy sory systems with diminished reflexes. The neuropathy
metabolism and dysautonomia, and can occur after 3 affects the legs most markedly, and these patients have
months of a thiamine-deficient diet. Patients present difficulty rising from a squatting position.
with an enlarged heart, tachycardia, high-output con- Alcoholic patients with chronic thiamine deficiency
gestive heart failure, peripheral edema, and peripheral also may have central nervous system (CNS) manifestations
588 Active derivative or Principal
Vitamin cofactor form function
CH2
C OH
O
HOCH2
OH Cbl
Figure 54-1
The structures and principal functions of vitamins associated with human disorders.
Active derivative or Principal 589
Vitamin cofactor form function
CHAPTER 54
and retinoic acid rhodopsin (vision)
and glycoproteins
(epithelial cell
(-Carotene) function); also
CH2OH regulates gene
transcription
(Retinol)
HO OH
HO
Figure 54-1
(Continued )
tide (FMN) as prosthetic groups are known as flavoenzymes The amino acid tryptophan can be converted to
(e.g., succinic acid dehydrogenase, monoamine oxidase, niacin with an efficiency of 60:1 by weight. Thus,
glutathione reductase). FAD is a cofactor for methyltetra- the RDA for niacin is expressed in niacin equivalents.
hydrofolate reductase and therefore modulates homocyste- A lower conversion of tryptophan to niacin occurs in
ine metabolism. The vitamin also plays a role in drug and vitamin B6 and/or riboflavin deficiencies and in the
steroid metabolism, including detoxification reactions. presence of isoniazid. The urinary excretion products of
Nutrition
Although much is known about the chemical and niacin include 2-pyridone and 2-methyl nicotinamide,
enzymatic reactions of riboflavin, the clinical mani- measurements of which are used in the diagnosis of
festations of riboflavin deficiency are nonspecific and niacin deficiency.
are similar to those of other deficiences of B vitamins.
Riboflavin deficiency is manifested principally by
lesions of the mucocutaneous surfaces of the mouth and Deficiency
skin (Table 54-1). In addition to the mucocutaneous Niacin deficiency causes pellagra, which is found mostly
lesions, corneal vascularization, anemia, and personality among people eating corn-based diets in parts of China,
changes have been described with riboflavin deficiency. Africa, and India. Pellagra in North America is found
mainly among alcoholics; in patients with congenital
defects of intestinal and kidney absorption of trypto-
Deficiency and excess phan (Hartnup disease); and in patients with carci-
Riboflavin deficiency almost always is due to dietary noid syndrome (Chap. 52), in which there is increased
deficiency. Milk, other dairy products, and enriched conversion of tryptophan to serotonin. In the setting
breads and cereals are the most important dietary sources of famine or population displacement, the occurrence
of riboflavin in the United States, although lean meat, of pellagra results from the absolute lack of niacin but
fish, eggs, broccoli, and legumes are also good sources. also from the deficiency of micronutrients required for
Riboflavin is extremely sensitive to light, and milk the conversion of tryptophan to niacin (e.g., iron, ribo-
should be stored in containers that protect against pho- flavin, and pyridoxine). The early symptoms of pellagra
todegradation. Laboratory diagnosis of riboflavin defi- include loss of appetite, generalized weakness and irri-
ciency can be made by measurement of red blood cell tability, abdominal pain, and vomiting. Bright red glos-
or urinary riboflavin concentrations or by measurement sitis then ensues, followed by a characteristic skin rash
of erythrocyte glutathione reductase activity, with and that is pigmented and scaling, particularly in skin areas
without added FAD. Because the capacity of the gas- exposed to sunlight. This rash is known as Casal’s
trointestinal tract to absorb riboflavin is limited (∼20 mg necklace because it forms a ring around the neck; it is seen
if given in one oral dose), riboflavin toxicity has not in advanced cases. Vaginitis and esophagitis also may
been described. occur. Diarrhea (in part due to proctitis and in part due
to malabsorption), depression, seizures, and dementia
are also part of the pellagra syndrome—the four Ds:
dermatitis, diarrhea, and dementia leading to death.
Niacin (Vitamin B3)
The term niacin refers to nicotinic acid and nicotin-
amide and their biologically active derivatives. Nico- Treatment Pellagra
tinic acid and nicotinamide serve as precursors of two
coenzymes, nicotinamide adenine dinucleotide (NAD) Treatment of pellagra consists of oral supplementation of
and NAD phosphate (NADP), which are impor- 100–200 mg of nicotinamide or nicotinic acid three times
tant in numerous oxidation and reduction reactions in daily for 5 days. High doses of nicotinic acid (2 g/d in a
the body. In addition, NAD and NADP are active in time-release form) are used for the treatment of elevated
adenine diphosphate–ribose transfer reactions involved cholesterol and triglyceride levels and/or a low high-
in DNA repair and calcium mobilization. density lipoprotein (HDL) cholesterol level.
Toxicity can lead to peripheral neuropathy, abnormal electro- 591
encephalograms, and personality changes that include
Prostaglandin-mediated flushing due to binding of depression and confusion. In infants, diarrhea, seizures,
the vitamin to a G protein–coupled receptor has been and anemia have been reported. Microcytic hypochro-
observed at daily doses as low as 50 mg of niacin when mic anemia is due to diminished hemoglobin synthesis,
taken as a supplement or as therapy for dyslipidemia. since the first enzyme involved in heme biosynthesis
There is no evidence of toxicity from niacin derived (aminolevulinate synthase) requires PLP as a cofactor.
from food sources. Flushing always starts in the face In some case reports, platelet dysfunction has been
and may be accompanied by skin dryness, itching, par- reported. Since vitamin B6 is necessary for the con-
esthesia, and headache. Pharmaceutical preparations of
CHAPTER 54
version of homocysteine to cystathionine, it is
nicotinic acid combined with laropiprant, a selective possible that chronic low-grade vitamin B6 deficiency
prostaglandin D2 receptor 1 antagonist, or premedica- may result in hyperhomocysteinemia and increased risk
tion with aspirin may alleviate these symptoms. Flush- of cardiovascular disease. Independent of homocysteine,
ing is subject to tachyphylaxis and often improves with low levels of circulating vitamin B6 have been associated
time. Nausea, vomiting, and abdominal pain also occur with inflammation and elevated levels of C-reactive
at similar doses of niacin. Hepatic toxicity is the most protein.
tion. Folates are found in virtually every kind of food available than synthetic forms. Smoking, hemodialysis,
but even more is required in the setting of high red pregnancy, and stress (e.g., infection, trauma) appear to
cell turnover such as hemolytic anemia or rapid growth increase vitamin C requirements.
such as pregnancy.
Vitamin B12 or cobalamin exists in a variety of forms
that all have a cobalt atom within a corrin ring. The Deficiency
Nutrition
2-deoxyadenosyl form is located in the mitochon- Vitamin C deficiency causes scurvy. In the United States,
dria and is a coafactor for methylmalonyl coenzyme A this is seen primarily among the poor and elderly, in
mutase, which is involved in myelin synthesis and other alcoholics who consume <10 mg/d of vitamin C, and
reactions. Methylcobalamin is a cofactor for methionine in individuals consuming macrobiotic diets. Vitamin C
synthase and participates in the reduction and methyla- deficiency also can occur in young adults who eat
tion of folate to donate a methyl group for thymidylate severely unbalanced diets. In addition to generalized
synthesis. Vitamin B12 is found only in meat, fish, and fatigue, symptoms of scurvy primarily reflect impaired
dairy products, not plants. Its absorption is mediated by formation of mature connective tissue and include
intrinsic factor produced by parietal cells in the stomach bleeding into skin (petechiae, ecchymoses, perifol-
and the intrinsic factor-B12 complex is absorbed in the licular hemorrhages); inflamed and bleeding gums;
terminal ileum. Gastritis and acid blockers can inhibit and manifestations of bleeding into joints, the perito-
intrinsic factor production. Diseases of the terminal neal cavity, the pericardium, and the adrenal glands.
ileum may also inhibit absorption. Because folate cor- In children, vitamin C deficiency may cause impaired
rects the anemia of B12 deficiency, folate food supple- bone growth. Laboratory diagnosis of vitamin C defi-
mentation has also reduced the detection of B12 defi- ciency is made on the basis of low plasma or leukocyte
ciency from anemia symptoms. Accordingly, it is now levels.
more common to detect B12 deficiency in older patients Administration of vitamin C (200 mg/d) improves
with balance difficulties from posterior columns demy- the symptoms of scurvy within a matter of several days.
elination, B12 deficiency is also a reversible cause of High-dose vitamin C supplementation (e.g., 1–2 g/d) may
dementia. slightly decrease the symptoms and duration of upper respi-
ratory tract infections. Vitamin C supplementation has also
been reported to be useful in Chédiak-Higashi syndrome
Vitamin C and osteogenesis imperfecta. Diets high in vitamin C
have been claimed to lower the incidence of certain can-
Both ascorbic acid and its oxidized product dehydro- cers, particularly esophageal and gastric cancers. If proved,
ascorbic acid are biologically active. Actions of vitamin C this effect may be due to the fact that vitamin C can pre-
include antioxidant activity, promotion of nonheme vent the conversion of nitrites and secondary amines to
iron absorption, carnitine biosynthesis, the conver- carcinogenic nitrosamines. However, an intervention study
sion of dopamine to norepinephrine, and the synthesis from China did not show vitamin C to be protective. Par-
of many peptide hormones. Vitamin C is also impor- enteral ascorbic acid has been suggested to have a potential
tant for connective tissue metabolism and cross-linking therapeutic role in the treatment of advanced cancers.
(proline hydroxylation), and it is a component of many
drug-metabolizing enzyme systems, particularly the
mixed-function oxidase systems.
Toxicity
Taking >2 g of vitamin C in a single dose may result in
Absorption and dietary sources
abdominal pain, diarrhea, and nausea. Since vitamin C
Almost complete absorption of vitamin C occurs if may be metabolized to oxalate, it is feared that chronic
<100 mg is administered in a single dose; however, high-dose vitamin C supplementation could result in
only 50% or less is absorbed at doses >1 g. Enhanced an increased prevalence of kidney stones. However,
this has not been borne out in several trials, except in The vitamin is ubiquitous in the food supply. Liver, 593
patients with preexisting renal disease. Thus, it is rea- yeast, egg yolks, whole grains, and vegetables are par-
sonable to advise patients with a past history of kidney ticularly good sources. Human pantothenic acid defi-
stones not to take large doses of vitamin C. There is ciency has been demonstrated only in experimental
also an unproven but possible risk that chronic high feeding of diets low in pantothenic acid or by giving a
doses of vitamin C could promote iron overload in specific pantothenic acid antagonist. The symptoms of
patients taking supplemental iron. High doses of vita- pantothenic acid deficiency are nonspecific and include
min C can induce hemolysis in patients with glucose- gastrointestinal disturbance, depression, muscle cramps,
6-phosphate dehydrogenase deficiency, and doses paresthesia, ataxia, and hypoglycemia. Pantothenic acid
CHAPTER 54
>1 g/d can cause false-negative guaiac reactions as well deficiency is believed to have caused the burning feet
as interfere with tests for urinary glucose. High doses syndrome seen in prisoners of war during World War II.
may interfere with certain drugs (e.g., bortezomib in No toxicity of this vitamin has been reported.
myeloma patients).
Choline
miologic studies and limited clinical human and animal noic acid to the nucleus and enable its metabolism.
studies, flavonoids have been postulated to play a role in Retinoic acid is a ligand for certain nuclear recep-
the prevention of several chronic diseases, including neu- tors that act as transcription factors. Two families
rodegenerative disease, diabetes, and osteoporosis. The of receptors (RAR and RXR receptors) are active in
ultimate importance and usefulness of their compounds retinoid-mediated gene transcription. Retinoid receptors
against human disease have not been demonstrated. regulate transcription by binding as dimeric complexes
Nutrition
CHAPTER 54
that interfere with the absorption of vitamin A include
Uncomplicated vitamin A deficiency rarely occurs in
mineral oil, neomycin, and cholestyramine.
industrialized countries. One high-risk group, extremely
low-birth-weight infants (<1000 g), is likely to be
Deficiency vitamin A–deficient and should be supplemented with
Vitamin A deficiency is endemic in areas where 1500 μg (or RAE) of vitamin A three times a week for
diets are chronically poor, especially in southern 4 weeks. Severe measles in any society can lead to
who ingest 15 mg/d and children who ingest 6 mg/d of or brain dysfunction (e.g., depression). However, the
vitamin A over a period of several months. Manifestations importance of the exact physiologic role of vitamin D
include dry skin, cheilosis, glossitis, vomiting, alopecia, in these nonskeletal diseases has not been clarified.
bone demineralization and pain, hypercalcemia, lymph A major source of vitamin D is its synthesis in the skin
node enlargement, hyperlipidemia, amenorrhea, and fea- upon ultraviolet B (UV-B) (wavelength, 290–315 nm)
tures of pseudotumor cerebri with increased intracranial exposure. Except for fish, food (unless fortified) con-
Nutrition
pressure and papilledema. Liver fibrosis with portal tains only limited amounts of vitamin D. Vitamin D2
hypertension and bone demineralization may result from (ergocalciferol) is obtained from plant sources and is the
chronic vitamin A intoxication. When vitamin A is pro- chemical form found in some supplements.
vided in excess to pregnant women, congenital malfor-
mations have included spontaneous abortions, craniofacial Deficiency
abnormalities, and valvular heart disease. In pregnancy,
the daily dose of vitamin A should not exceed 3 mg. Vitamin D status has been assessed by measuring serum
Commercially available retinoid derivatives are also toxic, 25-dihydroxyvitamin D (25[OH]2 vitamin D) levels;
including 13-cis-retinoic acid, which has been associated however, there is no consensus on a uniform assay meth-
with birth defects. As a result, contraception should be odology or on optimal serum levels. The optimal level
continued for a least 1 year and possibly longer in women might, in fact, differ according to the targeted disease
who have taken 13-cis-retinoic acid. entity. Based on epidemiologic and experimental data, a
In malnourished children, vitamin A supplements 25(OH)2 vitamin D level >20 ng/mL (≥50 nmol/L; to
(100,000–200,000 IU) as a function of age in several convert ng/mL to nmol/L, multiply by 2.496) is suf-
rounds over 2 years are considered to amplify nonspe- ficient for good bone health. Some experts advocate
cific effects of vaccines. However, for unclear reasons, higher serum levels (e.g., >30 ng/mL) for other desirable
there may be a negative effect on mortality rates in endpoints of vitamin D action.
incompletely vaccinated girls. Risk factors for vitamin D deficiency are old age,
High doses of carotenoids do not result in toxic lack of sun exposure, dark skin (especially among those
symptoms but should be avoided in smokers due to living in northern latitudes), fat malabsorption, and
an increased risk of lung cancer. Very high doses of obesity. Rickets represents the classic disease of vitamin D
β-carotene (∼200 mg/d) have been used to treat or pre- deficiency. Signs of deficiency are muscle soreness,
vent the skin rashes of erythropoietic protoporphyria. weakness, and bone pain. Some of these effects are
Carotenemia, which is characterized by a yellowing of the independent of calcium intake.
skin (creases of the palms and soles) but not the sclerae, The U.S. National Academy of Science recently con-
may be present after ingestion of >30 mg of β-carotene cluded that the majority of North Americans are receiv-
daily. Hypothyroid patients are particularly susceptible to ing adequate amounts of vitamin D (RDA = 15 μg/d
the development of carotenemia due to impaired break- or 600 IU/d; Chap. 53). However, for people older
down of carotene to vitamin A. Reduction of carotenes than 70 years, the RDA is set at 20 μg/d (800 IU/d).
from the diet results in the disappearance of skin yellow- The consumption of fortified or enriched foods as well
ing and carotenemia over a period of 30–60 days. as suberythemal sun exposure should be encouraged
for people at risk for vitamin D deficiency. If an ade-
quate intake cannot be achieved, vitamin D supplements
Vitamin D
should be taken, especially during the winter months.
The biologic effects of vitamin D are mediated by Vitamin D deficiency can be treated by the oral admin-
vitamin D receptors, which are found in most tissues, istration of 50,000 IU/week for 6–8 weeks followed by
thus potentially expanding vitamin D actions on nearly a maintenance dose of 800 IU/d (100 μg/d) from food
all cell systems and organs (e.g., immune cells, brain, and supplements after achievement of normal plasma
breast, colon, and prostate) as well as exerting clas- levels. The physiologic effects of vitamin D2 and D3 are
sic endocrine effects on calcium metabolism and bone identical when ingested over long periods.
Toxicity defect in the α-tocopherol transport protein. Vitamin E 597
deficiency causes axonal degeneration of the large
The upper limit of intake has been set at 4000 IU/d.
myelinated axons and results in posterior column and
Contrary to earlier beliefs, acute vitamin D intoxication is
spinocerebellar symptoms. Peripheral neuropathy is ini-
rare and usually is caused by the uncontrolled and exces-
tially characterized by areflexia, with progression to an
sive ingestion of supplements or faulty food fortification
ataxic gait, and by decreased vibration and position sen-
practices. High plasma 1,25(OH)2 vitamin D and high
sations. Ophthalmoplegia, skeletal myopathy, and pig-
plasma calcium levels are central features of toxicity. Stop-
mented retinopathy may also be features of vitamin E
ping vitamin D and calcium supplements is mandatory,
deficiency. Either vitamin E or selenium deficiency in
and treatment of hypercalcemia may be required.
CHAPTER 54
the host has been shown to increase certain viral muta-
tions and, therefore, virulence. The laboratory diagnosis
Vitamin E of vitamin E deficiency is made on the basis of low
blood levels of α-tocopherol (<5 μg/mL, or <0.8 mg of
Vitamin E is a collective name for all stereoisomers of α-tocopherol per gram of total lipids).
tocopherols and tocotrienols, although only the RR
tocopherols meet human requirements. Vitamin E
Table 54-2.
of vascular calcification is not known. Warfarin-type drugs
inhibit γ-carboxylation by preventing the conversion of
vitamin K to its active hydroquinone form. Zinc
Dietary sources Zinc is an integral component of many metalloenzymes
in the body; it is involved in the synthesis and stabiliza-
Nutrition
Vitamin K is found in green leafy vegetables such as kale tion of proteins, DNA, and RNA and plays a structural
and spinach, and appreciable amounts are also present in role in ribosomes and membranes. Zinc is necessary for
margarine and liver. Vitamin K is present in vegetable the binding of steroid hormone receptors and several
oils; olive, canola, and soybean oils are particularly rich other transcription factors to DNA. Zinc is absolutely
sources. The average daily intake by Americans is esti- required for normal spermatogenesis, fetal growth, and
mated to be approximately 100 μg/d. embryonic development.
Deficiency Absorption
The symptoms of vitamin K deficiency are due The absorption of zinc from the diet is inhibited by
to hemorrhage, and newborns are particularly dietary phytate, fiber, oxalate, iron, and copper, as well
susceptible because of low fat stores, low breast as by certain drugs, including penicillamine, sodium
milk levels of vitamin K, sterility of the infantile intesti- valproate, and ethambutol. Meat, shellfish, nuts, and
nal tract, liver immaturity, and poor placental transport. legumes are good sources of bioavailable zinc, whereas
Intracranial bleeding, as well as gastrointestinal and skin zinc in grains and legumes is less available for absorption.
bleeding, can occur in vitamin K–deficient infants
1–7 days after birth. Thus, vitamin K (1 mg IM) is
Deficiency
given prophylactically at the time of delivery.
Vitamin K deficiency in adults may be seen in Mild zinc deficiency has been described in many
patients with chronic small-intestinal disease (e.g., celiac diseases, including diabetes mellitus, HIV/AIDS,
disease, Crohn’s disease), in those with obstructed bili- cirrhosis, alcoholism, inflammatory bowel disease,
ary tracts, or after small-bowel resection. Broad-spectrum malabsorption syndromes, and sickle cell disease. In these
antibiotic treatment can precipitate vitamin K deficiency diseases, mild chronic zinc deficiency can cause stunted
by reducing gut bacteria, which synthesize menaqui- growth in children, decreased taste sensation (hypogeu-
nones, and by inhibiting the metabolism of vitamin K. sia), and impaired immune function. Severe chronic zinc
In patients with warfarin therapy, the antiobesity drug deficiency has been described as a cause of hypogonad-
orlistat can lead to international normalized ratio (INR) ism and dwarfism in several Middle Eastern countries. In
changes due to vitamin K malabsorption. The diag- these children, hypopigmented hair is also part of the
nosis of vitamin K deficiency usually is made on the syndrome. Acrodermatitis enteropathica is a rare autoso-
basis of an elevated prothrombin time or reduced clot- mal recessive disorder characterized by abnormalities in
ting factors, although vitamin K may also be measured zinc absorption. Clinical manifestations include diarrhea,
directly by HPLC. Vitamin K deficiency is treated by alopecia, muscle wasting, depression, irritability, and a
using a parenteral dose of 10 mg. For patients with rash involving the extremities, face, and perineum. The
chronic malabsorption, 1–2 mg/d of vitamin K should rash is characterized by vesicular and pustular crusting
be given orally, or 1–2 mg/week can be taken paren- with scaling and erythema. Occasional patients with
terally. Patients with liver disease may have an elevated Wilson’s disease have developed zinc deficiency as a
prothrombin time because of liver cell destruction as consequence of penicillamine therapy.
well as vitamin K deficiency. If an elevated prothrom- The diagnosis of zinc deficiency is usually made by a
bin time does not improve on vitamin K therapy, it serum zinc level <12 μmol/L (<70 μg/dL). Pregnancy
can be deduced that it is not the result of vitamin K and birth control pills may cause a slight depression
deficiency. in serum zinc levels, and hypoalbuminemia from any
cause can result in hypozincemia. In acute stress situa- a rare autosomal recessive disease characterized by tissue 599
tions, zinc may be redistributed from serum into tissues. iron overload, mental deterioration, microcytic anemia,
Zinc deficiency may be treated with 60 mg elemen- and low serum iron and copper concentrations.
tal zinc, orally twice a day. Zinc gluconate lozenges The diagnosis of copper deficiency is usually made on
(13 mg elemental zinc every 2 h while awake) have the basis of low serum levels of copper (<65 μg/dL) and
been reported to reduce the duration and symptoms of low ceruloplasmin levels (<20 mg/dL). Serum levels of
the common cold in adults, but studies are conflicting. copper may be elevated in pregnancy or stress conditions
Zinc deficiency is prevalent in many developing since ceruloplasmin is an acute-phase reactant and 90%
countries and usually coexists with other micronutrient of circulating copper is bound to ceruloplasmin.
CHAPTER 54
deficiencies (especially iron). Zinc (20 mg/d) may be
an effective adjunctive therapeutic strategy for diarrheal Toxicity
disease and pneumonia in children.
Copper toxicity is usually accidental (Table 54-2). In
severe cases, kidney failure, liver failure, and coma may
Toxicity
ensue. In Wilson’s disease, mutations in the copper-
Acute zinc toxicity after oral ingestion causes nausea, transporting ATP7B gene lead to accumulation of cop-
normal diet each day and about 100 mg/d is absorbed and in a few patients receiving prolonged total paren-
and is matched by the levels of excretion. teral nutrition. Several manganese-specific enzymes
Hypomagnesemia is generally a reflection of increased have been identified (e.g., manganese superoxide dis-
losses through nausea, vomiting, diarrhea, or increased mutase). Deficiencies of manganese have been reported
renal excretion due to failure of reabsorption. Hypo- to result in bone demineralization, poor growth, ataxia,
magnesemic patients may have tetany, tremor, muscle disturbances in carbohydrate and lipid metabolism, and
weakness, ataxia, nystagmus, vertigo, seizures, apathy, convulsions.
depression, irritability, delirium, or psychosis. Cardiac Ultratrace elements are defined as those needed in
arrhythmias may also occur. Hypocalcemia and hypoka- amounts <1 mg/d. Essentiality has not been established
lemia may also be seen. Magnesium supplementation is for most ultratrace elements, although selenium, chro-
usually corrective mium, and iodine are clearly essential. Molybdenum is
Hypermagnesemia occurs mainly in the setting of renal necessary for the activity of sulfite and xanthine oxidase,
failure or overingestion of magnesium-containing cathartics. and molybdenum deficiency may result in skeletal and
Vasodilatation is the common result with hypotension brain lesions.
cHaPter 55
Douglas C. Heimburger
Malnutrition can arise from primary or secondary or sepsis and chronic illnesses such as cancer, lung or
causes, with the former resulting from inadequate or heart disease, and HIV can erode lean body mass even
poor-quality food intake and the latter from diseases in the presence of relatively sufficient dietary intake,
that alter food intake or nutrient requirements, metabo- leading to a kwashiorkor-like state. Quite often, inflam-
lism, or absorption. Primary malnutrition occurs mainly matory illnesses impair appetite and dietary intake,
in developing countries and under conditions of politi- producing combinations of the two.
cal unrest, war, or famine. Secondary malnutrition, An international consensus committee has proposed
the main form encountered in industrialized countries, the following revised definitions. Starvation-related mal-
was largely unrecognized until the early 1970s, when it nutrition is suggested for instances of chronic starvation
was appreciated that persons with adequate food sup- without inflammation, chronic disease–related malnutrition
plies can become malnourished as a result of acute or when inflammation is chronic and of mild to moderate
chronic diseases that alter nutrient intake or metabo- degree, and acute disease– or injury-related malnutrition when
lism, particularly diseases that cause acute or chronic inflammation is acute and of a severe degree. However,
inflammation. Various studies have shown that pro- because distinguishing diagnostic criteria for these con-
tein-energy malnutrition (PEM) affects one-third to ditions have not been elaborated, this chapter outlines
one-half of patients on general medical and surgical criteria that have served well and are embedded in the
wards in teaching hospitals. The consistent finding that medical literature.
nutritional status influences patient prognosis under-
scores the importance of preventing, detecting, and
treating malnutrition. MarasMus or CaChexia
Marasmus is a state in which virtually all available
body fat stores have been exhausted due to starvation.
Protein-enerGY Malnutrition Cachexia is a state that involves substantial loss of lean
body mass due to chronic systemic inflammation.
Definitions for forms of PEM are in flux. Tradition- Conditions that produce cachexia in high-income
ally, the two major types of PEM have been marasmus countries tend to be chronic and indolent, such as
and kwashiorkor. These conditions are compared in cancer and chronic pulmonary disease, whereas maras-
Table 55-1. Marasmus has been considered the end mus occurs in patients with anorexia nervosa. These
result of a long-term deficit of dietary energy, whereas conditions are relatively easy to detect because of the
kwashiorkor has been understood to result from a patient’s starved appearance. The diagnosis is based on
protein-poor diet. Although the former concept remains fat and muscle wastage resulting from prolonged calorie
essentially correct, evidence is accumulating that PEM deficiency and/or inflammation. Diminished skinfold
syndromes are distinguished by two main features: dietary thickness reflects the loss of fat reserves; reduced arm
intake and underlying inflammatory processes. Energy- muscle circumference with temporal and interosseous
poor diets with minimal inflammation cause gradual muscle wasting reflects the catabolism of protein
erosion of body mass, resulting in classic marasmus. By throughout the body, including vital organs such as the
contrast, inflammation from acute illnesses such as injury heart, liver, and kidneys.
601
602 Table 55-1
Comparison of Marasmus/Cachexia and Kwashiorkor/Protein-Calorie Malnutrition
Marasmus or Cachexia Kwashiorkor or Protein-Calorie Malnutritiona
breakdown
Mortality Low unless related to underlying disease High
Diagnostic criteria Triceps skinfold <3 mm Serum albumin <2.8 g/dL
Midarm muscle circumference At least one of the following:
<15 cm Poor wound healing, decubitus ulcers, or skin
breakdown
Easy hair pluckabilityb
Edema
a
The findings used to diagnose kwashiorkor must be unexplained by other causes.
b
Tested by firmly pulling a lock of hair from the top (not the sides or back), grasping with the thumb and forefinger. An average of three or more
hairs removed easily and painlessly is considered abnormal hair pluckability.
Routine laboratory findings in cachexia/marasmus illnesses such as trauma and sepsis. The physiologic stress
are relatively unremarkable. The creatinine-height index produced by these illnesses increases protein and energy
(24-h urinary creatinine excretion compared with nor- requirements at a time when intake is often limited. A
mal values based on height) is low, reflecting the loss classic scenario for PCM is an acutely stressed patient
of muscle mass. Occasionally, the serum albumin level who receives only 5% dextrose solutions for periods
is reduced, but it stays above 2.8 g/dL in uncompli- as brief as 2 weeks; this gives rise to the proposed term
cated cases. Despite a morbid appearance, immuno- acute disease– or injury-related malnutrition. Although the
competence, wound healing, and the ability to handle etiologic mechanisms are not fully known, the protein-
short-term stress are reasonably well preserved in most sparing response normally seen in starvation is blocked
patients. by the stressed state and by carbohydrate infusion.
Pure starvation-related malnutrition is a chronic, In its early stages, the physical findings of kwashiorkor/
fairly well adapted form of starvation rather than an PCM are few and subtle. Fat reserves and muscle mass
acute illness; it should be treated cautiously in an are initially unaffected, giving the deceptive appearance
attempt to reverse the downward trend gradually. of adequate nutrition. Signs that support the diagnosis
Although nutritional support is necessary, overly aggres- of kwashiorkor/PCM include easy hair pluckability,
sive repletion can result in severe, even life-threatening edema, skin breakdown, and poor wound healing.
metabolic imbalances such as hypophosphatemia and The major sine qua non is severe reduction of levels
cardiorespiratory failure (refeeding syndrome). When of serum proteins such as albumin (<2.8 g/dL) and
possible, oral or enteral nutritional support is preferred; transferrin (<150 mg/dL) or iron-binding capacity
treatment started slowly allows readaptation of meta- (<200 μg/dL). Cellular immune function is depressed,
bolic and intestinal functions (Chap. 56). reflected by lymphopenia (<1500 lymphocytes/μL in
adults and older children) and lack of response to skin
test antigens (anergy).
Kwashiorkor or Protein-Calorie The prognosis of adult patients with full-blown
Malnutrition (PCM) kwashiorkor/PCM is not good even with aggres-
By contrast, kwashiorkor or PCM in developed countries sive nutritional support. Surgical wounds often dehisce
occurs mainly in connection with acute, life-threatening (fail to heal), pressure sores develop, gastroparesis and
diarrhea can occur with enteral feeding, the risk of gas- Table 55-2 603
trointestinal bleeding from stress ulcers is increased, host Physiologic Characteristics of
defenses are compromised, and death from overwhelm- Hypometabolic and Hypermetabolic States
ing infection may occur despite antibiotic therapy. Hypometabolic, Hypermetabolic,
Unlike treatment in marasmus, aggressive nutritional Nonstressed Stressed Patient
support is indicated to restore better metabolic balance Physiologic Patient (Kwashiorkor
Characteristics (Marasmic) Riska)
rapidly (Chap. 56). Although kwashiorkor in children is
less foreboding, perhaps because a lesser degree of stress Cytokines, ↓ ↑
is required to precipitate the disorder, it is still a serious catecholamines,
glucagon,
CHAPTER 55
condition.
cortisol, insulin
Metabolic rate, O2 ↓ ↑
consumption
Physiologic Characteristics
Of Hypometabolic and Proteolysis, ↓ ↑
Hypermetabolic States gluconeogenesis
Ureagenesis, urea ↓ ↑
(anaerobic glycolysis), white blood cells, and newly holic patients receiving intravenous glucose. The adverse
generated fibroblasts. Infusions of glucose partially off- clinical sequelae are numerous; some, such as acute car-
set a negative energy balance but do not significantly diopulmonary failure, are collectively called refeeding
suppress the high rates of gluconeogenesis in catabolic syndrome and can be life-threatening.
patients. Hence, adequate supplies of protein are needed
to replace the amino acids utilized for this metabolic
Nutrition
CHAPTER 55
both underlying disease and nutritional status. There-
Anthropometrics
fore, the nutritional evaluation of a patient requires an
integration of the history, physical examination, anthro- Anthropometric measurements provide information on
pometrics, and laboratory studies. This approach helps body muscle mass and fat reserves. The most practical
both to detect nutritional problems and to prevent con- and commonly used measurements are body weight,
cluding that isolated findings indicate nutritional prob- height, triceps skinfold (TSF), and midarm muscle cir-
lems when they do not. For example, hypoalbuminemia cumference (MAMC). Body weight is one of the most
Hair, Nails
Corkscrew hairs and unemerged coiled hairs Vitamin C
Easily pluckable hair Protein
Flag sign (transverse depigmentation of hair) Protein
Sparse hair Protein, biotin, zinc Vitamin A
Transverse ridging of nails Protein
Section X
Skin
Cellophane appearance Protein
Cracking (flaky paint or crazy pavement dermatosis) Protein
Follicular hyperkeratosis Vitamins A, C
Petechiae (especially perifollicular) Vitamin C
Purpura Vitamins C, K
Nutrition
a
In this table, “protein deficiency” is used to signify kwashiorkor/PCM.
Table 55-5 607
Laboratory Tests for Nutritional Assessment
Causes of Normal
Value Despite Other Causes of
Test (Normal Values) Nutritional Use Malnutrition Abnormal Value
CHAPTER 55
protein balance or whole blood intake
Burns, trauma
Congestive heart failure
Fluid overload
Severe liver disease
Uncommon:
Nephrotic syndrome
Zinc deficiency
Assessment of circulating (visceral) proteins physiologic stress persists, serum protein levels remain
low, even with aggressive nutritional support. How-
The serum proteins most commonly used to assess ever, if the levels do not rise after the underlying illness
nutritional status include albumin, total iron-binding improves, the patient’s protein and calorie needs should
capacity (or transferrin), thyroxine-binding prealbumin be reassessed to ensure that intake is sufficient.
(or transthyretin), and retinol-binding protein. Because
they have differing synthesis rates and half-lives—the
half-life of serum albumin is about 21 days, whereas Assessment of vitamin and mineral status
those of prealbumin and retinol-binding protein are The use of laboratory tests to confirm suspected micro-
about 2 days and 12 h, respectively—some of these pro- nutrient deficiencies is desirable because the physical
teins reflect changes in nutritional status more quickly findings for those deficiencies are often equivocal or
than do others. However, rapid fluctuations can also nonspecific. Low blood micronutrient levels can pre-
make shorter-half-life proteins less reliable. date more serious clinical manifestations and also may
Levels of circulating proteins are influenced by their indicate drug-nutrient interactions.
rates of synthesis and catabolism, “third spacing” (loss
into interstitial spaces), and, in some cases, external loss.
Although an adequate intake of calories and protein is Estimating Energy and Protein
necessary to achieve optimal circulating protein levels, Requirements
serum protein levels generally do not reflect protein
intake. For example, a drop in the serum level of albu- A patient’s basal energy expenditures (BEE, measured
min or transferrin often accompanies significant physi- in kilocalories per day) can be estimated from height,
ologic stress (e.g., from infection or injury) and is not weight, age, and gender by using the Harris-Benedict
necessarily an indication of malnutrition or poor intake. equations:
A low serum albumin level in a burned patient with Men: BEE = 66.47 + 13.75W + 5.00H − 6.76A
both hypermetabolism and increased dermal losses of Women: BEE = 655.10 + 9.56W + 1.85H − 4.68A
protein may not indicate malnutrition. However, ade-
quate nutritional support of the patient’s calorie and where W is weight in kilograms; H is height in centi-
protein needs is critical for returning circulating proteins meters, and A is age in years. After these equations are
to normal levels as stress resolves. Thus low values by solved, total energy requirements are estimated by mul-
themselves do not define malnutrition, but they often tiplying BEE by a factor that accounts for the stress of
point to increased risk of malnutrition because of illness. Multiplying by 1.1–1.4 yields a range 10–40%
the hypermetabolic stress state. As long as significant above basal that estimates the 24-h energy expenditure
of the majority of patients. The lower value (1.1) is used and determine whether protein intake is adequate to 609
for patients without evidence of significant physiologic offset it. Total protein loss and protein balance can be
stress; the higher value (1.4) is appropriate for patients calculated from urinary urea nitrogen (UUN) as follows:
with marked stress such as sepsis or trauma. The result is
Protein catabolic rate (g/d) = [24-h UUN (g) + 4]
used as a 24-h energy goal for feeding.
× 6.25 (g protein/g nitrogen)
When it is important to have a more accurate assess-
ment of energy expenditure, it can be measured at the The value of 4 g added to the UUN represents a
bedside by using indirect calorimetry. This technique liberal estimate of the unmeasured nitrogen lost in the
is useful in patients who are believed to be hypermet- urine (e.g., creatinine and uric acid), sweat, hair, skin,
CHAPTER 55
abolic from sepsis or trauma and whose body weights and feces. When protein intake is low (e.g., less than
cannot be obtained accurately. Indirect calorimetry can about 20 g/d), the equation indicates both the patient’s
also be useful in patients who have difficulty weaning protein requirement and the severity of the catabolic
from a ventilator, as their energy needs should not be state (Table 55-5). More substantial protein intakes
exceeded to avoid excessive CO2 production. Patients can raise the UUN because some of the ingested (or
at the extremes of weight (e.g., obese persons) and/ infused) protein is catabolized and converted to UUN.
or age are good candidates as well, because the Harris-
The ability to provide specialized nutritional support teams. For the postoperative patient with preexisting
(SNS) represents a major advance in medical therapy. malnutrition, or in trauma patients who were previ-
Nutritional support, via either enteral or parenteral ously well nourished, SNS is cost-effective. In the most
routes, is used in two main settings: (1) to provide ade- critically ill patient in the intensive care unit, SNS can
quate nutritional intake during the recuperative phase enhance survival. Although enteral nutrition (EN) can
of illness or injury, when the patient’s ability to ingest be provided by most health care teams caring for hos-
or absorb nutrients is impaired, and (2) to support the pitalized patients, safe and effective parenteral nutrition
patient during the systemic response to inflammation, (PN) usually requires specialized teams.
injury, or infection during an extended critical illness.
SNS is also used in patients with permanent loss of
intestinal length or function. In addition, an increasing APPROACH TO THE Requirements for Specialized
PATIENT Nutritional Support
number of elderly patients living in nursing homes and
chronic care facilities receive enteral feeding, usually as iNDicatioNS for SpEcializED Nutri-
a consequence of inadequate nutritional intake. tioNal Support Although at least 15–20% of
Enteral refers to feeding via a tube placed into the gut patients in acute care hospitals have evidence of signifi-
to deliver liquid formulas containing all essential nutri- cant malnutrition, only a small fraction will benefit from
ents. Parenteral refers to the infusion of complete nutri- SNS. For others, wasting is an inevitable component of
ent solutions into the bloodstream via a peripheral vein a terminal disease and the course of the disease will
or, more commonly, by central venous access to meet not be altered by SNS. The decision to use SNS should
nutritional needs. Enteral feeding is generally the pre- be based on the likelihood that preventing protein-
ferred route because of benefits derived from maintain- calorie malnutrition (PCM) will increase the likelihood
ing the digestive, absorptive, and immunologic barrier of recovery, reduce infection rates, improve healing, or
functions of the gastrointestinal tract. Small-bore pli- otherwise shorten the hospital stay. In the case of the
able tubes have largely replaced large-bore rubber elderly or chronically ill patient for whom full recovery is
tubes, making placement easier and more acceptable not anticipated, the decision to feed is usually based on
to patients. Infusion pumps have also improved the whether SNS will extend the duration or quality of life.
delivery of nutrient solutions. The decision-making process used to assess whether to
For short-term use, enteral tubes can be placed via use SNS is depicted in Fig. 56-1.
the nose into the stomach, duodenum, or jejunum. For The first step in deciding to administer SNS is to con-
long-term use, these sites can be accessed through the sider the nutritional implications of the disease process.
abdominal wall using endoscopic, radiologic, or surgi- Is the condition or its treatment likely to impair food
cal procedures. Intestinal tolerance of tube feeding may intake and absorption for a prolonged period of time?
be limited during acute illness by gastric retention or For example, a well-nourished individual can tolerate
diarrhea. Parenteral feeding has greater risk of infec- approximately 7 days of starvation while experiencing
tion, reflecting the need for venous access, and a greater a systemic response to inflammation (SRI). The second
propensity for inducing hyperglycemia. However, these step is to determine if the patient is already significantly
risks can generally be managed successfully by SNS
610
ALGORITHM FOR IMPLEMENTATION OF SNS 611
Is disease process likely to cause nutritional impairment?
Yes
Yes
CHAPTER 56
with SNS improve the prognosis and quality of life?
Yes No
What are the fluid, energy, mineral, Risks and discomfort of SNS
and vitamin requirements and can these outweigh potential benefits.
be provided enterally? Explain issue to patient or
legal surrogate. Support patient
with general comfort measures
No Yes
malnourished to the degree that critical functions such to decide whether SNS will impact positively on the
as wound healing, immune responses, or ventilatory patient’s response to disease. In the end stages of many
function are impaired (Chap. 55). An unintentional chronic illnesses with accompanying PCM, particularly
weight loss of >10% during the previous 6 months or a those due to cancer or terminal neurologic disorders,
weight/height <90% of standard, when associated with nutrition may not reverse the PCM or improve qual-
physiologic impairment, represents significant PCM. ity of life. While the provision of food and water is part
Weight loss >20% of usual or <80% of standard reflects of basic medical care, nutrition delivered by tube or
severe PCM. The presence or absence of SRI should be catheter, either enterally or parenterally, is associated
noted, since inflammation, injury, and infection increase with risk and discomfort. Thus, SNS should be recom-
the rate of lean tissue loss. SRI also has pathophysiologic mended only when potential benefits exceed risks,
effects that influence nutritional responses such as fluid and it should be undertaken with the consent of the
retention and hyperglycemia, as well as impairment of patient. Like other life support measures, enteral or
anabolic responses to nutritional support. parenteral therapy is difficult to withdraw once started.
Once it is determined that a patient is already or Initiating nutrition support may be appropriate before
at risk of becoming malnourished, the next step is a final prognosis can be determined, but this should
612 not preclude its subsequent withdrawal. If prevent- the patient was initially well nourished. If severely mal-
ing or treating PCM with SNS is appropriate, nutritional nourished, candidates for elective major surgery ben-
requirements and the method of delivery should be efit from preoperative nutritional repletion for 5–7 days.
determined. The optimal route depends on the degree However, this is not often possible. Thus, early postop-
of gut function and somewhat on the available techni- erative feeding is indicated. Patients with a moderate
cal resources. SRI and moderate PCM also benefit from earlier feeding
The timing of nutritional support is based on evalu- within the first several days.
ation of the preexisting nutritional status, the presence
Efficacy of SNS in Different Disease
and extent of SRI, and the anticipated clinical course. SRI
States Efficacy studies have shown that malnour-
Section X
CHAPTER 56
omega-3 fatty acids, and nucleotides available in some cava can be accomplished at the bedside by trained
specialty enteral formulas are particularly important for personnel using sterile techniques. Peripherally inserted
maintaining immunity. Enteral feeding also supports central catheters (PICCs) can also be placed within the
gut function by stimulating splanchnic blood flow, neu- lumen in the central vein, but this technique is usually
ronal activity, IgA antibody release, and secretion of more appropriate for non-ICU patients. Subclavian or
gastrointestinal hormones that stimulate gut trophic internal jugular catheters carry a greater risk, including
Number Continued
in Age in Survivala on Full Oral on HPEN
Diagnosis Group Years Therapy, % Nutrition Rx Died C P M HPEN NonHPEN
disorder
Congenital 172 5 94 42 47 9 63 27 11 2.1 1.0
bowel defect
Hyperemesis 112 28 100 100 0 0 83 16 1 1.5 3.5
gravidarum
Chronic 156 42 90 82 10 5 60 38 2 1.2 2.5
pancreatitis
Radiation 145 58 87 28 49 22 42 49 9 0.8 1.1
enteritis
Chronic 120 53 83 47 34 13 23 68 10 1.7 1.4
adhesive
obstructions
Cystic fibrosis 51 17 50 38 13 36 24 66 16 0.8 3.7
Cancer 2122 44 20 26 8 63 29 57 14 1.1 3.3
AIDS 280 33 10 13 6 73 8 63 29 1.6 3.3
Home Enteral Nutrition
Neurologic 1134 65 55 19 25 48 5 24 71 0.3 0.9
disorders of
swallowing
Cancer 1644 61 30 30 6 59 21 59 21 0.4 2.7
a
Survival rates on therapy are values at 1 year, calculated by the life table method. This will differ from the percentage listed as died under
Therapy Status, since all patients with known endpoints are considered in this latter measure. The ratio of observed versus expected deaths is
equivalent to a Standard Mortality Ratio.
b
Not shown are those patients who were back in hospital or who had changed therapy type by 12 months.
c
Rehabilitation is designated complete (C), partial (P), or minimal (M), relative to the patient’s ability to sustain normal age-related activity.
d
Complications refer only to those complications that resulted in rehospitalization.
Source: Derived from North American HPEN Registry. Adapted from chapter in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.
For instance, in nitrogen accumulation disorders, pro- In hepatic failure, intakes of 1.2–1.4 g/kg up to the opti-
tein intake may need to be reduced. However, in renal mal 1.5 g/kg should be attempted, as long as encepha-
disease, except for brief periods of several days, protein lopathy due to protein intolerance is not encoun-
intakes should approach requirement levels of at least tered. In the presence of protein intolerance, formulas
0.8 g/kg or higher up to 1.2 g/kg as long as the blood containing 33–50% branched-chain amino acids are
urea nitrogen does not exceed 100 mg/dL. If this is available and should be provided at the 1.2–1.4-g/kg
not possible, then dialysis or other renal replacement level. Cardiac patients, and many severely stressed
therapy should be considered to allow better feeding. patients, often benefit from fluid and sodium restriction
aldosterone, insulin, glucagon, or cortisol) that cause 615
to levels of 1000 mL of total parenteral nutrition (TPN) fluid retention and hyperglycemia. Weight gain in the
formula and 5–20 meq of sodium per day. In patients critically ill, whether receiving SNS or not, is invari-
with severe chronic PCM characterized by severe weight ably the consequence of fluid retention, since lean tissue
loss and tissue wasting, TPN must be instituted gradu- accretion, even with feeding, is minimal in the acute
ally because of the profound antinatriuresis, antidiure- phase of illness. Because excess fluid removal can be dif-
sis, and intracellular accumulation of potassium, mag- ficult, limiting fluid intake to allow for balanced intake
nesium, and phosphorus that develop as a consequence and output is more effective.
of high insulin levels. This modification of TPN is usually
accomplished by limiting fluid intakes initially to about
CHAPTER 56
1000 mL containing modest carbohydrate content of Energy Requirements
10–20% dextrose, low sodium, and ample potassium,
magnesium, and phosphorus, with careful daily assess-
Total energy expenditure comprises resting energy
ment of fluid and electrolyte status. Protein need not be
expenditure, activity energy expenditure, and the ther-
restricted.
mal effect of feeding (Chap. 55). Resting energy expen-
diture (two-thirds) includes the calories necessary for
Table 56-3
Enteric Fluid Volumes and Their Electrolyte Contenta
L/d Na K Cl HCO3 H
a
All in meq/L.
Source: Adapted from chapter in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.
616 to aim for energy balance to 1.2 times measured expen- which have been shown to improve immune function
diture with SNS. and reduce the inflammatory response.
Insulin resistance due to SRI is associated with Carbohydrates are provided as hydrous glucose pro-
increased gluconeogenesis and reduced peripheral viding 3.4 kcal/g in PN formulas. In enteral formulas,
glucose utilization, predisposing a patient to hypergly- glucose is the carbohydrate source in so-called mono-
cemia. This is aggravated in patients receiving exog- meric diets. These diets provide protein as amino acids
enous carbohydrate from SNS. Normalization of blood and fat in minimal amounts (3%) to meet essential fatty
glucose levels by insulin infusion in critically ill patients acid requirements. Monomeric formulas are designed to
receiving SNS reduces morbidity and mortality. In mild optimize absorption in the seriously compromised gut.
or moderately malnourished patients, a reasonable goal These formulas, like the immune-enhancing diets, are
Section X
is to provide metabolic support to improve protein syn- quite expensive. In polymeric diets, the carbohydrate
thesis and maintain metabolic homeostasis. Hypocaloric source is usually an osmotically less active polysaccha-
nutrition providing only about 1000 kcal/d and 70 g ride, protein is usually soy or casein protein, and fat is
protein for up to 10 days requires less fluid and reduces present in amounts from 25 to 50%. Such formulas are
the likelihood of poor glycemic control. Energy content usually well tolerated by patients with normal intestinal
can be advanced to 20–25 kcal/kg with 1.5 g protein/kg length, and some are acceptable for oral consumption.
Nutrition
CHAPTER 56
Manganese 0.1–0.3 mg/d, possibility of retention in
Potassium 40–100 meq/d + replace-
biliary tract obstruction
ment of unusual losses
Chromium 10–15 μg/d
Chloride As needed for acid-base
balance, but usually Selenium 20–100 μg/d, necessary for long-term
2:1 to 1:1 with acetate PN, optional for short-term TPN
Acetate As needed for acid-base Molybdenum 20–120 μg/d, necessary for long-term
gauze at regular intervals should be performed by nurses tion and catheter infection. Temporary catheters that
skilled in catheter care to avoid infection. Chlorhexi- develop a thrombus should be removed and, based on
dine solution is more effective than alcohol or iodine clinical findings, treated with anticoagulants. Throm-
compounds. Appropriate monitoring for patients receiv- bolytic therapy can be considered for patients with
ing PN is summarized in Table 56-7. permanent catheters, depending on the ease of replace-
ment and presence of alternate, reasonably accept-
Nutrition
Hyponatremia Increased total body water or decreased total body sodium Decrease free water or increase sodium
Hypernatremia Occurs commonly with excessive isotonic or hypertonic Increase free water to produce net posi-
fluid followed by diuretic administration with free water tive fluid balance maintaining sodium
clearance; can also occur with dehydration and normal and chloride balance
total body sodium
CHAPTER 56
Hypokalemia Inadequate intake relative to need Use supplements
Excessive diuresis, tubular dysfunction Use supplements
Magnesium deficiency Increase PN magnesium
Metabolic alkalosis Correct alkalosis
Hyperinsulinemia Maintain constant PN, increase
potassium
Hyperkalemia Excessive provision Reduce supplements
patients. It is generally best to start PN with <200 g the next day’s order, with SC insulin supplements as
glucose/d to assess glucose tolerance. Regular insulin needed. Advances in TPN concentration should be
can be added to the PN formula to establish glycemic made when reasonable glucose control is established,
control, and the insulin doses can be increased propor- and the insulin dose adjusted proportionately to the cal-
tionately as the glucose is advanced. As a general rule, ories added as glucose and amino acids. These are gen-
patients with insulin-dependent diabetes require about eral rules, and they are conservative. Given the adverse
twice their usual home insulin doses when they are clinical impact of hyperglycemia, it may be necessary to
receiving TPN at 20–25 kcal/kg, largely as a conse- use intensive insulin therapy as a separate infusion with
quence of parenteral glucose administration and some a standard protocol to initially establish control. Once
loss of insulin to the TPN container. As a rough esti- established, this insulin dose can be added to the PN
mate, the amount of insulin can be provided in a similar formula. Acid-base imbalance is also common during
proportion to the amount of calories provided as TPN PN therapy. Amino acid formulas are buffered, but crit-
relative to full feeding, and the insulin can be placed in ically ill patients are prone to metabolic acidosis, often
the TPN formula. Subcutaneous (SC) regular insulin due to renal tubular impairment. The use of sodium and
can be provided to improve glucose control as assessed potassium acetate salts in the PN formula may address
by measurements of blood glucose every 6 h. About this problem. Bicarbonate salts should not be used
two-thirds of the total 24-h amount can be added to because they are incompatible with TPN formulations.
620 Nasogastric drainage produces a hypochloremic alkalosis formulas are listed in Table 56-10. Patients receiving
that can be managed by attention to chloride balance. EN are at risk for many of the same metabolic com-
Occasionally, hydrochloric acid may be required for a plications as those who receive PN and should be
more rapid response or when diuretic therapy limits the monitored in the same manner. EN can be a source of
ability to provide substantial sodium chloride. Up to similar problems, but not to the same degree, because
100 meq/L and up to 150 meq of hydrochloric acid per the insulin response to EN is about half of that seen
day may be placed in a fat-free TPN formula. with PN. Enteral feeding formulas have fixed electro-
lyte compositions that are generally modest in sodium
Infectious and somewhat higher in potassium content. Acid-base
disturbances can be addressed to a more limited extent
Section X
Infections of the central access catheter rarely occur in with EN. Acetate salts can be added to the formula
the first 72 h. Fever during this period is usually from to treat chronic metabolic acidosis. Calcium chloride
infection elsewhere or another cause. Fever that develops can be added to treat mild chronic metabolic alkalosis.
during PN can be addressed by checking the catheter Medications and other additives to enteral feeding for-
site and, if the site looks clean, exchanging the catheter mulas can clog the tubes (e.g., calcium chloride may
over a wire with cultures taken through the catheter and interact with casein-based formulas to produce insoluble
Nutrition
at the catheter tip. If these cultures are negative, as they calcium caseinate products) and may reduce the efficacy
are most of the time, the new catheter can continue to of some drugs (e.g., phenytoin). Since small-bore tubes
be used. If a culture is positive for a relatively nonpatho- are easily displaced, tube position should be checked at
genic bacteria like Staphylococcus epidermidis, consider a intervals by aspirating and measuring the pH of the gut
second exchange over a wire with repeat cultures or fluid (<4 in the stomach, >6 in the jejunum).
replace the catheter depending on the clinical circum-
stances. If cultures are positive for more pathogenic
bacteria, or for fungi like Candida albicans, it is gener- Complications
ally best to replace the catheter at a new site. Whether
antibiotic treatment is required is a clinical decision, but Aspiration
C. albicans grown from the blood culture in a patient The debilitated patient with poor gastric emptying
receiving PN should always be treated because the con- and impairment of swallowing and cough is at risk for
sequences of failure to treat can be dire. aspiration; this is particularly true for those who are
Catheter infections can be minimized by dedicat- mechanically ventilated. Tracheal suctioning induces
ing the feeding catheter to TPN, without blood sam- coughing and gastric regurgitation, and cuffs on endo-
pling or medication administration. Central catheter tracheal or tracheostomy tubes seldom protect against
infections are a serious complication with an attributed aspiration. Preventive measures include elevating the
mortality of 12–25%. Infections in central venous cath- head of the bed to 30 degrees, using nurse-directed
eters dedicated to feeding should occur less frequently algorithms for formula advancement, combining enteral
than 3 per 1000 catheter-days. Home TPN catheters with parenteral feeding, and using post–ligament of
that become infected may be treated through the cath- Treitz feeding. Tube feeding should not be discontin-
eter without removal of the catheter, particularly if the ued for gastric residuals of <300 mL unless there are
offending organism is S. epidermidis. Clearing of the bio- other signs of gastrointestinal intolerance such as nausea,
film and fibrin sheath by local treatment of the catheter vomiting, or abdominal distention. Continuous feed-
with indwelling alteplase may increase the likelihood of ing using pumps is better tolerated intragastrically and is
eradication. Antibiotic lock therapy with high concen- essential for feeding into the jejunum. For small-bowel
trations of antibiotic, with or without heparin in addi- feeding, residuals are not assessed but abdominal pain
tion to systemic therapy, may improve efficacy. Sepsis and distention should be monitored.
with hypotension should precipitate catheter removal in
either the temporary or permanent TPN setting.
Diarrhea
Enteral feeding often leads to diarrhea, especially if
bowel function is compromised by disease or drugs,
Enteral Nutrition particularly broad-spectrum antibiotics. Diarrhea may
be controlled by the use of a continuous drip, with a
Tube Placement and
fiber-containing formula, or by adding an antidiar-
Patient Monitoring
rheal agent to the formula. However, Clostridium dif-
The types of enteral feeding tubes, methods of inser- ficile, which is a common cause of diarrhea in patients
tion, their clinical uses, and potential complications are being tube fed, should be ruled out before using antidi-
outlined in Table 56-9. The different types of enteral arrheal agents. H2 blockers may also assist in reducing
Table 56-9 621
Enteral Feeding Tubes
Type/Insertion Technique Clinical Uses Potential Complications
Nasogastric Tube
External measurement: nostril, ear, Short-term clinical situation (weeks) Aspiration; ulceration of nasal and
xiphisternum; tube stiffened by ice or longer periods with intermittent esophageal tissues, leading to stricture
water or stylet; position verified by insertion; bolus feeding simpler, but
injecting air and auscultating, or by continuous drip with pump better
x-ray tolerated
CHAPTER 56
Nasoduodenal Tube
External measurement: nostril, ear, Short-term clinical situations where Spontaneous pulling back into stomach
anterior superior iliac spine; tube stiff- gastric emptying impaired or proximal (position verified by aspirating content,
ened by stylet and passed through leak suspected; requires continuous pH >6); diarrhea common, fiber-
pylorus under fluoroscopy or with drip with pump containing formulas may help
endoscopic loop
Note: All small tubes are at risk for clogging, especially if used for crushed medications. In long-term enteral patients, gastrostomy and jejunos-
tomy tubes can be exchanged for a low-profile “button” once the tract is established. PEJ, percutaneous endoscopic jejunostomy.
Source: Adapted from chapter in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.
Table 56-10
Enteral Formulas
Composition Characteristics Clinical Indications
(continued)
622 Table 56-10
Enteral Formulas (Continued)
Composition Characteristics Clinical Indications
b. ↑ Fat >40% cals (++) Pulmonary failure with CO2 retention on standard
formula, limited utility
c. ↑ Fat from MUFA (++) Improvement in glycemic index control in diabetes
d. ↑ Fat from ω3 and ↓ ω6 linoleic acid (+++) Improved ventilation in ARDS
4. Fiber provided as soy polysaccharide (+) Improved laxation
Nutrition
a
Cost: +, inexpensive; ++, moderately expensive; +++, very expensive.
Abbreviations: ARDS, acute respiratory distress syndrome; CHO, carbohydrate; MCT, medium-chain triglyceride; MUFA, monounsaturated fatty
acids; ω3 or ω6, polyunsaturated fat with first double bond at carbon 3 (fish oils) or carbon 6 (vegetable oils).
Source: Adapted from chapter in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.
the net fluid presented to the colon. Diarrhea associ- circumstances. In Europe and Japan there are a num-
ated with enteral feeding does not necessarily imply ber of other lipid emulsions available, including those
inadequate absorption of nutrients other than water containing fish oil only; mixtures of fish oil, medium-
and electrolytes. Amino acids and glucose are particu- chain triglycerides, and long-chain triglycerides as olive
larly well absorbed in the upper small bowel except oil and/or soybean oil; mixtures of medium-chain tri-
in the most diseased or shortest bowel. Since luminal glycerides and long-chain triglycerides as soybean oil;
nutrients exert trophic effects on the gut mucosa, it is and long-chain triglyceride mixtures of olive oil and
often appropriate to persist with tube feeding, despite soybean oil, which may be more beneficial in terms of
the diarrhea, even when this necessitates supplemental metabolism and hepatic and immune function. Further-
parenteral fluid support. more, a glutamine-containing dipeptide for inclusion in
TPN formulas is available in Europe and may be helpful
in terms of immune function and resistance to infection.
Global Considerations
Acknowledgment
In the United States the only parenteral lipid
emulsion available is made with soybean oil, The authors acknowledge the contributions of Lyn Howard,
and it has been suggested that its constituent MD, the author in earlier editions of Harrison’s Principles of
fatty acids may be immunosuppressive under certain Internal Medicine, to material in this chapter.
SECTION XI
BIOLOGY OF OBESITY
In a world where food supplies are intermittent, the in both men and women. Large-scale epidemiologic
ability to store energy in excess of what is required for studies suggest that all-cause, metabolic, cancer, and
immediate use is essential for survival. Fat cells, resid- cardiovascular morbidity begin to rise (albeit at a slow
ing within widely distributed adipose tissue depots, are rate) when BMIs are ≥25, suggesting that the cutoff
adapted to store excess energy efficiently as triglycer- for obesity should be lowered. Most authorities use the
ide and, when needed, to release stored energy as free term overweight (rather than obese) to describe individu-
fatty acids for use at other sites. This physiologic sys- als with BMIs between 25 and 30. A BMI between
tem, orchestrated through endocrine and neural path- 25 and 30 should be viewed as medically significant and
ways, permits humans to survive starvation for as long worthy of therapeutic intervention, especially in the
as several months. However, in the presence of nutri- presence of risk factors that are influenced by adiposity
tional abundance and a sedentary lifestyle, and influ- such as hypertension and glucose intolerance.
enced importantly by genetic endowment, this system The distribution of adipose tissue in different anatomic
increases adipose energy stores and produces adverse depots also has substantial implications for morbidity.
health consequences. Specifically, intraabdominal and abdominal subcutane-
ous fat have more significance than subcutaneous fat
present in the buttocks and lower extremities. This dis-
dEfINITION aNd mEaSuREmENT tinction is most easily made clinically by determining
the waist-to-hip ratio, with a ratio >0.9 in women and
Obesity is a state of excess adipose tissue mass. Although
>1.0 in men being abnormal. Many of the most impor-
often viewed as equivalent to increased body weight,
tant complications of obesity such as insulin resistance,
this need not be the case—lean but very muscular
diabetes, hypertension, hyperlipidemia, and hyper-
individuals may be overweight by numerical standards
androgenism in women, are linked more strongly to
without having increased adiposity. Body weights are
intraabdominal and/or upper body fat than to overall
distributed continuously in populations, so that choice
adiposity (Chap. 60). The mechanism underlying this
of a medically meaningful distinction between lean and
association is unknown but may relate to the fact that
obese is somewhat arbitrary. Obesity is therefore more
intraabdominal adipocytes are more lipolytically active
effectively defined by assessing its linkage to morbidity
than those from other depots. Release of free fatty acids
or mortality.
into the portal circulation has adverse metabolic actions,
Although not a direct measure of adiposity, the most
especially on the liver. Whether adipokines and cyto-
widely used method to gauge obesity is the body mass
kines secreted by visceral adipocytes play an additional
index (BMI), which is equal to weight/height2 (in kg/m2)
role in systemic complications of obesity is an area of
(Fig. 57-1). Other approaches to quantifying obesity
active investigation.
include anthropometry (skinfold thickness), densitom-
etry (underwater weighing), CT or MRI, and electri-
cal impedance. Using data from the Metropolitan Life
Tables, BMIs for the midpoint of all heights and frames
PREValENCE
among both men and women range from 19 to 26 kg/ Data from the National Health and Nutrition Exami-
m2; at a similar BMI, women have more body fat than nation Surveys (NHANES) show that the percent-
men. Based on data of substantial morbidity, a BMI of age of the American adult population with obesity
30 is most commonly used as a threshold for obesity (BMI >30) has increased from 14.5% (between 1976
624
Weight Height 625
kg lb cm in.
340
150
320 125
140
300 Body Mass Index 50
130 [kg/m2]
280 130
120 70
260
110 240 WOMEN 60 MEN 135
RELATIVE RELATIVE
100 220 50 55
RISK RISK 140
95
90 200
VERY HIGH VERY HIGH 145
85 190 40
180 HIGH HIGH
80
170 150
75
160 MODERATE MODERATE 60
70 30
150 155
65 LOW LOW
140
CHAPTER 57
160
60 130
VERY LOW VERY LOW
20 165 65
55 120
50 110 170
100 175
45
95 70
Biology of Obesity
180
90
40
85
185
80
35 10
75 190 75
70 195
30 65
200
60 80
205
25 55
210
85
50
Figure 57-1
Nomogram for determining body mass index. To use this centimeters or inches located on the right-hand line. The
nomogram, place a ruler or other straight edge between the body mass index is read from the middle of the scale and is
body weight (without clothes) in kilograms or pounds located in metric units. (Copyright 1979, George A. Bray, MD; used
on the left-hand line and the height (without shoes) in with permission.)
and 1980) to 33.9% (between 2007 and 2008). As many ultimately influence the effector arms of energy intake
as 68% of U.S. adults aged ≥20 years were overweight and expenditure. This complex regulatory system
(defined as BMI >25) between the years of 2007 and is necessary because even small imbalances between
2008. Extreme obesity (BMI ≥40) has also increased and energy intake and expenditure will ultimately have large
affects 5.7% of the population. The increasing preva- effects on body weight. For example, a 0.3% positive
lence of medically significant obesity raises great con- imbalance over 30 years would result in a 9-kg (20-lb)
cern. Obesity is more common among women and in weight gain. This exquisite regulation of energy bal-
the poor, and among blacks and Hispanics; the preva- ance cannot be monitored easily by calorie-counting
lence in children is also rising at a worrisome rate. in relation to physical activity. Rather, body weight
regulation or dysregulation depends on a complex
interplay of hormonal and neural signals. Alterations in
Physiologic Regulation
stable weight by forced overfeeding or food depriva-
of Energy Balance
tion induce physiologic changes that resist these pertur-
Substantial evidence suggests that body weight is regu- bations: with weight loss, appetite increases and energy
lated by both endocrine and neural components that expenditure falls; with overfeeding, appetite falls and
626 Central controllers
final expression of appetite. Apart from rare genetic syn-
of appetite dromes involving leptin, its receptor, and the melano-
Psychological Cultural
factors Increase Decrease factors
cortin system, specific defects in this complex appetite
appetite control network that influence common cases of obesity
NPY α-MSH are not well defined.
MCH CART
AgRP GLP-1 Energy expenditure includes the following compo-
Orexin Serotonin nents: (1) resting or basal metabolic rate; (2) the energy
Endocannabinoid Hormones
Leptin cost of metabolizing and storing food; (3) the ther-
Neural afferents
Insulin mic effect of exercise; and (4) adaptive thermogenesis,
Cortisol
(vagal) which varies in response to long-term caloric intake
Gut peptides Metabolites (rising with increased intake). Basal metabolic rate
CCK Glucose
Ghrelin Ketones accounts for ∼70% of daily energy expenditure, whereas
PYY active physical activity contributes 5–10%. Thus, a sig-
Figure 57-2 nificant component of daily energy consumption is
The factors that regulate appetite through effects on fixed.
central neural circuits. Some factors that increase or Genetic models in mice indicate that mutations
decrease appetite are listed. NPY, neuropeptide Y; MCH, in certain genes (e.g., targeted deletion of the insulin
Section XI
melanin-concentrating hormone; AgRP, Agouti-related pep- receptor in adipose tissue) protect against obesity, appar-
tide; α-MSH, α-melanocyte-stimulating hormone; CART, ently by increasing energy expenditure. Adaptive ther-
cocaine- and amphetamine-related transcript; GLP-1, glucagon- mogenesis occurs in brown adipose tissue (BAT), which
related peptide-1; CCK, cholecystokinin. plays an important role in energy metabolism in many
mammals. In contrast to white adipose tissue, which is
used to store energy in the form of lipids, BAT expends
Obesity and Eating Disorders
CHAPTER 57
(Fig. 57-3). These include the energy balance–regulating among poor women, whereas in underdeveloped coun-
hormone leptin, cytokines such as tumor necrosis factor tries, wealthier women are more often obese. In chil-
(TNF)-α and interleukin (IL)-6, complement factors such dren, obesity correlates to some degree with time spent
as factor D (also known as adipsin), prothrombotic agents watching television. Although the role of diet compo-
such as plasminogen activator inhibitor I, and a compo- sition in obesity continues to generate controversy, it
nent of the blood pressure–regulating system, angiotensin- appears that high-fat diets may promote obesity when
Biology of Obesity
ogen. Adiponectin, an abundant adipose-derived protein combined with diets rich in simple, rapidly absorbed
whose levels are reduced in obesity, enhances insulin carbohydrates.
sensitivity and lipid oxidation and it has vascular-pro- Additional environmental factors may contribute to
tective effects, whereas resistin and RBP4, whose lev- the increasing obesity prevalence. Both epidemiologic
els are increased in obesity, may induce insulin resistance. correlations and experimental data suggest that sleep
These factors, and others not yet identified, play a role deprivation leads to increased obesity. Changes in gut
in the physiology of lipid homeostasis, insulin sensitivity, microbiome with capacity to alter energy balance are
blood pressure control, coagulation, and vascular health, receiving experimental support from animal studies, and
and are likely to contribute to obesity-related pathologies. a possible role for obesigenic viral infections continues
to receive sporadic attention.
Table 57-1
Some Obesity Genes in Humans and Mice
Gene Gene Product Mechanism of Obesity In Human In Rodent
Lep (ob) Leptin, a fat-derived hormone Mutation prevents leptin from delivering Yes Yes
satiety signal; brain perceives starvation
LepR (db) Leptin receptor Same as above Yes Yes
POMC Proopiomelanocortin, a precursor of Mutation prevents synthesis of melanocyte- Yes Yes
several hormones and neuropeptides stimulating hormone (MSH), a satiety signal
MC4R Type 4 receptor for MSH Mutation prevents reception of satiety signal Yes Yes
from MSH
AgRP Agouti-related peptide, a neuropeptide Overexpression inhibits signal through MC4R No Yes
expressed in the hypothalamus
PC-1 Prohormone convertase 1, a Mutation prevents synthesis of neuropeptide, Yes No
processing enzyme probably MSH
Fat Carboxypeptidase E, a processing Same as above No Yes
enzyme
Tub Tub, a hypothalamic protein of Hypothalamic dysfunction No Yes
unknown function
TrkB TrkB, a neurotrophin receptor Hyperphagia due to uncharacterized Yes Yes
hypothalamic defect
PC-1 processing enzyme 15q11-13 chromosomal region, and reduced expression 629
of the signaling protein necdin may be an important
Proopio-
Leptin melanocortin Melanocortin 4 cause of defective hypothalamic neural development in
Leptin receptor (POMC) -MSH receptor this disorder. Bardet-Biedl syndrome (BBS) is a geneti-
signal expression signal
cally heterogeneous disorder characterized by obesity,
mental retardation, retinitis pigmentosa, diabetes, renal
Decreased and cardiac malformations, polydactyly, and hypogo-
AgRP appetite nadotropic hypogonadism. At least 12 genetic loci have
Known
mutations in been identified, and most of the encoded proteins form
man two multiprotein complexes that are involved in ciliary
function and microtubule-based intracellular transport.
Figure 57-5
Recent evidence suggests that mutations might disrupt
A central pathway through which leptin acts to regulate
leptin receptor trafficking in key hypothalamic neurons,
appetite and body weight. Leptin signals through pro
opiomelanocortin (POMC) neurons in the hypothalamus to
causing leptin resistance.
induce increased production of α-melanocyte-stimulating
hormone (α-MSH), requiring the processing enzyme PC-1
Other specific syndromes
(proenzyme convertase 1). α-MSH acts as an agonist on
CHAPTER 57
associated with obesity
melanocortin-4 receptors to inhibit appetite, and the neuro-
peptide AgRp (Agouti-related peptide) acts as an antagonist Cushing’s syndrome
of this receptor. Mutations that cause obesity in humans are Although obese patients commonly have central obe-
indicated by the solid green arrows. sity, hypertension, and glucose intolerance, they lack
other specific stigmata of Cushing’s syndrome. None-
theless, a potential diagnosis of Cushing’s syndrome
Biology of Obesity
is often entertained. Cortisol production and urinary
loci linked to obesity have been identified, but together metabolites (17OH steroids) may be increased in simple
they account for less than 3% of interindividual varia- obesity. Unlike in Cushing’s syndrome, however, cor-
tion in BMI. The most replicated of these is a gene tisol levels in blood and urine in the basal state and in
named FTO, which is of unknown function, but like response to corticotropin-releasing hormone (CRH) or
many of the other recently described candidates, is ACTH are normal; the overnight 1-mg dexamethasone
expressed in the brain. Since the heritability of obesity is suppression test is normal in 90%, with the remain-
estimated to be 40–70%, it is likely that many more loci der being normal on a standard 2-day low-dose dexa-
remain to be identified. methasone suppression test. Obesity may be associated
In addition to these human obesity genes, stud- with excessive local reactivation of cortisol in fat by
ies in rodents reveal several other molecular candidates 11β-hydroxysteroid dehydrogenase 1, an enzyme that
for hypothalamic mediators of human obesity or lean- converts inactive cortisone to cortisol.
ness. The tub gene encodes a hypothalamic peptide of
unknown function; mutation of this gene causes late- Hypothyroidism
onset obesity. The fat gene encodes carboxypeptidase The possibility of hypothyroidism should be considered,
E, a peptide-processing enzyme; mutation of this gene but it is an uncommon cause of obesity; hypothyroid-
is thought to cause obesity by disrupting production of ism is easily ruled out by measuring thyroid-stimulating
one or more neuropeptides. AgRP is coexpressed with hormone (TSH). Much of the weight gain that occurs
NPY in arcuate nucleus neurons. AgRP antagonizes in hypothyroidism is due to myxedema.
α-MSH action at MC4 receptors, and its overexpres- Insulinoma
sion induces obesity. In contrast, a mouse deficient in Patients with insulinoma often gain weight as a result
the peptide MCH, whose administration causes feeding, of overeating to avoid hypoglycemic symptoms. The
is lean. increased substrate plus high insulin levels promote
A number of complex human syndromes with defined energy storage in fat. This can be marked in some indi-
inheritance are associated with obesity (Table 57-2). viduals but is modest in most.
Although specific genes have limited definition at pres-
ent, their identification will likely enhance our under- raniopharyngioma and other disorders
C
standing of more common forms of human obesity. In involving the hypothalamus
the Prader-Willi syndrome, a multigenic neurodevel- Whether through tumors, trauma, or inflammation,
opmental disorder, obesity coexists with short stature, hypothalamic dysfunction of systems controlling sati-
mental retardation, hypogonadotropic hypogonadism, ety, hunger, and energy expenditure can cause vary-
hypotonia, small hands and feet, fish-shaped mouth, ing degrees of obesity. It is uncommon to identify
and hyperphagia. Most patients have a deletion in the a discrete anatomic basis for these disorders. Subtle
630 Table 57-2
A Comparison of Syndromes of Obesity—Hypogonadism and Mental Retardation
Syndrome
Strabismus
V-shaped mouth
High-arched
palate
Limbs Small hands and feet Polydactyly No Hypotonia Polydactyly
Hypotonia abnormalities Narrow hands and Syndactyly
Obesity and Eating Disorders
hypothalamic dysfunction is probably a more common is difficult to perform direct and accurate measurements
cause of obesity than can be documented using cur- of energy intake in free-living individuals; and the obese,
rently available imaging techniques. Growth hormone in particular, often underreport intake. Measurements
(GH), which exerts lipolytic activity, is diminished in of chronic energy expenditure are possible using doubly
obesity and is increased with weight loss. Despite low labeled water or metabolic chamber/rooms. In subjects
GH levels, insulin-like growth factor (IGF)-I (somato- at stable weight and body composition, energy intake
medin) production is normal, suggesting that GH equals expenditure. Consequently, these techniques allow
suppression is a compensatory response to increased assessment of energy intake in free-living individuals.
nutritional supply. The level of energy expenditure differs in established
obesity, during periods of weight gain or loss, and in the
pre- or postobese state. Studies that fail to take note of
Pathogenesis of common obesity
this phenomenon are not easily interpreted.
Obesity can result from increased energy intake, There is continued interest in the concept of a body
decreased energy expenditure, or a combination of the weight “set point.” This idea is supported by physio-
two. Thus, identifying the etiology of obesity should logic mechanisms centered around a sensing system in
involve measurements of both parameters. However, it adipose tissue that reflects fat stores and a receptor, or
“adipostat,” that is in the hypothalamic centers. When such as the activities of daily living, fidgeting, sponta- 631
fat stores are depleted, the adipostat signal is low, and neous muscle contraction, and maintaining posture.
the hypothalamus responds by stimulating hunger and NEAT accounts for about two-thirds of the increased
decreasing energy expenditure to conserve energy. daily energy expenditure induced by overfeeding. The
Conversely, when fat stores are abundant, the signal is wide variation in fat storage seen in overfed individuals
increased, and the hypothalamus responds by decreasing is predicted by the degree to which NEAT is induced.
hunger and increasing energy expenditure. The recent The molecular basis for NEAT and its regulation is
discovery of the ob gene, and its product leptin, and the unknown.
db gene, whose product is the leptin receptor, provides
important elements of a molecular basis for this physi- Leptin in typical obesity
ologic concept (discussed earlier).
The vast majority of obese persons have increased
leptin levels but do not have mutations of either leptin
What is the status of food intake in obesity? or its receptor. They appear, therefore, to have a form
(Do the obese eat more than the lean?) of functional “leptin resistance.” Data suggesting that
This question has stimulated much debate, due in part some individuals produce less leptin per unit fat mass
to the methodologic difficulties inherent in determin- than others or have a form of relative leptin deficiency
CHAPTER 57
ing food intake. Many obese individuals believe that that predisposes to obesity are at present contradictory
they eat small quantities of food, and this claim has and unsettled. The mechanism for leptin resistance,
often been supported by the results of food intake ques- and whether it can be overcome by raising leptin levels
tionnaires. However, it is now established that average or combining leptin with other treatments in a subset
energy expenditure increases as individuals get more of obese individuals, is not yet established. Some data
obese, due primarily to the fact that metabolically active suggest that leptin may not effectively cross the blood-
brain barrier as levels rise. It is also apparent from ani-
Biology of Obesity
lean tissue mass increases with obesity. Given the laws
of thermodynamics, the obese person must therefore mal studies that leptin signaling inhibitors, such as
eat more than the average lean person to maintain their SOCS3 and PTP1b, are involved in the leptin-resistant
increased weight. It may be the case, however, that a state.
subset of individuals who are predisposed to obesity
have the capacity to become obese initially without an
Pathologic Consequences
absolute increase in caloric consumption.
of Obesity
What is the state of energy (See also Chap. 58) Obesity has major adverse effects on
expenditure in obesity? health. Obesity is associated with an increase in mor-
tality, with a 50–100% increased risk of death from all
The average total daily energy expenditure is higher causes compared to normal-weight individuals, mostly
in obese than lean individuals when measured at stable due to cardiovascular causes. Obesity and overweight
weight. However, energy expenditure falls as weight together are the second leading cause of preventable
is lost, due in part to loss of lean body mass and to death in the United States, accounting for 300,000
decreased sympathetic nerve activity. When reduced to deaths per year. Mortality rates rise as obesity increases,
near-normal weight and maintained there for awhile, particularly when obesity is associated with increased
(some) obese individuals have lower energy expenditure intraabdominal fat (discussed earlier). Life expectancy
than (some) lean individuals. There is also a tendency of a moderately obese individual could be shortened by
for those who will develop obesity as infants or children 2–5 years, and a 20- to 30-year-old male with a BMI
to have lower resting energy expenditure rates than >45 may lose 13 years of life. It is also apparent that
those who remain lean. the degree to which obesity affects particular organ sys-
The physiologic basis for variable rates of energy tems is influenced by susceptibility genes that vary in
expenditure (at a given body weight and level of energy the population.
intake) is essentially unknown. A mutation in the
human β3-adrenergic receptor may be associated with
Insulin resistance and type 2 diabetes mellitus
increased risk of obesity and/or insulin resistance in cer-
tain (but not all) populations. Hyperinsulinemia and insulin resistance are pervasive
One recently described component of thermogenesis, features of obesity, increasing with weight gain and
called nonexercise activity thermogenesis (NEAT), has been diminishing with weight loss (Chap. 60). Insulin resis-
linked to obesity. It is the thermogenesis that accom- tance is more strongly linked to intraabdominal fat than
panies physical activities other than volitional exercise to fat in other depots. Molecular links between obesity
632 and insulin resistance in fat, muscle, and liver have been women with lower body obesity, may contribute to the
sought for many years. Major factors include: (1) insu- increased incidence of uterine cancer in postmenopausal
lin itself, by inducing receptor downregulation; (2) free women with obesity.
fatty acids that are increased and capable of impairing
insulin action; (3) intracellular lipid accumulation; and Cardiovascular disease
(4) several circulating peptides produced by adipocytes,
including the cytokines TNF-α and IL-6, RBP4, and The Framingham Study revealed that obesity was an
the “adipokines” adiponectin and resistin that have independent risk factor for the 26-year incidence of
altered expression in obese adipocytes, and can modify cardiovascular disease in men and women (including
insulin action. Additional mechanisms are obesity- coronary disease, stroke, and congestive heart failure
linked inflammation, including infiltration of macro- [CHF]). The waist-to-hip ratio may be the best predic-
phages into tissues including fat, and induction of the tor of these risks. When the additional effects of hyper-
endoplasmic reticulum stress response, that can bring tension and glucose intolerance associated with obesity
about resistance to insulin action in cells. Despite the are included, the adverse impact of obesity is even more
prevalence of insulin resistance, most obese individu- evident. The effect of obesity on cardiovascular mor-
als do not develop diabetes, suggesting that diabetes tality in women may be seen at BMIs as low as 25.
requires an interaction between obesity-induced insu- Obesity, especially abdominal obesity, is associated with
Section XI
lin resistance and other factors such as impaired insulin an atherogenic lipid profile; with increased low-density
secretion. Obesity, however, is a major risk factor for lipoprotein cholesterol, very low density lipoprotein,
diabetes, and as many as 80% of patients with type 2 and triglyceride; and with decreased high-density lipo-
diabetes mellitus are obese. Weight loss and exercise, protein cholesterol and decreased levels of the vascular
even of modest degree, increase insulin sensitivity and protective adipokine adiponectin. Obesity is also associ-
often improve glucose control in diabetes. ated with hypertension. Measurement of blood pres-
sure in the obese requires use of a larger cuff size to
Obesity and Eating Disorders
CHAPTER 57
is associated with higher mortality from cancer of the severity of underlying insulin resistance and diminishes
gallbladder, bile ducts, breasts, endometrium, cervix, with weight loss. Friability of skin may be increased,
and ovaries. Some of the latter may be due to increased especially in skinfolds, enhancing the risk of fungal and
rates of conversion of androstenedione to estrone in yeast infections. Finally, venous stasis is increased in the
adipose tissue of obese individuals. Other possible obese.
Biology of Obesity
CHAPTER 58
Robert F. Kushner
Over 66% of U.S. adults are categorized as overweight consider include polycystic ovarian syndrome, hypothy-
or obese, and the prevalence of obesity is increasing roidism, Cushing’s syndrome, and hypothalamic disease.
rapidly in most of the industrialized world. Children Drug-induced weight gain also should be considered.
and adolescents also are becoming more obese, indi- Common causes include medications for diabetes (insulin,
cating that the current trends will accelerate over time. sulfonylureas, thiazolidinediones); steroid hormones; psy-
Obesity is associated with an increased risk of mul- chotropic agents; mood stabilizers (lithium); antidepres-
tiple health problems, including hypertension, type 2 sants (tricyclics, monoamine oxidase inhibitors, paroxetine,
diabetes, dyslipidemia, degenerative joint disease, and mirtazapine); and antiepileptic drugs (valproate, gabapen-
some malignancies. Thus, it is important for physicians tin, carbamazepine). Other medications, such as nonsteroi-
to identify, evaluate, and treat patients for obesity and dal anti-inflammatory drugs and calcium channel blockers,
associated comorbid conditions. may cause peripheral edema but do not increase body fat.
The patient’s current diet and physical activity pat-
eValuaTIon terns may reveal factors that contribute to the develop-
ment of obesity in addition to identifying behaviors to
Physicians should screen all adult patients for obesity and target for treatment. This type of historic information is
offer intensive counseling and behavioral interventions best obtained by using a questionnaire in combination
to promote sustained weight loss. The five main steps with an interview.
in the evaluation of obesity, as described in the fol-
lowing sections, are (1) focused obesity-related history,
(2) physical examination to determine the degree and BMI and waist circumference
type of obesity, (3) comorbid conditions, (4) fitness level, Three key anthropometric measurements are important
and (5) the patient’s readiness to adopt lifestyle changes. to evaluate the degree of obesity: weight, height, and
waist circumference. The body mass index (BMI), calcu-
The obesity-focused history lated as weight (kg)/height (m)2, or weight (lbs)/height
Information from the history should address the follow- (inches)2 × 703, is used to classify weight status and risk
ing six questions: of disease (Tables 58-1 and 58-2). BMI is used since it
provides an estimate of body fat and is related to risk of
• What factors contribute to the patient’s obesity?
disease. Lower BMI thresholds for overweight and obe-
• How is the obesity affecting the patient’s health?
sity have been proposed for the Asia-Pacific region since
• What is the patient’s level of risk from obesity?
this population appears to be at risk for glucose and lipid
• What are the patient’s goals and expectations?
abnormalities at lower body weights.
• Is the patient motivated to begin a weight
Excess abdominal fat, assessed by measurement of
management program?
waist circumference or waist-to-hip ratio, is indepen-
• What kind of help does the patient need?
dently associated with higher risk for diabetes mellitus
Although the vast majority of cases of obesity can and cardiovascular disease. Measurement of the waist
be attributed to behavioral features that affect diet and circumference is a surrogate for visceral adipose tissue
physical activity patterns, the history may suggest sec- and should be performed in the horizontal plane above
ondary causes that merit further evaluation. Disorders to the iliac crest (Table 58-3).
634
Table 58-1 635
Body Mass Index (BMI) Table
BMI 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
Height,
inches Body Weight, pounds
58 91 96 100 105 110 115 119 124 129 134 138 143 148 153 158 162 167
59 94 99 104 109 114 119 124 128 133 138 143 148 153 158 163 168 173
60 97 102 107 112 118 123 128 133 138 143 148 153 158 163 168 174 179
61 100 106 111 116 122 127 132 137 143 148 153 158 164 169 174 180 185
62 104 109 115 120 126 131 136 142 147 153 158 164 169 175 180 186 191
63 107 113 118 124 130 135 141 146 152 158 163 169 175 180 186 191 197
64 110 116 122 128 134 140 145 151 157 163 169 174 180 186 192 197 204
65 114 120 126 132 138 144 150 156 162 168 174 180 186 192 198 204 210
66 118 124 130 136 142 148 155 161 167 173 179 186 192 198 204 210 216
67 121 127 134 140 146 153 159 166 172 178 185 191 198 204 211 217 223
68 125 131 138 144 151 158 164 171 177 184 190 197 203 210 216 223 230
CHAPTER 58
69 128 135 142 149 155 162 169 176 182 189 196 203 209 216 223 230 236
70 132 139 146 153 160 167 174 181 188 195 202 209 216 222 229 236 243
71 136 143 150 157 165 172 179 186 193 200 208 215 222 229 236 243 250
72 140 147 154 162 169 177 184 191 199 206 213 221 228 235 242 250 258
73 144 151 159 166 174 182 189 197 204 212 219 227 235 242 250 257 265
74 148 155 163 171 179 186 194 202 210 218 225 233 241 249 256 264 272
75 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 279
58 172 177 181 186 191 196 201 205 210 215 220 224 229 234 239 244 248 253 258
59 178 183 188 193 198 203 208 212 217 222 227 232 237 242 247 252 257 262 267
60 184 189 194 199 204 209 215 220 225 230 235 240 245 250 255 261 266 271 276
61 190 195 201 206 211 217 222 227 232 238 243 248 254 259 264 269 275 280 285
62 196 202 207 213 218 224 229 235 240 246 251 256 262 267 273 278 284 289 295
63 203 208 214 220 225 231 237 242 248 254 259 265 270 278 282 287 293 299 304
64 209 215 221 227 232 238 244 250 256 262 267 273 279 285 291 296 302 308 314
65 216 222 228 234 240 246 252 258 264 270 276 282 288 294 300 306 312 318 324
66 223 229 235 241 247 253 260 266 272 278 284 291 297 303 309 315 322 328 334
67 230 236 242 249 255 261 268 274 280 287 293 299 306 312 319 325 331 338 344
68 236 243 249 256 262 269 276 282 289 295 302 308 315 322 328 335 341 348 354
69 243 250 257 263 270 277 284 291 297 304 311 318 324 331 338 345 351 358 365
70 250 257 264 271 278 285 292 299 306 313 320 327 334 341 348 355 362 369 376
71 257 265 272 279 286 293 301 308 315 322 329 338 343 351 358 365 372 379 386
72 265 272 279 287 294 302 309 316 324 331 338 346 353 361 368 375 383 390 397
73 272 280 288 295 302 310 318 325 333 340 348 355 363 371 378 386 393 401 408
74 280 287 295 303 311 319 326 334 342 350 358 365 373 381 389 396 404 412 420
75 287 295 303 311 319 327 335 343 351 359 367 375 383 391 399 407 415 423 431
76 295 304 312 320 328 336 344 353 361 369 377 385 394 402 410 418 426 435 443
increasing levels of obesity. Patients at very high abso- Social stigmatization Idiopathic intracranial
lute risk include those with the following: established Integument hypertension
coronary heart disease; presence of other atherosclerotic Striae distensae Meralgia paresthetica
diseases, such as peripheral arterial disease, abdominal Stasis pigmentation of Dementia
legs
aortic aneurysm, and symptomatic carotid artery disease;
Lymphedema
type 2 diabetes; and sleep apnea. Cellulitis
Intertrigo, carbuncles
Acanthosis nigricans
Acrochordon (skin tags)
Table 58-3 Hidradenitis suppurativa
Ethnic-Specific Values for Waist
Circumference
Ethnic Group Waist Circumference
Europeans
Men >94 cm (37 in) Assessing the patient’s readiness
Women >80 cm (31.5 in) to change
South Asians and Chinese
An attempt to initiate lifestyle changes when the patient
Men >90 cm (35 in)
Women >80 cm (31.5 in)
is not ready usually leads to frustration and may hamper
Japanese future weight-loss efforts. Assessment includes patient
Men >85 cm (33.5 in) motivation and support, stressful life events, psychiatric
Women >90 cm (35 in) status, time availability and constraints, and appropriate-
Ethnic South and Central Use south Asian recommen- ness of goals and expectations. Readiness can be viewed
Americans dations until more specific as the balance of two opposing forces: (1) motivation,
data are available. or the patient’s desire to change, and (2) resistance, or
Sub-Saharan Africans Use European data until more
the patient’s resistance to change.
specific data are available.
Eastern Mediterranean Use European data until more
A helpful method to begin a readiness assessment is to
and Middle East (Arab) specific data are available. “anchor” the patient’s interest and confidence to change on
populations a numerical scale. With this technique, the patient is asked
to rate his or her level of interest and confidence on a scale
Source: From KGMM Alberti et al for the IDF Epidemiology Task from 0 to 10, with 0 being not so important (or confident)
Force Consensus Group: Lancet 366:1059, 2005. and 10 being very important (or confident) to lose weight
at this time. This exercise helps establish readiness to change 637
and also serves as a basis for further dialogue. physical examination, and diagnostic tests is used to
determine risk and develop a treatment plan (Fig. 58-1).
The decision of how aggressively to treat the patient and
Treatment Obesity which modalities to use is determined by the patient’s
risk status, expectations, and available resources. Therapy
The Goal of Therapy The primary goal of for obesity always begins with lifestyle management and
treatment is to improve obesity-related comorbid may include pharmacotherapy or surgery, depending on
conditions and reduce the risk of developing future BMI risk category (Table 58-5). Setting an initial weight-
comorbidities. Information obtained from the history, loss goal of 10% over 6 months is a realistic target.
1 Patient encounter
Examination
Treatment
2 Hx of ≥ 25 BMI?
CHAPTER 58
No
BMI Yes
measured in
3
past 2 years?
6 BMI ≥ 30 OR
BMI ≥ 25 OR {[BMI 26 to 29.9
5 Yes 7 Yes
waist circumference Assess risk OR waist circumference > 88
> 88 cm (F) factors cm (F) >102 cm (M)]
>102 cm (M) AND ≥ 2 risk factors}
No
No
14
Yes Does
Hx BMI ≥ 25? 12
patient want to Yes
lose weight?
8
15 No 13 Clinician and patient devise goals
Brief reinforcement/ Advise to maintain and treatment strategy for weight loss
No
educate on weight weight, address and risk factor control
management other risk factors
9
Yes Progress being
16 Periodic weight check made/goal
achieved? No
11 10
Maintenance counseling:
Assess reasons
• Dietary therapy
for failure to lose
• Behavior therapy
weight
• Physical therapy
Figure 58-1
Treatment algorithm. This algorithm applies only to the Hx, history; Wt, weight. (From National, Heart, Lung, and
assessment for overweight and obesity and subsequent Blood Institute: Clinical guidelines on the identification, eval-
decisions on that assessment. It does not reflect any initial uation, and treatment of overweight and obesity in adults:
overall assessment for other conditions that the physician The evidence report. Washington, DC, U.S. Department of
may wish to perform. BMI, body mass index; Ht, height; Health and Human Services, 1998.)
638 Table 58-5
A Guide to Selecting Treatment
BMI Category
Source: From National Heart, Lung, and Blood Institute, North American Association for the Study of Obesity: Practical guide: Identification,
evaluation, and treatment of overweight and obesity in adults. Bethesda, MD, National Institutes of Health pub number 00-4084, Oct. 2000.
Available online at www.nhlbi.nih.gov/guidelines/obesity/practgde.htm.
Lifestyle Management Obesity care involves guidelines to specific calorie goals can be found on the
attention to three essential elements of lifestyle: dietary website www.mypyramid.gov. The revised Dietary Refer-
habits, physical activity, and behavior modification. ence Intakes for Macronutrients released by the Insti-
Section XI
Because obesity is fundamentally a disease of energy tute of Medicine recommends 45–65% of calories from
imbalance, all patients must learn how and when carbohydrates, 20–35% from fat, and 10–35% from
energy is consumed (diet), how and when energy is protein. The guidelines also recommend daily fiber
expended (physical activity), and how to incorporate intake of 38 g (men) and 25 g (women) for persons over
this information into their daily lives (behavior therapy). 50 years of age and 30 g (men) and 21 g (women) for
Lifestyle management has been shown to result in a those under age 50.
Obesity and Eating Disorders
modest (typically 3–5 kg) weight loss compared with no Since portion control is one of the most difficult
treatment or usual care. strategies for patients to manage, the use of pre-
Diet Therapy The primary focus of diet therapy is
prepared products such as meal replacements is a
to reduce overall calorie consumption. The National simple and convenient suggestion. Examples include
Heart, Lung, and Blood Institute (NHLBI) guidelines rec- frozen entrees, canned beverages, and bars. Use of meal
ommend initiating treatment with a calorie deficit of replacements in the diet has been shown to result in a
500–1000 kcal/d compared with the patient’s habitual 7–8% weight loss.
diet. This reduction is consistent with a goal of losing An ongoing area of investigation is the use of low-
approximately 1–2 lb per week. This calorie deficit can carbohydrate, high-protein diets for weight loss. These
be accomplished by suggesting substitutions or alter- diets are based on the concept that carbohydrates are
natives to the diet. Examples include choosing smaller the primary cause of obesity and lead to insulin
portion sizes, eating more fruits and vegetables, con- resistance. Most low-carbohydrate diets (e.g., South
suming more whole-grain cereals, selecting leaner cuts Beach, Zone, and Sugar Busters!) recommend a carbo-
of meat and skimmed dairy products, reducing fried hydrate level of approximately 40–46% of energy. The
foods and other added fats and oils, and drinking water Atkins diet contains 5–15% carbohydrate, depending
instead of caloric beverages. It is important that the on the phase of the diet. Low-carbohydrate, high-pro-
dietary counseling remain patient-centered and that tein diets appear to be more effective in lowering BMI;
the goals be practical, realistic, and achievable. improving coronary heart disease risk factors, including
The macronutrient composition of the diet will vary an increase in HDL cholesterol and a decrease in triglyc-
with the patient’s preference and medical condition. The eride levels; and controlling satiety in the short term
2005 U.S. Department of Agriculture Dietary Guidelines compared with low-fat diets. However, after 12 months,
for Americans (Chap. 53), which focus on health promo- there is no significance difference among diets. Multiple
tion and risk reduction, can be applied to treatment of studies have shown that sustained adherence to the
overweight or obese patients. The recommendations diet rather than diet type is likely to be the best predic-
include maintaining a diet rich in whole grains, fruits, tor of weight-loss outcome.
vegetables, and dietary fiber; consuming two serv- Another dietary approach to consider is the concept
ings (8 oz) of fish high in omega-3 fatty acids per week; of energy density, which refers to the number of
decreasing sodium to <2300 mg/d; consuming 3 cups calories (energy) a food contains per unit of weight.
of milk (or equivalent low-fat or fat-free dairy products) People tend to ingest a constant volume of food
per day; limiting cholesterol to <300 mg/d; and keeping regardless of caloric or macronutrient content. Add-
total fat between 20 and 35% of daily calories and satu- ing water or fiber to a food decreases its energy density
rated fats to <10% of daily calories. Application of these by increasing weight without affecting caloric content.
639
Examples of foods with low-energy density include physical activity (more than 300 min of moderate-inten-
soups, fruits, vegetables, oatmeal, and lean meats. Dry sity activity a week) is often needed to lose weight and
foods and high-fat foods such as pretzels, cheese, egg sustain weight loss. These exercise recommendations
yolks, potato chips, and red meat have a high-energy are daunting to most patients and need to be imple-
density. Diets containing low-energy dense foods have mented gradually. Consultation with an exercise physi-
been shown to control hunger and result in decreased ologist or personal trainer may be helpful.
caloric intake and weight loss.
Behavioral Therapy Cognitive behavioral therapy
Occasionally, very low calorie diets (VLCDs) are pre-
is used to help change and reinforce new dietary and
scribed as a form of aggressive dietary therapy. The
physical activity behaviors. Strategies include self-
primary purpose of a VLCD is to promote a rapid and
monitoring techniques (e.g., journaling, weighing, and
significant (13–23 kg) short-term weight loss over a
measuring food and activity); stress management;
3- to 6-month period. These propriety formulas typi-
stimulus control (e.g., using smaller plates, not eating
cally supply ≤800 kcal, 50–80 g protein, and 100%
in front of the television or in the car); social support;
of the recommended daily intake for vitamins and
problem solving; and cognitive restructuring to help
minerals. According to a review by the National Task
patients develop more positive and realistic thoughts
Force on the Prevention and Treatment of Obesity, indi-
about themselves. When recommending any behav-
CHAPTER 58
cations for initiating a VLCD include well-motivated
ioral lifestyle change, have the patient identify what,
individuals who are moderately to severely obese (BMI
when, where, and how the behavioral change will be
>30), have failed at more conservative approaches to
performed. The patient should keep a record of the
weight loss, and have a medical condition that would
anticipated behavioral change so that progress can be
be immediately improved with rapid weight loss. These
reviewed at the next office visit. Because these tech-
conditions include poorly controlled type 2 diabetes,
niques are time-consuming to implement, they are
hypertriglyceridemia, obstructive sleep apnea, and
rats.
Surgery Bariatric surgery can be considered for
patients with severe obesity (BMI ≥40 kg/m2) or those
with moderate obesity (BMI ≥35 kg/m2) associated with
a serious medical condition. Surgical weight loss func-
z
tions by reducing caloric intake and, depending on the
CHAPTER 58
x x
procedure, macronutrient absorption.
Weight-loss surgeries fall into one of two categories:
restrictive and restrictive-malabsorptive (Fig. 58-2).
y
Restrictive surgeries limit the amount of food the stom- z
ach can hold and slow the rate of gastric emptying. The
vertical banded gastroplasty (VBG) is the prototype 150 cm
EATING DISORDERS
643
644 Table 59-1
Common Characteristics of Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder
Anorexia Nervosaa Bulimia Nervosa Binge Eating Disorderb
Clinical Characteristics
Onset Mid-adolescence Late adolescence/early adulthood Late adolescence/early
adulthood
Female:male 10:1 10:1 2:1
Lifetime prevalence 1% of women 1–3% of women 4% of men and women
Weight Markedly decreased Usually normal Usually obese
Menstruation Absent Usually normal Usually normal
Binge eating 25–50% Required for diagnosis Required for diagnosis
Mortality ∼5% per decade Low Low
a
Physical and Laboratory Findings
Skin/extremities Lanugo Callus/abrasion on dorsum of hand
Acrocyanosis
Section XI
Edema
Cardiovascular Bradycardia
Hypotension
Gastrointestinal Salivary gland enlargement Salivary gland enlargement
Slow gastric emptying Dental erosion
Constipation
Obesity and Eating Disorders
a
Patients with anorexia nervosa who frequently induce purging may also exhibit the physical and laboratory findings associated with bulimia
nervosa.
b
Obese patients with binge eating disorder are at risk for complications of obesity.
Abbreviations: BUN, blood urea nitrogen; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
occasionally develops in early puberty, before men- rarely complain of hunger or fatigue and often exercise
arche, but seldom begins after age 40. Despite being extensively. Despite the denial of hunger, one-quarter
underweight, patients with AN are irrationally afraid of to one-half of patients with AN engage in eating binges.
gaining weight. They also exhibit a distortion of body Patients tend to become socially withdrawn and increas-
image; despite being emaciated, patients with AN may ingly committed to work or study, dieting, and exercise.
believe that their body as a whole, or some part of their As weight loss progresses, thoughts of food dominate
body, is too fat. Further weight loss is viewed by the mental life and idiosyncratic rules develop around eating.
patient as a fulfilling accomplishment, whereas weight Patients with AN may obsessively collect cookbooks and
gain is seen as a personal failure. Patients with AN recipes and be drawn to food-related occupations.
Physical features The reduction in leptin is the primary factor responsible 645
for the disturbances of the hypothalamic-pituitary-gonadal
Patients with AN typically have few physical complaints axis, and an important mediator of the other neuroendo-
but may note cold intolerance. Gastrointestinal motil- crine abnormalities characteristic of AN (Chap. 57).
ity is diminished, leading to reduced gastric empty- Serum cortisol and 24-h urine-free cortisol levels
ing and constipation. Some women who develop AN are generally elevated but without characteristic clinical
after menarche report that their menses ceased before signs of cortisol excess. Thyroid function tests resemble
significant weight loss occurred. Weight and height the pattern seen in euthyroid sick syndrome. Thyroxine
should be measured to allow calculation of body mass (T4) and free T4 levels are usually in the low-
index (BMI; kg/m2). Vital signs may reveal bradycardia, normal range, triiodothyronine (T3) levels are reduced,
hypotension, and mild hypothermia. Soft, downy hair and reverse T3 (rT3) is elevated. The level of thyroid-
growth (lanugo) sometimes occurs, as does alopecia. stimulating hormone (TSH) is normal or partially sup-
Salivary gland enlargement, which is associated with pressed. Growth hormone is increased, but insulin-like
starvation as well as with binge eating and vomiting, growth factor I (IGF-I), which is produced mainly by
may make the face appear surprisingly full in contrast the liver, is reduced, as in other conditions of starvation.
to the marked general wasting. Acrocyanosis of the Diminished bone density is routinely observed in AN
digits is common, and peripheral edema can be seen and reflects the effects of multiple nutritional deficien-
CHAPTER 59
in the absence of hypoalbuminemia, particularly when cies, reduced gonadal steroids, increased cortisol, and
the patient begins to regain weight. Consumption of reduced IGF-I. The degree of bone-density reduction
large amounts of vegetables containing vitamin A can is proportional to the length of the illness, and patients
result in a yellow tint to the skin (hypercarotenemia), are at risk for the development of symptomatic fractures.
which is especially notable on the palms. The occurrence of AN during adolescence may lead to
the premature cessation of linear bone growth and a
Laboratory abnormalities
Eating Disorders
failure to achieve expected adult height.
Mild normochromic, normocytic anemia is frequent, as
is mild to moderate leukopenia, with a disproportion- Cardiac abnormalities
ate reduction of polymorphonuclear leukocytes. Dehy- Cardiac output is reduced, and congestive heart failure
dration may result in slightly increased levels of blood occurs rarely during rapid refeeding. The electrocar-
urea nitrogen and creatinine. Serum transaminase lev- diogram usually shows sinus bradycardia, reduced QRS
els may increase, especially during the early phases of voltage, and nonspecific ST-T-wave abnormalities.
refeeding. The level of serum proteins is usually normal. Some patients develop a prolonged QTc interval, which
Blood sugar is often low and serum cholesterol may may predispose to serious arrhythmias, particularly
be moderately elevated. Hypokalemia, often accompa- when electrolyte abnormalities are present.
nied by alkalosis, suggests self-induced vomiting or use
of diuretics. Hyponatremia is common and may result
from excess fluid intake and disturbances in the secre- Diagnosis
tion of antidiuretic hormone. Hypophosphatemia and
hypomagnesemia may be present in severe AN, espe- The diagnosis of AN is based on the presence of char-
cially as part of a refeeding syndrome. acteristic behavioral, psychological, and physical attri-
butes (Table 59-2). Widely accepted diagnostic criteria
are provided by the American Psychiatric Association’s
Endocrine abnormalities
Diagnostic and Statistical Manual of Mental Disorders (DSM-
The regulation of virtually every endocrine system IV). These criteria include maintenance of a less than
is altered in AN, but the most striking changes occur minimally normal body weight for age and height.
in the reproductive system. Amenorrhea is hypotha- Weights less than 85% of that expected, roughly equiva-
lamic in origin and reflects diminished production of lent to a BMI of 18.5 kg/m2, are commonly considered
gonadotropin-releasing hormone (GnRH). The result- to meet this criterion, but a patient weighing somewhat
ing gonadotropin deficiency causes low plasma estrogen more who meets all other diagnostic criteria would still
in women and reduced testosterone in men. The hypo- merit the diagnosis of AN. The current diagnostic crite-
thalamic GnRH pulse generator is exquisitely sensi- ria require that women with AN not have spontaneous
tive, particularly in women, to body weight, stress, and menses, patients who have other characteristics of AN but
exercise, each of which may contribute to hypothalamic report menstrual activity probably merit the diagnosis.
amenorrhea in AN. The diagnosis of AN can usually be made confi-
Serum leptin levels are markedly reduced in AN as a dently in a patient with a history of weight loss accom-
result of undernutrition and decreased body-fat mass. plished by restrictive dieting and excessive exercise
646 Table 59-2
Diagnostic Features of Anorexia Nervosa exaggerate their food intake and minimize their symp-
toms. Some patients resort to subterfuge to make their
Refusal to maintain body weight at or above a minimally
normal weight for age and height. (This includes a failure
weights appear higher, for example, by water-loading
to achieve weight gain expected during a period of before they are weighed. In attempting to engage
growth leading to an abnormally low body weight.) the patient in treatment, it may be useful to elicit the
Intense fear of weight gain or becoming fat. patient’s physical concerns (e.g., about osteoporosis,
Distortion of body image (e.g., feeling fat despite an weakness, or fertility), and provide education about the
objectively low weight or minimizing the seriousness of importance of normalizing nutritional status in order
low weight). to address those concerns. The physician should reas-
Amenorrhea. (This criterion is met if menstrual periods
sure the patient that weight gain will not be permitted
occur only following hormone—e.g., estrogen—
administration.) to get out of control but simultaneously emphasize
that weight restoration is medically and psychologically
imperative.
accompanied by a marked reluctance to gain weight. The intensity of the initial treatment, including the
Patients with AN often deny that they have a serious need for hospitalization, is determined by the patient’s
problem and may be brought to medical attention by current weight, the rapidity of recent weight loss, and
Section XI
concerned family or friends. Especially in atypical pre- the severity of medical and psychological complications
sentations, other causes of significant weight loss in (Fig. 59-1). Hospitalization should be strongly consid-
previously healthy young people should be considered, ered for patients weighing <75% of that expected age
including inflammatory bowel disease, gastric outlet and height, even if the results of routine blood stud-
obstruction, diabetes mellitus, CNS tumors, or neo- ies are within normal limits. Acute medical problems,
plasm (Chap. 10). such as severe electrolyte imbalances, should be iden-
tified and addressed. Nutritional restoration can almost
Obesity and Eating Disorders
Prognosis
The course and outcome of AN are highly variable. TREATMENT ALGORITHM FOR EATING DISORDERS
One-quarter to one-half of patients eventually recover Meets criteria for anorexia nervosa or bulimia nervosa?
fully, with few psychological or physical sequelae. Yes
However, many patients have persistent difficulties
with weight maintenance, depression, and eating dis- Weight <75% of
expected body weight
turbances, including BN. The development of obesity for age and height?*
following AN is rare. The long-term mortality of AN
is among the highest associated with any psychiatric No
disorder. Approximately 5% of patients die per decade Yes
of follow-up, primarily due to the physical effects of Medically unstable?
(e.g., heart rate <40 bpm, Yes
chronic starvation or by suicide. potassium <2.5 mmol/L)
Inpatient
Virtually all of the physiologic abnormalities associ- Treatment
No or
ated with AN are observed in other forms of starvation Partial
Hospitalization
and markedly improve or disappear with weight gain. Other psychiatric problems
A worrisome exception is the reduction in bone mass, requiring intensive treatment?
(e.g., serious suicidal Yes
which may not recover fully, particularly if AN occurs ideation, substance abuse)
during adolescence when peak bone mass is normally No
achieved. If unsuccessful
Outpatient Treatment
CHAPTER 59
usually necessary. sity in underweight patients, and the small benefit of
Less severely affected patients may be treated in a bisphosphonate treatment appears to be outweighed
partial hospitalization program where medical and psy- by the potential risks of such agents in young women.
chiatric supervision is available and several meals can
be monitored each day. Outpatient treatment may suf-
fice for mildly ill patients. Weight must be monitored
at frequent intervals, and explicit goals agreed on for Bulimia Nervosa
Eating Disorders
weight gain, with the understanding that more inten-
Epidemiology
sive treatment will be required if the level of care ini-
tially employed is not successful. For younger patients, In women, the full syndrome of BN occurs with a life-
the active involvement of the family in treatment is cru- time prevalence of 1–3%. Variants of the disorder, such
cial regardless of treatment setting. Outpatient inter- as occasional binge eating or purging, are much more
ventions that help parents refeed their child have been common and occur in 5–10% of young women. The
be quite successful at achieving weight restoration. frequency of BN among men is less than one-tenth of
Psychiatric treatment focuses primarily on two issues. that among women. The prevalence of BN increased
First, patients require much emotional support dur- dramatically in the early 1970s and 1980s but may have
ing the period of weight gain. They often intellectually leveled off or declined somewhat in recent years.
agree with the need to gain weight, but strenuously
resist increases in caloric intake, and often surrepti-
tiously discard food that is provided. Second, patients Etiology
must learn to base their self-esteem not on the achieve- As with AN, the etiology of BN is likely to be multi-
ment of an inappropriately low weight, but on the factorial. Patients who develop BN describe a higher-
development of satisfying personal relationships and than-expected prevalence of childhood and parental
the attainment of reasonable academic and occupa- obesity, suggesting that a predisposition toward obesity
tional goals. While this is often possible, some patients may increase vulnerability to this eating disorder. The
with AN develop other serious emotional and behav- marked increase in the number of cases of BN during
ioral symptoms such as depression, self-mutilation, the past 30 years and the rarity of BN in underdevel-
obsessive-compulsive behavior, and suicidal ideation. oped countries imply that cultural factors are important.
These symptoms may require additional therapeutic
interventions, in the form of psychotherapy, medication,
or hospitalization. Clinical Features
Medical complications occasionally occur during The typical patient presenting for treatment of BN is
refeeding. Especially in the early stages of treatment, a woman of normal weight in her mid-twenties who
severely malnourished patients may develop a “refeeding reports binge eating and purging 5–10 times a week
syndrome” characterized by hypophosphatemia, hypo- for 5–10 years (Table 59-3). The disorder usually
magnesemia, and cardiovascular instability. Acute gas- begins in late adolescence or early adulthood during
tric dilatation has been described when refeeding is or following a diet, often in association with depressed
rapid. As in other forms of malnutrition, fluid retention mood. The self-imposed caloric restriction leads to
and peripheral edema may occur, but they generally do increased hunger and to overeating. In an attempt to
648 Table 59-3 reflex. Recurrent vomiting and the exposure of the lin-
Diagnostic Features of Bulimia Nervosa gual surfaces of the teeth to stomach acid lead to loss
Recurrent episodes of binge eating, which is characterized of dental enamel and eventually to chipping and ero-
by the consumption of a large amount of food in a short sion of the front teeth. Laboratory abnormalities are sur-
period of time and a feeling that the eating is out of prisingly infrequent, but hypokalemia, hypochloremia,
control. and hyponatremia are observed occasionally. Repeated
Recurrent inappropriate behavior to compensate for the vomiting may lead to alkalosis, whereas repeated laxa-
binge eating, such as self-induced vomiting. tive abuse may produce a mild metabolic acidosis. Serum
The occurrence of both the binge eating and the
amylase may be slightly elevated due to an increase in
inappropriate compensatory behavior at least twice
weekly, on average, for 3 months. the salivary isoenzyme.
Overconcern with body shape and weight. Serious physical complications resulting from BN
are rare. Oligomenorrhea and amenorrhea are more
Note: If the diagnostic criteria for anorexia nervosa are simultane- frequent than among women without eating disorders.
ously met, only the diagnosis of anorexia nervosa is given. Arrhythmias occasionally occur secondary to electro-
lyte disturbances. Tearing of the esophagus and rup-
avoid weight gain, the patient induces vomiting, takes ture of the stomach have been reported and constitute
laxatives or diuretics, or engages in some other form of life-threatening events. Some patients who chronically
Section XI
compensatory behavior. During binges, patients with abuse laxatives or diuretics develop transient peripheral
this disorder tend to consume large amounts of sweet edema when this behavior ceases, presumably due to
foods with a high fat content, such as dessert items. The high levels of aldosterone secondary to persistent fluid
most frequent compensatory behaviors are self-induced and electrolyte depletion.
vomiting and laxative abuse, but a wide variety of tech-
niques have been described, including the omission
of insulin injections by individuals with type 1 diabetes Diagnosis
Obesity and Eating Disorders
CHAPTER 59
of these medications in BN and in depression.
Global Considerations
A subset of patients does not respond to CBT, antide-
pressant medication, or their combination. More inten- Eating disorders are more common in cultures
sive forms of treatment, including hospitalization, may where food is available and thinness is idealized.
be required. Nevertheless, eating disorders have been reported
across the world, including in many parts of Asia and
Eating Disorders
Africa. Cultural variation may contribute to differing
Binge Eating Disorder presentations of eating disorder symptoms. For example,
in some cultural groups, the rationale for food refusal of
Binge eating disorder (BED) is characterized by fre- low weight individuals who exhibit many symptoms of
quent episodes of eating unusually large amounts of AN may not include the DSM IV criterion, “intense fear
food accompanied by feeling loss of control. In contrast of gaining weight or becoming fat.”
CHAPTER 60
Robert H. Eckel
TABLe 60-1
NcEP:atPiii 2001 aND iDF cRitERia FoR tHE MEtaBolic syNDRoME
NcEP:atPiii 2001 iDF cRitERia FoR cENtRal aDiPositya
a
In this analysis, the following thresholds for waist circumference were used: white men, ≥94 cm; African-American men, ≥94 cm; Mexican-
American men, ≥90 cm; white women, ≥80 cm; African-American women, ≥80 cm; Mexican-American women, ≥80 cm. For participants whose
designation was “other race—including multiracial,” thresholds that were once based on Europid cut points (≥94 cm for men and ≥80 cm for
women) and once based on South Asian cut points (≥90 cm for men and ≥80 cm for women) were used. For participants who were considered
“other Hispanic,” the IDF thresholds for ethnic South and Central Americans were used.
Abbreviations: HDL, high-density lipoprotein; IDF, International Diabetes Foundation; NCEP:ATPIII, National Cholesterol Education Program,
Adult Treatment Panel III.
650
60 of obesity, patients who are normal weight may also be 651
Population prevalence (%)
50
insulin-resistant and have the syndrome.
40
Sedentary lifestyle
30
Physical inactivity is a predictor of CVD events and
20 related mortality rate. Many components of the meta-
bolic syndrome are associated with a sedentary lifestyle,
10
including increased adipose tissue (predominantly central),
0 reduced HDL cholesterol, and a trend toward increased tri-
Waist circ TG150 HDL chol BP Glucose glycerides, high blood pressure, and increased glucose in
Men Women the genetically susceptible. Compared with individuals
who watched television or videos or used the computer
Figure 60-1 <1 h daily, those who carried out those behaviors for
Prevalence of the metabolic syndrome components,
>4 h daily had a twofold increased risk of the metabolic
from NHANES III. NHANES, National Health and Nutrition
syndrome.
Examination Survey; TG, triglyceride; HDL, high-density lipo-
protein; BP, blood pressure. The prevalence of elevated glucose
CHAPTER 60
includes individuals with known diabetes mellitus. (Created Aging
from data in ES Ford et al: Diabetes Care 27:2444, 2004.) The metabolic syndrome affects 44% of the U.S. popula-
tion older than age 50. A greater percentage of women
over age 50 have the syndrome than men. The age
dependency of the syndrome’s prevalence is seen in most
common in African-American men and more common populations around the world.
Hypertension
C-II
C-III HDL cholesterol
B-100 and
TG
Small dense LDL FFA Insulin IL-6 SNS
VLDL
Obesity and Eating Disorders
Glucose
TNF-α −
IL-6 Insulin
−
CRP
Glycogen
−
−
FFA CO2
−
FFA
−
Fibrinogen
PAI-1 Adiponectin
Prothrombotic Triglyceride
state (intramuscular droplet)
Figure 60-2
Pathophysiology of the metabolic syndrome. Free fatty is superimposed and contributory to the insulin resistance
acids (FFAs) are released in abundance from an expanded produced by excessive FFAs. The enhanced secretion of inter-
adipose tissue mass. In the liver, FFAs result in an increased leukin 6 (IL-6) and tumor necrosis factor α (TNF-α) produced
production of glucose and triglycerides and secretion of very by adipocytes and monocyte-derived macrophages results in
low density lipoproteins (VLDLs). Associated lipid/lipoprotein more insulin resistance and lipolysis of adipose tissue triglyc-
abnormalities include reductions in high-density lipoprotein eride stores to circulating FFAs. IL-6 and other cytokines also
(HDL) cholesterol and an increased density of low-density enhance hepatic glucose production, VLDL production by the
lipoproteins (LDLs). FFAs also reduce insulin sensitivity in liver, and insulin resistance in muscle. Cytokines and FFAs
muscle by inhibiting insulin-mediated glucose uptake. Asso- also increase the hepatic production of fibrinogen and adipo-
ciated defects include a reduction in glucose partitioning to cyte production of plasminogen activator inhibitor 1 (PAI-1),
glycogen and increased lipid accumulation in triglyceride resulting in a prothrombotic state. Higher levels of circulating
(TG). Increases in circulating glucose, and to some extent cytokines also stimulate the hepatic production of C-reactive
FFA, increase pancreatic insulin secretion, resulting in hyper- protein (CRP). Reduced production of the anti-inflammatory
insulinemia. Hyperinsulinemia may result in enhanced sodium and insulin-sensitizing cytokine adiponectin is also associated
reabsorption and increased sympathetic nervous system with the metabolic syndrome. (Reprinted from RH Eckel et al:
(SNS) activity and contribute to the hypertension, as might Lancet 365:1415, 2005, with permission from Elsevier.)
increased levels of circulating FFAs. The proinflammatory state
syndrome. In studies carried out in insulin-resistant sub- always a predominance of small dense LDLs. Small 653
jects with obesity or type 2 diabetes, the offspring of dense LDLs are thought to be more atherogenic. They
patients with type 2 diabetes, and the elderly, a defect may be toxic to the endothelium, and they are able to
has been identified in mitochondrial oxidative phos- transit through the endothelial basement membrane and
phorylation, leading to the accumulation of triglycerides adhere to glycosaminoglycans. They also have increased
and related lipid molecules in muscle. The accumu- susceptibility to oxidation and are selectively bound to
lation of lipids in muscle is associated with insulin scavenger receptors on monocyte-derived macrophages.
resistance. Subjects with increased small dense LDL particles and
hypertriglyceridemia also have increased cholesterol
Increased waist circumference content of both VLDL1 and VLDL2 subfractions. This
relatively cholesterol-rich VLDL particle may contrib-
Waist circumference is an important component of the ute to the atherogenic risk in patients with metabolic
most recent and frequently applied diagnostic criteria syndrome.
for the metabolic syndrome. However, measuring waist
circumference does not reliably distinguish increases in
subcutaneous adipose tissue vs. visceral fat; this distinc- Glucose intolerance
tion requires CT or MRI. With increases in visceral
The defects in insulin action lead to impaired suppres-
CHAPTER 60
adipose tissue, adipose tissue-derived FFAs are directed
sion of glucose production by the liver and kidney
to the liver. In contrast, increases in abdominal subcu-
and reduced glucose uptake and metabolism in insulin-
taneous fat release lipolysis products into the systemic
sensitive tissues, i.e., muscle and adipose tissue. The
circulation and avoid more direct effects on hepatic
relationship between impaired fasting glucose (IFG)
metabolism. Relative increases in visceral versus sub-
or impaired glucose tolerance (IGT) and insulin resis-
cutaneous adipose tissue with increasing waist circum-
tance is well supported by human, nonhuman primate,
ference in Asians and Asian Indians may explain the
Dyslipidemia
Hypertension
In general, FFA flux to the liver is associated with
increased production of apoB-containing, triglyceride- The relationship between insulin resistance and hyper-
rich very low density lipoproteins (VLDLs). The effect tension is well established. Paradoxically, under normal
of insulin on this process is complex, but hypertriglyc- physiologic conditions, insulin is a vasodilator with sec-
eridemia is an excellent marker of the insulin-resistant ondary effects on sodium reabsorption in the kidney.
condition. However, in the setting of insulin resistance, the vaso-
The other major lipoprotein disturbance in the meta- dilatory effect of insulin is lost but the renal effect on
bolic syndrome is a reduction in HDL cholesterol. This sodium reabsorption is preserved. Sodium reabsorption
reduction is a consequence of changes in HDL compo- is increased in whites with the metabolic syndrome
sition and metabolism. In the presence of hypertriglyc- but not in Africans or Asians. Insulin also increases the
eridemia, a decrease in the cholesterol content of HDL activity of the sympathetic nervous system, an effect
is a consequence of reduced cholesteryl ester content that also may be preserved in the setting of the insulin
of the lipoprotein core in combination with cholesteryl resistance. Finally, insulin resistance is characterized by
ester transfer protein–mediated alterations in triglycer- pathway-specific impairment in phosphatidylinositol-
ide, making the particle small and dense. This change in 3-kinase signaling. In the endothelium, this may cause
lipoprotein composition also results in increased clear- an imbalance between the production of nitric oxide
ance of HDL from the circulation. The relationships of and the secretion of endothelin 1, leading to decreased
these changes in HDL to insulin resistance are proba- blood flow. Although these mechanisms are provoca-
bly indirect, occurring in concert with the changes in tive, when insulin action is assessed by levels of fast-
triglyceride-rich lipoprotein metabolism. ing insulin or by the Homeostasis Model Assessment
In addition to HDL, low-density lipoproteins (LDLs) (HOMA), insulin resistance contributes only modestly
are modified in composition. With fasting serum to the increased prevalence of hypertension in the met-
triglycerides >2.0 mM (∼180 mg/dL), there is almost abolic syndrome.
654 Proinflammatory cytokines syndrome are also at increased risk for peripheral vascu-
lar disease.
The increases in proinflammatory cytokines, including
interleukin (IL)-1, IL-6, IL-18, resistin, tumor necrosis Type 2 diabetes
factor (TNF) α, and C-reactive protein (CRP), reflect Overall, the risk for type 2 diabetes in patients with the
overproduction by the expanded adipose tissue mass metabolic syndrome is increased three- to fivefold. In
(Fig. 60-2). Adipose tissue-derived macrophages may be the FOS’s 8-year follow-up of middle-aged men and
the primary source of proinflammatory cytokines locally women, the population-attributable risk for developing
and in the systemic circulation. It remains unclear, type 2 diabetes was 62% in men and 47% in women.
however, how much of the insulin resistance is caused
by the paracrine vs. endocrine effects of these cytokines.
Other associated conditions
Adiponectin In addition to the features specifically associated with
metabolic syndrome, insulin resistance is accompanied
Adiponectin is an anti-inflammatory cytokine produced by other metabolic alterations. Those alterations include
exclusively by adipocytes. Adiponectin enhances insu- increases in apoB and apoC-III, uric acid, prothrombotic
lin sensitivity and inhibits many steps in the inflammatory factors (fibrinogen, plasminogen activator inhibitor 1),
process. In the liver, adiponectin inhibits the expression of serum viscosity, asymmetric dimethylarginine, homo-
Section XI
gluconeogenic enzymes and the rate of glucose production. cysteine, white blood cell count, proinflammatory
In muscle, adiponectin increases glucose transport and cytokines, CRP, microalbuminuria, nonalcoholic fatty
enhances fatty acid oxidation, partially due to activation of liver disease (NAFLD) and/or nonalcoholic steatohep-
adenosine monophosphate (AMP) kinase. Adiponectin is atitis (NASH), polycystic ovarian disease (PCOS), and
reduced in the metabolic syndrome. The relative contri- obstructive sleep apnea (OSA).
bution of adiponectin deficiency versus overabundance of
Obesity and Eating Disorders
CHAPTER 60
Fasting lipids and glucose are needed to determine if
the metabolic syndrome is present. The measurement of in physical activity can lead to modest weight reduction,
additional biomarkers associated with insulin resistance 60–90 min of daily activity is required to achieve this goal.
can be individualized. Such tests might include apoB, Even if an overweight or obese adult is unable to achieve
high-sensitivity CRP, fibrinogen, uric acid, urinary this level of activity, he or she will still derive a significant
microalbumin, and liver function tests. A sleep study health benefit from at least 30 min of moderate-intensity
should be performed if symptoms of OSA are present. daily activity. The caloric value of 30 min of a variety of
Of note, for each doubling of the statin dose, there is metabolic syndrome and diabetes, nicotinic acid may
only ∼6% additional lowering of LDL cholesterol. Side increase fasting glucose. Omega-3 fatty acid prepara-
effects are rare and include an increase in hepatic trans- tions that include high doses of docosahexaenoic acid
aminases and/or myopathy. The cholesterol absorption and eicosapentaenoic acid (∼3.0–4.5 g daily) lower fast-
inhibitor ezetimibe is well tolerated and should be the ing triglycerides by ∼40%. No interactions with fibrates
second choice. Ezetimibe typically reduces LDL choles- or statins occur, and the main side effect is eructation
terol by 15–20%. The bile acid sequestrants cholestyr- with a fishy taste. This can be partially blocked by inges-
Obesity and Eating Disorders
amine and colestipol are more effective than ezetimibe tion of the nutraceutical after freezing. Clinical trials
but must be used with caution in patients with the of nicotinic acid or high-dose omega-3 fatty acids in
metabolic syndrome because they can increase tri- patients with the metabolic syndrome have not been
glycerides. In general, bile sequestrants should not be reported.
administered when fasting triglycerides are >200 mg/dL.
Side effects include gastrointestinal symptoms (palat- HDL Cholesterol Beyond weight reduction,
ability, bloating, belching, constipation, anal irritation). there are very few lipid-modifying compounds that
Nicotinic acid has modest LDL cholesterol–lowering increase HDL cholesterol. Statins, fibrates, and bile acid
capabilities (<20%). Fibrates are best employed to lower sequestrants have modest effects (5–10%), and there is
LDL cholesterol when both LDL cholesterol and triglyc- no effect on HDL cholesterol with ezetimibe or omega-3
erides are elevated. Fenofibrate may be more effective fatty acids. Nicotinic acid is the only currently available
than gemfibrozil in this group. drug with predictable HDL cholesterol-raising proper-
ties. The response is dose-related and can increase HDL
Triglycerides The NCEP:ATPIII has focused on cholesterol ∼30% above baseline. There is limited evi-
non-HDL cholesterol rather than triglycerides. However, dence at present that raising HDL has a benefit on CVD
a fasting triglyceride value of <150 mg/dL is recom- events independent of lowering LDL cholesterol, partic-
mended. In general, the response of fasting triglycerides ularly in patients with the metabolic syndrome.
relates to the amount of weight reduction achieved. A
weight reduction of >10% is necessary to lower fasting Blood Pressure The direct relationship
triglycerides. between blood pressure and all-cause mortality rate has
A fibrate (gemfibrozil or fenofibrate) is the drug been well established, including patients with hyper-
of choice to lower fasting triglycerides and typically tension (>140/90) versus prehypertension (>120/80
achieve a 35–50% reduction. Concomitant administra- but <140/90) versus individuals with normal blood
tion with drugs metabolized by the 3A4 cytochrome pressure (<120/80). In patients with the metabolic syn-
P450 system (including some statins) greatly increases drome without diabetes, the best choice for the first
the risk of myopathy. In these cases, fenofibrate may be antihypertensive should usually be an angiotensin-
preferable to gemfibrozil. In the Veterans Affairs HDL converting enzyme (ACE) inhibitor or an angioten-
Intervention Trial (VA-HIT), gemfibrozil was adminis- sin II receptor blocker, as these two classes of drugs
tered to men with known CHD and levels of HDL choles- appear to reduce the incidence of new-onset type 2
terol <40 mg/dL. A coronary disease event and mortal- diabetes. In all patients with hypertension, a sodium-
ity rate benefit was experienced predominantly in men restricted diet enriched in fruits and vegetables and
with hyperinsulinemia and/or diabetes, many of whom low-fat dairy products should be advocated. Home
657
monitoring of blood pressure may assist in maintaining Insulin Resistance Several drug classes
good blood pressure control. (biguanides, thiazolidinediones [TZDs]) increase insu-
lin sensitivity. Because insulin resistance is the primary
Impaired Fasting Glucose In patients
pathophysiologic mechanism for the metabolic syn-
with the metabolic syndrome and type 2 diabetes,
drome, representative drugs in these classes reduce its
aggressive glycemic control may favorably mod-
prevalence. Both metformin and TZDs enhance insulin
ify fasting triglycerides and/or HDL cholesterol. In
action in the liver and suppress endogenous glucose
patients with IFG without a diagnosis of diabetes, a
production. TZDs, but not metformin, also improve
lifestyle intervention that includes weight reduction,
insulin-mediated glucose uptake in muscle and adi-
dietary fat restriction, and increased physical activ-
pose tissue. Benefits of both drugs have also been seen
ity has been shown to reduce the incidence of type 2
in patients with NAFLD and PCOS, and the drugs have
diabetes. Metformin has also been shown to reduce the
been shown to reduce markers of inflammation and
incidence of diabetes, although the effect was less than
small dense LDL.
that seen with lifestyle intervention.
CHAPTER 60
The Metabolic Syndrome
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appenDiX
This Appendix contains tables of reference values for units (SI, système international d’unités) is used in most
laboratory tests, special analytes, and special function countries and in some medical journals. However,
tests. A variety of factors can influence reference values. clinical laboratories may continue to report values in
Such variables include the population studied, the dura- “traditional” or conventional units. Therefore, both
tion and means of specimen transport, laboratory meth- systems are provided in the Appendix. The dual system
ods and instrumentation, and even the type of container is also used in the text except for (1) those instances in
used for the collection of the specimen. The reference which the numbers remain the same but only the ter-
or “normal” ranges given in this appendix may there- minology is changed (mmol/L for meq/L or IU/L for
fore not be appropriate for all laboratories, and these mIU/mL), when only the SI units are given; and (2)
values should only be used as general guidelines. When- most pressure measurements (e.g., blood and cerebrospi-
ever possible, reference values provided by the labora- nal fluid pressures), when the traditional units (mmHg,
tory performing the testing should be utilized in the mmH2O) are used. In all other instances in the text the
interpretation of laboratory data. Values supplied in SI unit is followed by the traditional unit in parentheses.
this Appendix reflect typical reference ranges in adults.
Pediatric reference ranges may vary significantly from
adult values.
RefeRence Values foR
In preparing the Appendix, the authors have taken
into account the fact that the system of international
laBoRatoRy tests
Table 1
Hematology and Coagulation
analyte SpeCimen Si unitS Conventional unitS
Antithrombin III P
Antigenic 220–390 mg/L 22–39 mg/dL
Functional 0.7–1.30 U/L 70–130%
Anti-Xa assay (heparin assay) P
Unfractionated heparin 0.3–0.7 kIU/L 0.3–0.7 IU/mL
Low-molecular-weight heparin 0.5–1.0 kIU/L 0.5–1.0 IU/mL
Danaparoid (Orgaran) 0.5–0.8 kIU/L 0.5–0.8 IU/mL
Autohemolysis test WB 0.004–0.045 0.4–4.50%
Autohemolysis test with glucose WB 0.003–0.007 0.3–0.7%
Bleeding time (adult) <7.1 min <7.1 min
Bone marrow: See Table 7
Clot retraction WB 0.50–1.00/2 h 50–100%/2 h
Cryofibrinogen P Negative Negative
D-dimer P 220–740 ng/mL FEU 220–740 ng/mL FEU
Differential blood count WB
Relative counts:
Neutrophils 0.40–0.70 40–70%
Bands 0.0–0.05 0–5%
Lymphocytes 0.20–0.50 20–50%
Monocytes 0.04–0.08 4–8%
Eosinophils 0.0–0.6 0–6%
Basophils 0.0–0.02 0–2%
Absolute counts:
APPENDIX
Erythrocyte count WB
Adult males 4.30–5.60 × 1012/L 4.30–5.60 × 106/mm3
Adult females 4.00–5.20 × 1012/L 4.00–5.20 × 106/mm3
Erythrocyte life span WB
Normal survival 120 days 120 days
Chromium labeled, half-life (t1/2) 25–35 days 25–35 days
Erythrocyte sedimentation rate WB
Females 0–20 mm/h 0–20 mm/h
Males 0–15 mm/h 0–15 mm/h
Euglobulin lysis time P 7200–14400 s 120–240 min
Factor II, prothrombin P 0.50–1.50 50–150%
Factor V P 0.50–1.50 50–150%
Factor VII P 0.50–1.50 50–150%
Factor VIII P 0.50–1.50 50–150%
Factor IX P 0.50–1.50 50–150%
Factor X P 0.50–1.50 50–150%
Factor XI P 0.50–1.50 50–150%
Factor XII P 0.50–1.50 50–150 %
Factor XIII screen P Not applicable Present
Factor inhibitor assay P <0.5 Bethesda Units <0.5 Bethesda Units
Fibrin(ogen) degradation products P 0–1 mg/L 0–1 μg/mL
Fibrinogen P 2.33–4.96 g/L 233–496 mg/dL
Glucose-6-phosphate dehydrogenase (erythrocyte) WB <2400 s <40 min
Ham’s test (acid serum) WB Negative Negative
(continued)
Table 1 661
Hematology and Coagulation (CONtinued)
Analyte Specimen SI Units Conventional Units
Hematocrit WB
Adult males 0.388–0.464 38.8–46.4
Adult females 0.354–0.444 35.4–44.4
Hemoglobin
Plasma P 6–50 mg/L 0.6–5.0 mg/dL
Whole blood: WB
Adult males 133–162 g/L 13.3–16.2 g/dL
Adult females 120–158 g/L 12.0–15.8 g/dL
Hemoglobin electrophoresis WB
Hemoglobin A 0.95–0.98 95–98%
Hemoglobin A2 0.015–0.031 1.5–3.1%
Hemoglobin F 0–0.02 0–2.0%
Hemoglobins other than A, A2, or F Absent Absent
Heparin-induced thrombocytopenia antibody P Negative Negative
Immature platelet fraction (IPF) WB 0.011–0.061 1.1–6.1%
Joint fluid crystal JF Not applicable No crystals seen
Joint fluid mucin JF Not applicable Only type I mucin present
Leukocytes
Alkaline phosphatase (LAP) WB 0.2–1.6 μkat/L 13–100 μ/L
Count (WBC) WB 3.54–9.06 × 109/L 3.54–9.06 × 103/mm3
Mean corpuscular hemoglobin (MCH) WB 26.7–31.9 pg/cell 26.7–31.9 pg/cell
Mean corpuscular hemoglobin concentration (MCHC) WB 323–359 g/L 32.3–35.9 g/dL
APPENDIX
Mean corpuscular hemoglobin of reticulocytes (CH) WB 24–36 pg 24–36 pg
Mean corpuscular volume (MCV) WB 79–93.3 fL 79–93.3 μm3
Mean platelet volume (MPV) WB 9.00–12.95 fL 9.00–12.95
Osmotic fragility of erythrocytes WB
Direct 0.0035–0.0045 0.35–0.45%
Indirect 0.0030–0.0065 0.30–0.65%
Protoporphyrin, free erythrocyte WB 0.28–0.64 μmol/L of 16–36 μg/dL of red blood cells
red blood cells
Red cell distribution width WB <0.145 <14.5%
Reptilase time P 16–23.6 s 16–23.6 s
Reticulocyte count WB
Adult males 0.008–0.023 red cells 0.8–2.3% red cells
Adult females 0.008–0.020 red cells 0.8–2.0% red cells
Reticulocyte hemoglobin content WB >26 pg/cell >26 pg/cell
Ristocetin cofactor (functional von Willebrand factor) P
Blood group O 0.75 mean of normal 75% mean of normal
Blood group A 1.05 mean of normal 105% mean of normal
Blood group B 1.15 mean of normal 115% mean of normal
Blood group AB 1.25 mean of normal 125% mean of normal
Serotonin release assay S <0.2 release <20% release
Sickle cell test WB Negative Negative
Sucrose hemolysis WB <0.1 <10% hemolysis
Thrombin time P 15.3–18.5 s 15.3–18.5 s
Total eosinophils WB 150–300 × 106/L 150–300/mm3
Transferrin receptor S, P 9.6–29.6 nmol/L 9.6–29.6 nmol/L
Viscosity
Plasma P 1.7–2.1 1.7–2.1
Serum S 1.4–1.8 1.4–1.8
APPENDIX
Abbreviations: JF, joint fluid; P, plasma; PRP, platelet-rich plasma; S, serum; WB, whole blood.
Table 2
Clinical Chemistry and Immunology
Analyte Specimen SI Units Conventional Units
(continued)
Table 2 663
Clinical Chemistry and Immunology (CONTINUED)
Analyte Specimen SI Units Conventional Units
Androstendione (adult) S
Males 0.81–3.1 nmol/L 23–89 ng/dL
Females
Premenopausal 0.91–7.5 nmol/L 26–214 ng/dL
Postmenopausal 0.46–2.9 nmol/L 13–82 ng/dL
Angiotensin-converting enzyme (ACE) S 0.15–1.1 μkat/L 9–67 U/L
Anion gap S 7–16 mmol/L 7–16 mmol/L
Apolipoprotein A-1 S
Male 0.94–1.78 g/L 94–178 mg/dL
Female 1.01–1.99 g/L 101–199 mg/dL
Apolipoprotein B S
Male 0.55–1.40 g/L 55–140 mg/dL
Female 0.55–1.25 g/L 55–125 mg/dL
Arterial blood gases WB
[HCO3–] 22–30 mmol/L 22–30 meq/L
Pco2 4.3–6.0 kPa 32–45 mmHg
pH 7.35–7.45 7.35–7.45
Po2 9.6–13.8 kPa 72–104 mmHg
Aspartate aminotransferase (AST, SGOT) S 0.20–0.65 μkat/L 12–38 U/L
Autoantibodies S
Anti-centromere antibody IgG ≤29 AU/mL ≤29 AU/mL
APPENDIX
Anti-double-strand (native) DNA <25 IU/L <25 IU/L
Anti-glomerular basement membrane antibodies
Qualitative IgG, IgA Negative Negative
Quantitative IgG antibody ≤19 AU/mL ≤19 AU/mL
Anti-histone antibodies <1.0 U <1.0 U
Anti-Jo-1 antibody ≤29 AU/mL ≤29 AU/mL
Anti-mitochondrial antibody Not applicable <20 Units
APPENDIX
Midcycle peak 411–1626 pmol/L 112–443 pg/mL
Luteal phase 74–885 pmol/L <20–241 pg/mL
Postmenopausal 217 pmol/L <59 pg/mL
Male 74 pmol/L <20 pg/mL
Estrone S, P
Female
Menstruating:
APPENDIX
Male 2.0–12.0 U/L 2.0–12.0 mIU/mL
Magnesium S 0.62–0.95 mmol/L 1.5–2.3 mg/dL
Metanephrine P <0.5 nmol/L <100 pg/mL
Methemoglobin WB 0.0–0.01 0–1%
Myoglobin S
APPENDIX
Triiodothyronine, total (T3) S 1.2–2.1 nmol/L 77–135 ng/dL
Troponin I (method dependent) S, P
99th percentile of a healthy population 0–0.04 μg/L 0–0.04 ng/mL
Troponin T S, P
99th percentile of a healthy population 0–0.01 μg/L 0–0.01 ng/mL
Codeine 43–110 nmol/mL 13–33 ng/mL >3700 nmol/mL >1100 ng/mL (lethal)
Cyclosporine
Renal transplant
0–6 months 208–312 nmol/L 250–375 ng/mL >312 nmol/L >375 ng/mL
6–12 months after transplant 166–250 nmol/L 200–300 ng/mL >250 nmol/L >300 ng/mL
>12 months 83–125 nmol/L 100–150 ng/mL >125 nmol/L >150 ng/mL
Laboratory Values of Clinical Importance
Cardiac transplant
0–6 months 208–291 nmol/L 250–350 ng/mL >291 nmol/L >350 ng/mL
6–12 months after transplant 125–208 nmol/L 150–250 ng/mL >208 nmol/L >250 ng/mL
>12 months 83–125 nmol/L 100–150 ng/mL >125 nmol/L 150 ng/mL
Lung transplant
0–6 months 250–374 nmol/L 300–450 ng/mL >374 nmol/L >450 ng/mL
Liver transplant
Initiation 208–291 nmol/L 250–350 ng/mL >291 nmol/L >350 ng/mL
Maintenance 83–166 nmol/L 100–200 ng/mL >166 nmol/L >200 ng/mL
Desipramine 375–1130 nmol/L 100–300 ng/mL >1880 nmol/L >500 ng/mL
Diazepam (and metabolite)
Diazepam 0.7–3.5 μmol/L 0.2–1.0 μg/mL >7.0 μmol/L >2.0 μg/mL
Nordiazepam 0.4–6.6 μmol/L 0.1–1.8 μg/mL >9.2 μmol/L >2.5 μg/mL
Digoxin 0.64–2.6 nmol/L 0.5–2.0 ng/mL >5.0 nmol/L >3.9 ng/mL
Disopyramide 5.3–14.7 μmol/L 2–5 μg/mL >20.6 μmol/L >7 μg/mL
Doxepin and nordoxepin
Doxepin 0.36–0.98 μmol/L 101–274 ng/mL >1.8 μmol/L >503 ng/mL
Nordoxepin 0.38–1.04 μmol/L 106–291 ng/mL >1.9 μmol/L >531 ng/mL
Ethanol
Behavioral changes >4.3 mmol/L >20 mg/dL
Legal limit ≥17 mmol/L ≥80 mg/dL
Critical with acute exposure >54 mmol/L >250 mg/dL
Ethylene glycol
Toxic >2 mmol/L >12 mg/dL
Lethal >20 mmol/L >120 mg/dL
(continued)
Table 3 671
Toxicology and Therapeutic Drug Monitoring (CONTINUED)
Therapeutic Range Toxic Level
APPENDIX
High-dose (24h) <5.0 μmol/L <5.0 μmol/L >5.0 μmol/L >5.0 μmol/L
High-dose (48h) <0.50 μmol/L <0.50 μmol/L >0.5 μmol/L >0.5 μmol/L
High-dose (72h) <0.10 μmol/L <0.10 μmol/L >0.1 μmol/L >0.1 μmol/L
Morphine 232–286 μmol/L 65–80 ng/mL >720 μmol/L >200 ng/mL
Mycophenolic acid 3.1–10.9 μmol/L 1.0–3.5 ng/mL >37 μmol/L >12 ng/mL
Nitroprusside (as thiocyanate) 103–499 μmol/L 6–29 μg/mL 860 μmol/L >50 μg/mL
Nortriptyline 190–569 nmol/L 50–150 ng/mL >1900 nmol/L >500 ng/mL
Table 4
Vitamins and Selected Trace Minerals
APPENDIX
Reference Range
APPENDIX
Program: Circulation 110:227, 2004. Ventricular 0.06–0.15 g/L 6–15 mg/dL
Albumin 0.066–0.442 g/L 6.6–44.2 mg/dL
IgG 0.009–0.057 g/L 0.9–5.7 mg/dL
IgG indexb 0.29–0.59
Oligoclonal <2 bands not pres-
bands (OGB) ent in matched
serum sample
a
Since cerebrospinal fluid concentrations are equilibrium values,
measurements of the same parameters in blood plasma obtained
at the same time are recommended. However, there is a time lag in
attainment of equilibrium, and cerebrospinal levels of plasma con-
stituents that can fluctuate rapidly (such as plasma glucose) may
not achieve stable values until after a significant lag phase.
b
IgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG
(g/dL) × CSF albumin (mg/dL).
674 Table 7A Table 8
Differential Nucleated Cell Counts of Stool Analysis
Bone Marrow Aspiratesa
Reference Range
Observed 95% Range
Range (%) (%) Mean (%) Conventional
SI Units Units
Blast cells 0–3.2 0–3.0 1.4
Promyelocytes 3.6–13.2 3.2–12.4 7.8 Alpha-1- ≤540 mg/L ≤54 mg/dL
Neutrophil 4–21.4 3.7–10.0 7.6 antitrypsin
myelocytes Amount 0.1–0.2 kg/d 100–200 g/24 h
Eosinophil 0–5.0 0–2.8 1.3 Coproporphyrin 611–1832 nmol/d 400–1200 μg/24 h
myelocytes Fat
Adult <7 g/d
Metamyelocytes 1–7.0 2.3–5.9 4.1 Adult on <4 g/d
Neutrophils fat-free diet
Males 21.0–45.6 21.9–42.3 32.1 Fatty acids 0–21 mmol/d 0–6 g/24 h
Females 29.6–46.6 28.8–45.9 37.4 Leukocytes None None
Eosinophils 0.4–4.2 0.3–4.2 2.2 Nitrogen <178 mmol/d <2.5 g/24 h
Eosinophils 0.9–7.4 0.7–6.3 3.5 pH 7.0–7.5
plus eosinophil Potassium 14–102 mmol/L 14–102 mmol/L
myelocytes Occult blood Negative Negative
Basophils 0–0.8 0–0.4 0.1 Osmolality 280–325 mosmol/ 280–325 mosmol/
Erythroblasts kg kg
Male 18.0–39.4 16.2–40.1 28.1 Sodium 7–72 mmol/L 7–72 mmol/L
Females 14.0–31.8 13.0–32.0 22.5 Trypsin 20–95 U/g
Urobilinogen 85–510 μmol/d 50–300 mg/24 h
Lymphocytes 4.6–22.6 6.0–20.0 13.1 Uroporphyrins 12–48 nmol/d 10–40 μg/24 h
Plasma cells 0–1.4 0–1.2 0.6 Water <0.75 <75%
Monocytes 0–3.2 0–2.6 1.3
APPENDIX
Macrophages 0–1.8 0–1.3 0.4 Source: Modified from: FT Fishbach, MB Dunning III: A Manual of
M:E ratio Laboratory and Diagnostic Tests, 7th ed. Philadelphia, Lippincott
Males 1.1–4.0 1.1–4.1 2.1 Williams & Wilkins, 2004.
Females 1.6–5.4 1.6–5.2 2.8
a
Based on bone marrow aspirate from 50 healthy volunteers
Laboratory Values of Clinical Importance
Table 7B
Bone Marrow Cellularity
Observed
Age Range 95% Range Mean
APPENDIX
Copper <0.95 μmol/d <60 μg/d
Coproporphyrins (types I and III) 0–20 μmol/mol creatinine 0–20 μmol/mol creatinine
Cortisol, free 55–193 nmol/d 20–70 μg/d
Creatine, as creatinine
Female <760 μmol/d <100 mg/d
(continued)
676 Table 9
Urine Analysis and Renal Function Tests (CONTINUED)
Reference Range
Microalbumin
Normal 0.0–0.03 g/d 0–30 mg/d
Microalbuminuria 0.03–0.30 g/d 30–300 mg/d
Clinical albuminuria >0.3 g/d >300 mg/d
Microalbumin/creatinine ratio
Normal 0–3.4 g/mol creatinine 0–30 μg/mg creatinine
Microalbuminuria 3.4–34 g/mol creatinine 30–300 μg/mg creatinine
Clinical albuminuria >34 g/mol creatinine >300 μg/mg creatinine
β2-Microglobulin 0–160 μg/L 0–160 μg/L
Norepinephrine 89–473 nmol/d 15–80 μg/d
N-telopeptide (cross-linked), NTx
Female, premenopausal 17–94 nmol BCE/mmol creatinine 17–94 nmol BCE/mmol creatinine
Female, postmenopausal 26–124 nmol BCE/mmol creatinine 26–124 nmol BCE/mmol creatinine
Male 21–83 nmol BCE/mmol creatinine 21–83 nmol BCE/mmol creatinine
BCE = bone collagen equivalent
Osmolality 100–800 mosm/kg 100–800 mosm/kg
Oxalate
Male 80–500 μmol/d 7–44 mg/d
Female 45–350 μmol/d 4–31 mg/d
pH 5.0–9.0 5.0–9.0
APPENDIX
Table 10
Normal Pressures in Heart and Great Vessels
Pressure (mmHg) Average Range
Right Atrium
Mean 2.8 1–5
a wave 5.6 2.5–7
c wave 3.8 1.5–6
x wave 1.7 0–5
v wave 4.6 2–7.5
y wave 2.4 0–6
Right Ventricle
Peak systolic 25 17–32
End-diastolic 4 1–7
Pulmonary Artery
Mean 15 9–19
Peak systolic 25 17–32
End-diastolic 9 4–13
Pulmonary Artery Wedge
Mean 9 4.5–13
Left Atrium
APPENDIX
Mean 7.9 2–12
a wave 10.4 4–16
v wave 12.8 6–21
Left Ventricle
Peak systolic 130 90–140
End-diastolic 8.7 5–12
Source: Reproduced from: MJ Kern The Cardiac Catheterization Handbook, 4th ed.
Philadelphia, Mosby, 2003.
678 Table 11
Circulatory Function Tests
Results: Reference Range
Source: E Braunwald et al: Heart Disease, 6th ed. Philadelphia, W.B. Saunders Co., 2001.
Laboratory Values of Clinical Importance
Table 12
Normal Echocardiographic Reference Limits and Partition Values in Adults
Women Men
Reference Mildly Moderately Severely Reference Mildly Moderately Severely
Range Abnormal Abnormal Abnormal Range Abnormal Abnormal Abnormal
679
680
Laboratory Values of Clinical Importance APPENDIX
Table 12
Normal Echocardiographic Reference Limits and Partition Values in Adults (CONTINUED)
Women Men
Reference Mildly Moderately Severely Reference Mildly Moderately Severely
Range Abnormal Abnormal Abnormal Range Abnormal Abnormal Abnormal
LA area, cm2 <20 20–30 30–40 ≥41 <20 20–30 30–40 ≥41
LA volume, mL 22–52 53–62 63–72 ≥73 18–58 59–68 69–78 ≥79
LA volume/BSA, mL/m2 16–28 29–33 34–39 ≥40 16–28 29–33 34–39 ≥40
Aortic stenosis, classification of severity
Aortic jet velocity, m/s 2.6–2.9 3.0–4.0 >4.0 2.6–2.9 3.0–4.0 >4.0
Mean gradient, mmHg <20 20–40 >40 <20 20–40 >40
Valve area, cm2 >1.5 1.0–1.5 <1.0 >1.5 1.0–1.5 <1.0
Indexed valve area, cm2/m2 >0.85 0.60–0.85 <0.6 >0.85 0.60–0.85 <0.6
Velocity ratio >0.50 0.25–0.50 <0.25 >0.50 0.25–0.50 <0.25
Mitral stenosis, classification of severity
Valve area, cm2 >1.5 1.0–1.5 <1.0 >1.5 1.0–1.5 <1.0
Mean gradient, mmHg <5 5–10 >10 <5 5–10 >10
Pulmonary artery pressure, mmHg <30 30–50 >50 <30 30–50 >50
Aortic regurgitation, indices of severity
Vena contracta width, cm <0.30 0.30–0.60 ≥0.60 <0.30 0.30–0.60 ≥0.60
Jet width/LVOT width, % <25 25–64 ≥65 <25 25–64 ≥65
Jet CSA/LVOT CSA, % <5 5–59 ≥60 <5 5–59 ≥60
Regurgitant volume, mL/beat <30 30–59 ≥60 <30 30–59 ≥60
Regurgitant fraction, % <30 30–49 ≥50 <30 30–49 ≥50
Effective regurgitant orifice area, cm2 <0.10 0.10–0.29 ≥0.30 <0.10 0.10–0.29 ≥0.30
Mitral regurgitation, indices of severity
Vena contracta width, cm <0.30 0.30–0.69 ≥0.70 <0.30 0.30–0.69 ≥0.70
Regurgitant volume, mL/beat <30 30–59 ≥60 <30 30–59 ≥60
Regurgitant fraction, % <30 30–49 ≥50 <30 30–49 ≥50
Effective regurgitant orifice area, cm2 <0.20 0.20–0.39 ≥0.40 <0.20 0.20–0.39 ≥0.40
Abbreviations: BSA, body surface area; CSA, cross-sectional area; LA, left atrium; LVOT, left ventricular outflow tract; RA, right atrium; RV, right ventricle; RVOT, right ventricular outflow tract;
2D, 2-dimensional.
Source: Values adapted from: American Society of Echocardiography, Guidelines and Standards. http://www.asecho.org/i4a/pages/index.cfm?pageid=3317. Accessed Feb 23, 2010.
Table 13 681
Summary of Values Useful in Pulmonary Physiology
Typical Values
Pulmonary Mechanics
Spirometry—volume-time curves
Forced vital capacity FVC 5.0 L 3.4 L
Forced expiratory volume in 1 s FEV1 4.0 L 2.8 L
FEV1/FVC FEV1% 80% 78%
Maximal midexpiratory flow rate MMEF (FEF 25–75) 4.1 L/s 3.2 L/s
Maximal expiratory flow rate MEFR (FEF 200–1200) 9.0 L/s 6.1 L/s
Spirometry—flow-volume curves
Maximal expiratory flow at 50% of expired vital Vmax 50 (FEF 50%) 5.0 L/s 4.0 L/s
capacity
Maximal expiratory flow at 75% of expired vital Vmax 75 (FEF 75%) 2.1 L/s 2.0 L/s
capacity
Resistance to airflow:
Pulmonary resistance RL (RL) <3.0 (cmH2O/s)/L
Airway resistance Raw <2.5 (cmH2O/s)/L
Specific conductance SGaw >0.13 cmH2O/s
Pulmonary compliance
Static recoil pressure at total lung capacity Pst TLC 25 ± 5 cmH2O
Compliance of lungs (static) CL 0.2 L cmH2O
Compliance of lungs and thorax C(L + T) 0.1 L cmH2O
APPENDIX
Dynamic compliance of 20 breaths per minute C dyn 20 0.25 ± 0.05 L/cmH2O
Maximal static respiratory pressures:
Maximal inspiratory pressure MIP >110 cmH2O >70 cmH2O
Maximal expiratory pressure MEP >200 cmH2O >140 cmH2O
Lung Volumes
Total lung capacity TLC 6.9 L 4.9 L
Source: Based on: AH Morris et al: Clinical Pulmonary Function Testing. A Manual of Uniform Laboratory Procedures, 2nd ed. Salt Lake City,
Utah, Intermountain Thoracic Society, 1984.
682 Table 14
Gastrointestinal Tests
Results
Absorption tests
d-Xylose: after overnight fast, 25 g xylose given in oral
aqueous solution
Urine, collected for following 5 h 25% of ingested dose 25% of ingested dose
Serum, 2 h after dose 2.0–3.5 mmol/L 30–52 mg/dL
Vitamin A: a fasting blood specimen is obtained and Serum level should rise to twice Serum level should rise to
200,000 units of vitamin A in oil is given orally fasting level in 3–5 h twice fasting level in 3–5 h
Bentiromide test (pancreatic function): 500 mg
bentiromide (chymex) orally; p-aminobenzoic acid
(PABA) measured
Plasma >3.6 (±1.1) μg/mL at 90 min
Urine >50% recovered in 6 h >50% recovered in 6 h
Gastric juice
Volume
24 h 2–3 L 2–3 L
Nocturnal 600–700 mL 600–700 mL
Basal, fasting 30–70 mL/h 30–70 mL/h
Reaction
pH 1.6–1.8 1.6–1.8
Titratable acidity of fasting juice 4–9 μmol/s 15–35 meq/h
Acid output
Basal
APPENDIX
Table 15
Body Fluids and Other Mass Data
Reference Range
APPENDIX
Table 16
Radiation-Derived Units
Special Name
for SI Unit
Quantity Measures Old Unit SI Unit (Abbreviation) Conversion
QUESTIONS
DIRECTIONS: Choose the one best response to 3. (Continued)
each question. when she noticed that food no longer had the same
taste. Her daughter accompanies her to the visit and
1. A 41-year-old female presents to your clinic with a reports that her mother seems increasingly listless and
week of jaundice. She notes pruritus, icterus, and dark withdrawn. Her daughter also notes that her mother
urine. She denies fever, abdominal pain, or weight loss. seems more forgetful, and her home has become dis-
The examination is unremarkable except for yellow organized. The patient has a history of hypertension
discoloration of the skin. Total bilirubin is 6.0 mg/dL, and peripheral vascular disease. She had a transient
and direct bilirubin is 5.1 mg/dL. AST is 84 U/L, and ischemic attack 6 years ago, but has never had a stroke.
ALT is 92 U/L. Alkaline phosphatase is 662 U/L. CT There have been no recent changes to any medica-
scan of the abdomen is unremarkable. Right upper tions. Her weight in the clinic today is 60 kg. What
quadrant ultrasound shows a normal gallbladder but is the appropriate approach for the evaluation of this
does not visualize the common bile duct. What is the patient’s weight loss?
most appropriate next management step?
A. Ask the patient to return to the clinic in 1 month for
A. Antibiotics and observation repeat weight evaluation.
B. Endoscopic retrograde cholangiopancreatography B. Order thyroid function tests.
(ERCP) C. Perform a Mini-Mental State Examination.
C. Hepatitis serologies D. Reassure the patient and her daughter that this
D. HIDA scan degree of weight loss is not abnormal.
E. Serologies for antimitochondrial antibodies E. Both B and C are correct.
2. A 61-year-old male is admitted to your service for 4. The advantages of endoscopy over barium radio
swelling of the abdomen. You detect ascites on clin- graphy in the evaluation of dysphagia include all of
ical examination and perform a paracentesis. The the following EXCEPT:
results show a white blood cell count of 300 leuko-
cytes/μL with 35% polymorphonuclear cells. The A. Ability to intervene as well as diagnose
peritoneal albumin level is 1.2 g/dL, protein is 2.0 B. Ability to obtain biopsy specimens
g/dL, and triglycerides are 320 mg/dL. Peritoneal C. Increased sensitivity for the detection of abnormali-
cultures are pending. Serum albumin is 2.6 g/dL. ties identified by color, e.g., Barrett’s metaplasia
Which of the following is the most likely diagnosis? D. Increased sensitivity for the detection of mucosal lesions
E. No meaningful risk to procedure
A. Congestive heart failure
B. Peritoneal tuberculosis 5. A 47-year-old man is evaluated in the emergency
C. Peritoneal carcinomatosis department for chest pain that developed at a restaurant
D. Chylous ascites after swallowing a piece of steak. He reports intermit-
E. Bacterial peritonitis tent episodes of meat getting stuck in his lower chest
over the past 3 years, but none as severe as this event.
3. An 80-year-old woman is evaluated for a complaint He denies food regurgitation outside of these episodes
of involuntary weight loss. Her baseline weight at her or heartburn symptoms. He is able to swallow liquids
clinic visit 6 months ago was 67 kg. She reports that without difficulty and has not had any weight loss.
her appetite began to decrease about 2 months ago Which of the following is the most likely diagnosis?
a
Questions and answers were taken from Wiener C et al (eds): Harrison’s Principles of Internal Medicine Self-Assessment and Board Review, 18th ed. New York:
McGraw-Hill, 2012.
685
686 Review and Self-Assessment
5. (Continued) 8. (Continued)
A. Achalasia C. The patient is not at risk for any associated cancers.
B. Adenocarcinoma of the esophagus D. Poor socioeconomic status is a risk factor for devel-
C. Esophageal diverticula opment of this condition.
D. Plummer-Vinson syndrome E. Antral gastritis is rarely found with this condition.
E. Schatzki’s ring
9. A 58-year-old man is evaluated for abdominal pain
6. Which of the following has a well-established asso- by his primary care physician. He reports severe stress
ciation with gastroesophageal reflux? at his job for the last 3 months and has since noted
that he has epigastric pain that is relieved by eating
A. Chronic sinusitis and drinking milk. He has not had food regurgita-
B. Dental erosion tion, dysphagia, or bloody emesis or bowel move-
C. Pulmonary fibrosis ments. He denies any symptoms in his chest. Peptic
D. Recurrent aspiration pneumonia ulcer disease is suspected. Which of the following
E. Sleep apnea statements regarding noninvasive testing for Helico-
bacter pylori is true?
7. A 36-year-old female with AIDS and a CD4 count
of 35/mm3 presents with odynophagia and pro- A. There is no reliable noninvasive method to detect
gressive dysphagia. The patient reports daily fevers H. pylori.
and a 20-lb weight loss. She has been treated with B. Stool antigen testing is appropriate for both diagnosis
clotrimazole troches without relief. On physical of and proof of cure after therapy for H. pylori.
examination the patient is cachectic with a body C. Plasma antibodies to H. pylori offer the greatest sensi-
mass index (BMI) of 16 and a weight of 86 lb. She tivity for diagnosis of infection.
has a temperature of 38.2°C (100.8°F) and is noted D. Exposure to low-dose radiation is a limitation to the
to be orthostatic by blood pressure and pulse. Exam- urea breath test.
ination of the oropharynx reveals no evidence of E. False-negative testing using the urea breath test may
thrush. The patient undergoes esophagogastroduo- occur with recent use of NSAIDs.
denoscopy (EGD), which reveals serpiginous ulcers
in the distal esophagus without vesicles. No yellow 10. A 44-year-old woman complains of 6 months of
plaques are noted. Multiple biopsies are taken that epigastric pain that is worst between meals. She also
show intranuclear and intracytoplasmic inclusions reports symptoms of heartburn. The pain is typically
in large endothelial cells and fibroblasts. What is the relieved by over-the-counter antacid medications.
best treatment for this patient’s esophagitis? She comes to the clinic after noting her stools dark-
ening. She has no significant past medical history
A. Ganciclovir and takes no medications. Her physical examination
B. Glucocorticoids is normal except for diffuse mid-epigastric pain. Her
C. Fluconazole stools are heme positive. She undergoes EGD, which
D. Foscarnet demonstrates a well-circumscribed 2-cm duodenal
E. Thalidomide ulcer that is positive for H. pylori. Which of the fol-
lowing is recommended initial therapy given these
8. A 57-year-old man is evaluated with an esophago- findings?
gastroduodenoscopy after an episode of hemateme-
sis. The patient reports a history of tobacco use and A. Lansoprazole plus clarithromycin plus amoxicillin for
hypercholesterolemia, but is otherwise healthy. He 14 days
has had lower back pain for the past month and has B. Pantoprazole plus amoxicillin for 21 days
been intermittently using acetaminophen 1000 mg C. Pantoprazole plus clarithromycin for 14 days
for relief. His endoscopy shows a 3-cm duodenal D. Omeprazole plus bismuth plus tetracycline plus met-
ulcer. Which of the following statements is correct ronidazole for 14 days
regarding this finding? E. Omeprazole plus metronidazole plus clarithromycin
for 7 days
A. The lesion should be biopsied as duodenal ulcers
have an elevated risk of being due to carcinoma. 11. A 57-year-old man with peptic ulcer disease experi-
B. First-line therapy should be discontinuation of acet- ences transient improvement with Helicobacter pylori
aminophen use. eradication. However, 3 months later symptoms
Review and Self-Assessment 687
25. A 78-year-old woman is admitted to the hospital 28. Which of the following statements regarding ano-
with fever, loss of appetite, and left lower quadrant rectal abscess is true?
pain. She is not constipated, but has not moved her
bowels recently. Laboratory examination is notable A. Anorectal abscess is more common in diabetic
for an elevated WBC count. These symptoms began patients.
approximately 3 days ago and have steadily wors- B. Anorectal abscess is more common in women.
ened. Which of the following statements regarding C. Difficulty voiding is uncommon and should prompt
the use of radiologic imaging to evaluate her condi- further evaluation of anorectal abscess.
tion is true? D. Examination in the operating room under anes-
thesia is required for adequate exploration in most
A. Air-fluid levels are commonly seen on plain abdomi- cases.
nal films. E. The peak incidence is the seventh decade of life.
B. Barium enema should not be performed because of
the risk of perforation. 29. An 88-year-old woman is brought to your clinic
C. Lower gastrointestinal bleeding will likely be visual- by her family because she has become increasingly
ized on CT angiography. socially withdrawn. The patient lives alone and has
D. A thickened colonic wall is not required on CT for been reluctant to visit or be visited by her fam-
the diagnosis of her likely condition. ily. Family members, including seven children, also
E. Ultrasound of the pelvis is the best modality to note a foul odor in her apartment and on her per-
visualize the likely pathologic process. son. She has not had any weight loss. Alone in the
examining room, she only complains of hemor-
26. Which of the following patients is MOST appro- rhoids. On mental status examination, she has signs
priate for surgical management of their acute diver- of depression. Which of the following interventions
ticulitis? is most appropriate at this time?
36. Which of the following is the source of the perito- A. Abdominal cramping
nitis of the patient in question 35? B. Diarrhea
C. Fever
A. Bile D. Vomiting
B. Blood
C. Foreign body 41. You are the on-call physician practicing in a subur-
D. Gastric contents ban community. You receive a call from a 28-year-
E. Pancreatic enzymes old woman with a past medical history significant for
sarcoidosis who is currently taking no medications.
37. Enteric pathogens can produce diarrheal illness She is complaining of an acute onset of crampy dif-
through a variety of mechanisms that lead to spe- fuse abdominal pain and multiple episodes of emesis
cific clinical characteristics. All of the following are that are nonbloody. She has not had any lighthead-
characteristics of diarrhea caused by Vibrio cholerae edness with standing or loss of consciousness. When
EXCEPT: questioned further, the patient states that her last
meal was 5 hours previously, when she joined her
A. Disease localized to the proximal small intestine friends for lunch at a local Chinese restaurant. She
B. Fecal leukocytes ate from the buffet, which included multiple poul-
C. Fecal lactoferrin try dishes and fried rice. What should you do for
D. Toxin production this patient?
E. Watery diarrhea
A. Ask the patient to go to the nearest emergency
38. A 46-year-old woman travels to a rural area of department for resuscitation with IV fluids.
Guatemala. Three days after arrival, she develops B. Initiate antibiotic therapy with azithromycin.
watery diarrhea with severe abdominal cramping. C. Reassure the patient that her illness is self-limited
She reports two unformed stools daily for the past and no further treatment is necessary if she can
2 days. She has noticed no blood in the stool and maintain adequate hydration.
has not experienced a fever. What is the most likely D. Refer the patient for CT to assess for appendicitis.
cause of the patient’s illness? E. Refer the patient for admission for IV vancomycin
and ceftriaxone because of her immunocompromised
A. Campylobacter jejuni state resulting from sarcoidosis.
B. Enterotoxigenic Escherichia coli
C. Giardia lamblia 42. Which of the following is a common manifestation
D. Norovirus of Clostridium difficile infection?
E. Shigella spp.
A. Fever
39. For the case above, which of the following treat- B. Nonbloody diarrhea
ments would you recommend? C. Adynamic ileus
D. Recurrence after therapy
A. Azithromycin 10 mg/kg on day 1 with 5 mg/kg on E. All of the above
days 2 and 3 if the diarrhea persists
B. Ciprofloxacin 500 mg three times daily for 5 days 43. All of the following patients should be treated for
C. Ciprofloxacin 750 mg once Clostridium difficile infection EXCEPT:
692 Review and Self-Assessment
74. What is the next step in the evaluation and manage- 76. In the scenario described in question 75, what
ment of the patient in question 73? would be the best approach to prevent development
of chronic hepatitis?
A. Genotype studies
B. Peripheral blood smear A. Administration of anti-hepatitis A virus IgG.
C. Prednisone B. Administration of lamivudine.
D. Reassurance C. Administration of pegylated interferon α plus
E. Right upper quadrant ultrasound ribavirin.
D. Administration of prednisone beginning at a dose of
1 mg/kg daily.
75. A 34-year-old man presents to the physician com- E. Do nothing and observe, as 99% of individuals with
plaining of yellow eyes. For the past week, he has this disease recover.
felt ill with decreased oral intake, low-grade fevers
(~100°F), fatigue, nausea, and occasional vomiting. 77. Which of the following viral causes of acute hepa-
With the onset of jaundice, he has noticed pain in titis is most likely to cause fulminant hepatitis in a
his right upper quadrant. He currently uses mari- pregnant woman?
juana and ecstasy, and has a prior history of injec-
tion drug use with cocaine. He has no other past A. Hepatitis A
medical history, but he was unable to donate blood B. Hepatitis B
4 years previously for reasons that he cannot recall. C. Hepatitis C
His social history is remarkable for working as a D. Hepatitis D
veterinary assistant. On sexual history, he reports E. Hepatitis E
five male sexual partners over the past 6 months.
He does not consistently use condoms. On physical 78. A 16-year-old woman had visited your clinic
examination, he appears ill and has obvious jaun- 1 month ago with jaundice, vomiting, malaise, and
dice with scleral icterus. His liver is 15 cm to per- anorexia. Two other family members were ill with
cussion and is palpable 6 cm below the right costal similar symptoms. Based on viral serologies, includ-
margin. The edge is smooth and tender to palpation. ing a positive anti-hepatitis A virus (HAV) IgM, a
The spleen is not enlarged. There are no stigmata diagnosis of hepatitis A was made. The patient was
698 Review and Self-Assessment
91. A 42-year-old man with cirrhosis related to 94. A 58-year-old man is evaluated for a new diagno-
hepatitis C and alcohol abuse has ascites requir- sis of cirrhosis. The patient has a medical history of
ing frequent large-volume paracentesis. All of the diabetes mellitus, hypertriglyceridemia, and hyper-
following therapies would be indicated for this tension. He takes pioglitazone, rosuvastatin, lisino-
patient EXCEPT: pril, and atenolol. He is a lifetime nonsmoker and
has never used IV drugs. He drinks about one glass
A. Fluid restriction to less than 2 L daily of wine weekly. For about 4–8 years in his 20s, he
B. Furosemide 40 mg daily admits to binge drinking as much as 12–18 beers
C. Sodium restriction to less than 2 g daily on the weekends, but has not drunk more than
D. Spironolactone 100 mg daily two glasses of wine weekly for many years. He has
E. Transjugular intrahepatic portosystemic shunt if never had a blood transfusion and has been in a
medical therapy fails monogamous sexual relationship for 30 years. He
has no family history of liver disease. He works as a
92. Which of the following statements about cardiac machinist in a factory making airplane engines. He
cirrhosis is TRUE? denies chemical exposures. His physical examina-
tion is notable for a body mass index of 45.9 kg/
A. AST and ALT levels may mimic the very high levels m2. He has stigmata of chronic liver disease includ-
seen in acute viral hepatitis. ing spider angiomata and caput medusa. Moderate
B. Budd-Chiari syndrome cannot be distinguished clini-
ascites is present. Workup has shown no evidence
cally from cardiac cirrhosis.
of viral hepatitis, hemochromatosis, Wilson’s disease,
C. Echocardiography is the gold standard for diag-
autoimmune hepatitis, or α1 antitrypsin deficiency.
nosing constrictive pericarditis as a cause of
cirrhosis.
He undergoes liver biopsy, which shows fibrosis in
D. Prolonged passive congestion from right-sided heart a perivenular and perisinusoidal distribution. Which
failure results first in congestion and necrosis of por- of the following statements is TRUE regarding the
tal triads, resulting in subsequent fibrosis. cause of the patient’s cirrhosis?
E. Venoocclusive disease can be confused with cardiac
cirrhosis and is a major cause of morbidity and mor- A. As opposed to individuals with metabolic syndrome
tality in patients undergoing liver transplantation. alone, these individuals do not show significant insu-
lin resistance.
93. You are asked to consult on a 62-year-old white B. The aspartate aminotransferase is commonly elevated
female with pruritus for 4 months. She has noted to more than twice the alanine aminotransferase
progressive fatigue and a 5-lb weight loss. She has level.
intermittent nausea but no vomiting and denies C. The lack of steatohepatitis on liver biopsy rules out
changes in her bowel habits. There is no history of nonalcoholic fatty liver disease as a cause of the
prior alcohol use, blood transfusions, or illicit drug patient’s cirrhosis.
use. The patient is widowed and had two heterosex- D. The prevalence of the milder form of this disorder
ual partners in her lifetime. Her past medical history is between 10 and 20% in the United States and
is significant only for hypothyroidism, for which she Europe, with as much as 10–15% of affected indi-
viduals developing cirrhosis in some series.
takes levothyroxine. Her family history is unremark-
E. Treatment with ursodeoxycholic acid and HMG-
able. On examination she is mildly icteric. She has
CoA reductase inhibitors has been demonstrated to
spider angiomata on her torso. You palpate a nodu-
improve outcomes in this disorder.
lar liver edge 2 cm below the right costal margin.
The remainder of the examination is unremarkable.
A right upper quadrant ultrasound confirms your 95. A 44-year-old woman is evaluated for complaints
suspicion of cirrhosis. You order a complete blood of abdominal pain. She describes the pain as a post-
count and a comprehensive metabolic panel. What prandial burning pain. It is worse with spicy or fatty
is the most appropriate next test? foods and is relieved with antacids. She is diagnosed
with a gastric ulcer and is treated appropriately for
A. 24-hour urine copper Helicobacter pylori. During the course of her evalua-
B. Antimitochondrial antibodies (AMA) tion for her abdominal pain, the patient had a right
C. Endoscopic retrograde cholangiopancreatography upper quadrant ultrasound that demonstrated the
(ERCP) presence of gallstones. Following treatment of
D. Hepatitis B serologies H. pylori, her symptoms have resolved. She is request-
E. Serum ferritin ing your opinion regarding whether treatment is
702 Review and Self-Assessment
ANSWERS
1. The answer is B.
(Chaps. 8 and 45) The clinical presentation is consis- e levation of the transaminases on the liver function tests
tent with a cholestatic picture. Painless jaundice always makes acute hepatitis unlikely. Antimitochondrial anti-
requires an extensive workup, as many of the underlying bodies are elevated in cases of primary biliary cirrhosis
pathologies are ominous and early detection and inter- (PBC), which may present in a similar fashion. However,
vention often offers the only hope for a good outcome. PBC is far more common in women than in men, and
The gallbladder showed no evidence of stones and the the average age of onset is the fifth or sixth decade. The
patient shows no evidence of clinical cholecystitis, and lack of an obvious lesion on CT scan does not rule out
so a hepatobiliary iminodiacetic acid (HIDA) scan is a source of the cholestasis in the biliary tree. Malignant
not indicated. Similarly, antibiotics are not necessary at causes such as cholangiocarcinoma and tumor of
this point. The cholestatic picture without significant the ampulla of Vater, and nonmalignant causes such
Review and Self-Assessment 705
as sclerosing cholangitis and Caroli’s disease may be in the elderly may also present with loss of appetite and
detected only by direct visualization with endoscopic should be assessed. Laboratory studies could include a
retrograde cholangiopancreatography (ERCP). ERCP is complete blood count, comprehensive metabolic panel,
useful both diagnostically and therapeutically, as stenting thyroid function tests, and erythrocyte sedimentation
procedures may be done to alleviate the obstruction. rate and C-reactive protein. HIV testing is indicated if
risk factors are identified.
2. The answer is A.
(Chaps. 9 and 36) Diagnostic paracentesis is part of the 4. The answer is E.
routine evaluation in a patient with ascites. Fluid should (Chap. 13) Endoscopy, also known as esophagogastro-
be examined for its gross appearance, protein content, duodenoscopy (EGD), is the best test for the evaluation
cell count and differential, and albumin. Cytologic and of the proximal gastrointestinal tract. Because of high-
culture studies should be performed when one suspects quality images, disorders of color such as Barrett’s meta-
infection or malignancy. The serum-ascites albumin gra- plasia, and mucosal irregularities are easily demonstrated.
dient (SAG) offers the best correlation with portal pres- The sensitivity of endoscopy is superior to that of bar-
sure. A high gradient (>1.1 g/dL) is characteristic of ium radiography for mucosal lesions. Because the endo-
uncomplicated cirrhotic ascites and differentiates ascites scope has an instrumentation channel, biopsy specimens
caused by portal hypertension from ascites not caused by are easily obtained and dilation of strictures can also be
portal hypertension in more than 95% of cases. Condi- performed. The only advantage that barium radiography
tions that cause a low gradient include more “exudative” confers is the absence of the requirement for sedation,
processes such as infection, malignancy, and inflamma- which, in some populations at risk for conscious seda-
tory processes. Similarly, congestive heart failure and tion, is an important consideration.
nephrotic syndrome cause high gradients. In this patient
the SAG is 1.5 g/dL, indicating a high gradient. The 5. The answer is E.
low number of leukocytes and polymorphonuclear cells (Chap. 13) Intermittent solid food dysphagia is a classic
makes bacterial or tubercular infection unlikely. Chylous symptom in Schatzki’s ring in which a distal esophageal
ascites often is characterized by an opaque milky fluid ring occurs at the squamocolumnar mucosal junction.
with a triglyceride level greater than 1000 mg/dL in The origin of these rings is unknown, and smaller rings
addition to a low SAG. with a lumen of greater than 13 mm are common in
the general population (up to 15%). When the lumen is
3. The answer is E. less than 13 mm, dysphagia may occur. Schatzki’s rings
(Chap. 10) Involuntary weight loss (IWL) is a frequent typically occur in persons older than 40 years and often
finding in older individuals, affecting more than 25% of cause “steakhouse syndrome” from meat getting stuck at
frail individuals older than 65 years. Clinically impor- the ring. The rings are easily treated with dilation. Plum-
tant weight loss is defined as a loss of more than 5% of mer-Vinson syndrome also includes esophageal rings,
body weight or more than 5 kg over the course of 6–12 but typically the rings occur in the proximal esophagus,
months. In older individuals, weight loss is associated are associated with iron-deficiency anemia, and occur in
with hip fracture, pressure ulcers, decreased functional middle-aged women. Achalasia involves both solid and
status, and death. There are many causes of IWL, with liquid dysphagia often with regurgitation. Adenocarci-
the most common categories being malignancy, chronic noma often includes solid and liquid dysphagia at later
inflammatory or infectious disease, metabolic disorders, stages. Most esophageal diverticulae are asymptomatic.
and psychiatric disorders. In older individuals, it is also
important to consider neurologic disorders, including 6. The answer is B.
stroke leading to dysphagia, progressive vision loss, and (Chap. 13) Aside from the discomfort and local com-
dementia. IWL can be one of the earliest manifesta- plications of gastroesophageal reflux disease (GERD), a
tions of Alzheimer’s disease. An under-recognized cause number of other non-GI–related sites may have a com-
of IWL is lack of access to food or inability to pay for plication related to it. Syndromes with a well-established
food. When evaluating an individual for IWL, a com- association with GERD include chronic cough, laryngi-
plete physical examination, including a dental examina- tis, asthma, and dental erosions. Other diseases have impli-
tion, should be performed to assess for obvious physi- cated GERD as potentially contributory, but the role of
cal causes that would lead to weight loss. Medications GERD is less well established. These include pharyngitis,
may also lead to changes in appetite or weight loss. pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias,
Patients should undergo age-appropriate cancer screen- sleep apnea, and recurrent aspiration pneumonia.
ing. In older individuals, a Mini-Mental State Examination,
Mini-Nutritional Assessment, and assessment of perfor- 7. The answer is A.
mance of activities of daily living may be helpful. It may (Chap. 13) This patient has symptoms of esophagitis.
also be useful to observe the patient’s eating. Depression In patients with HIV, various infections can cause this
706 Review and Self-Assessment
disease, including herpes simplex virus (HSV), cytomeg- several weeks to months to fall. The urea breath test,
alovirus (CMV), varicella-zoster virus (VZV), Candida, which relies on the presence of urease secreted by H.
and HIV itself. The lack of thrush does not rule out pylori to digest the swallowed radioactive urea and liber-
Candida as a cause of esophagitis, and EGD is necessary ate 14C or 13C as part of ammonia, is simple and rapid. It
for diagnosis. CMV classically causes serpiginous ulcers is useful for early follow-up, as it requires living bacteria
in the distal esophagus that may coalesce to form giant to secrete urease and produce a positive test. The limita-
ulcers. Brushings alone are insufficient for diagnosis, and tions to the test include the requirement for ingestion of
biopsies must be performed. Biopsies reveal intranuclear radioactive materials, albeit low dose, and false-negative
and intracytoplasmic inclusions with enlarged nuclei in results with recent use of PPI, antibiotics, or bismuth
large fibroblasts and endothelial cells. Given her notable compounds. Stool antigen testing is cheap and conve-
swallowing symptoms, IV ganciclovir is the treatment nient, but is not established for proof of eradication.
of choice. Valganciclovir is an effective oral preparation.
Foscarnet is useful in treating ganciclovir-resistant CMV. 10. The answer is A.
Herpes simplex virus manifests as vesicles and punched- (Chap. 14) H. pylori should be eradicated in patients
out lesions in the esophagus, with the characteris- with documented peptic ulcer disease no matter the
tic finding on biopsy of ballooning degeneration with number of episodes, severity, presence of confound-
ground-glass changes in the nuclei. It can be treated with ing factors (e.g., NSAID ingestion), or symptomatic
acyclovir or foscarnet in resistant cases. Candida esopha- status. Documented eradication of H. pylori is associated
gitis has the appearance of yellow nodular plaques with with substantially lower recurrence rates and symptom
surrounding erythema. Treatment usually requires flu- improvement. Treating patients with GERD who require
conazole therapy. Finally, HIV alone can cause esoph- long-term acid reduction therapy and the role of H. pylori
agitis that can be quite resistant to therapy. On EGD eradication to prevent gastric cancer are controversial.
these ulcers appear deep and linear. Treatment with tha- Fourteen-day regimens are most effective. Shorter dura-
lidomide or oral glucocorticoids is employed, and highly tion of therapy with current agents available has high
active antiretroviral therapy should be considered. recurrence rates. Dual-therapy regimens are not recom-
mended because of eradication rates of less than 80%.
8. The answer is D. A number of combinations are available (Table 14-4).
(Chap. 13) The patient has a duodenal ulcer, which is Triple-therapy regimens (one antacid plus two antibi-
almost universally due to H. pylori infection, although otics) for 14 days have an eradication rate of 85–90%.
in a minority of cases NSAID use may either facilitate Antibiotic resistance is the most common cause of failure
development or be the only identified cause. The patient to eradicate in compliant patients. Unfortunately, there
was taking acetaminophen and not a traditional NSAID, is no currently available test for H. pylori sensitivity to
making H. pylori–associated peptic ulcer disease the most direct therapy. Quadruple therapy should be reserved for
likely cause of the findings. H. pylori infection is closely patients with failure to eradicate after an effective initial
correlated with advancing age, low socioeconomic status, course.
and low education levels. After initial infection, antral gas-
tritis is very common, and in a portion of cases, duodenal 11. The answer is C.
or gastric ulcers form. Associated with these conditions is (Chap. 14) Fasting gastrin levels can be elevated in a
the development of gastric cancer or MALT lymphoma. variety of conditions including atrophic gastritis with
Duodenal ulcers are rarely cancerous, although this is a or without pernicious anemia, G-cell hyperplasia, and
not an uncommon finding in gastric cancers. After dis- acid suppressive therapy (gastrin levels increase as a con-
covery of the ulcer, first-line therapy is eradication of sequence of loss of negative feedback). The diagnostic
H. pylori in addition to acid suppression. concern in a patient with persistent ulcers following
optimal therapy is Zollinger-Ellison syndrome (ZES).
9. The answer is D. The result is not sufficient to make a diagnosis because
(Chap. 14) Noninvasive testing for H. pylori infection is gastrin levels may be elevated in a variety of conditions.
recommended in patients with suggestive symptoms and Elevated basal acid secretion also is consistent with ZES,
no other indication for endoscopy, e.g., GI bleeding, but up to 12% of patients with peptic ulcer disease may
atypical symptoms. Several tests have good sensitivity and have basal acid secretion as high as 15 meq/h. Thus,
specificity, including plasma serology for H. pylori, 14C- additional testing is necessary. Gastrin levels may go up
or 13C-urea breath test, and the fecal H. pylori antigen with a meal (>200%), but this test does not distinguish
test. Sensitivity and specificity are greater than 80% and G-cell hyperfunction from ZES. The best test in this set-
greater than 90%, respectively, for serology, while the ting is the secretin stimulation test. An increase in gastrin
urea breath test and fecal antigen testing are greater than levels greater than 200 pg within 15 minutes of admin-
90% for both. Serology is not useful for early follow- istering 2 μg/kg of secretin by IV bolus has a sensitivity
up after therapy completion, as antibody titers will take and specificity of greater than 90% for ZES. Endoscopic
Review and Self-Assessment 707
ultrasonography is useful in locating the gastrin-secreting oxalate and free oxalate is absorbed in the large intestine.
tumor once the positive secretin test is obtained. Increased bile acid pool size results in the generation of
Genetic testing for mutations in the gene that encodes cholesterol gallstones from supersaturating in gallbladder
the menin protein can detect the fraction of patients bile. Gastric hypersecretion of acid is well described and
with gastrinomas that are a manifestation of multiple thought to be due to loss of inhibition of gastric acid
endocrine neoplasia type I (Wermer’s syndrome). secretion because of absent short bowel to secrete inhibi-
Gastrinoma is the second most common tumor in this tory hormones. Coronary artery disease is not described
syndrome following parathyroid adenoma, but its peak as a complication of short bowel syndrome.
incidence is generally in the third decade.
14. The answer is E.
12. The answer is B. (Chap. 15) The patient presents with symptoms sug-
(Chap. 15) The patient presents with nonspecific gas- gestive of Whipple’s disease with a chronic multisystem
trointestinal symptoms, but the presence of weight loss disease often including diarrhea/steatorrhea, migratory
suggests malabsorption syndrome. Patients with lactose arthralgias, weight loss, and CNS or cardiac problems.
intolerance are usually able to relate symptoms to con- Generally the presentation is of insidious onset, and demen-
sumption of milk-based products and also report a strong tia is a late finding and poor prognostic sign. The disease
history of crampy pain and flatulence. Therefore, a lac- primarily occurs in middle-aged white males. The diag-
tose-free diet is unlikely to be helpful. The patient does nosis requires small bowel biopsy and demonstration of
not have nocturnal diarrhea, which is commonly a feature PAS-positive macrophages within the small bowel. Small
of steatorrhea along with floating stools. In the absence bacilli are often present and suggest the diagnosis of
of symptoms suggesting fat malabsorption, the first test Whipple’s disease. Similar macrophages may be found in
should not be fecal fat measurement. As the patient has other affected organs, e.g., the CNS. Dilated lymphatics
weight loss, irritable bowel syndrome is less likely, and an are present in patients with intestinal lymphangiectasia.
increase dietary fiber is unlikely to be useful. Finally, Mononuclear cell infiltrate in the lamina propria is
her symptoms may be consistent with celiac disease. The often demonstrated in patients with tropical sprue, and
widespread availability of antibodies to gliadin, endo- flat villi with crypt hyperplasia are the hallmark of
mysial, and tTG can be easily measured in peripheral celiac disease.
blood. Antiendomysial antibody has a 90–95% sensitivity
and equal specificity, making it a reasonable first test in 15. The answer is D.
symptomatic individuals. The presence of the antibody (Chap. 15) This patient has a stool osmolality gap (mea-
is not diagnostic, however, and duodenal biopsy is rec- sured stool osmolality - calculated stool osmolality) of
ommended. Duodenal biopsy will show villous atrophy, less than 50 mosmol/L, suggesting a secretory rather than
absence or reduced height of villi, cuboidal appearance an osmotic cause for diarrhea. Secretory causes of diar-
of surface epithelial cells, and increased lymphocytes and rhea include toxin-mediated diarrhea (cholera, entero-
plasma cells in the lamina propria. These changes regress toxigenic Escherichia coli) and intestinal peptide–mediated
with complete removal of gluten from the diet. diarrhea in which the major pathophysiology is a luminal
or circulating secretagogue. The distinction between
13. The answer is B. secretory diarrhea and osmotic diarrhea aids in forming
(Chap. 15) Short bowel syndrome is a descriptive term a differential diagnosis. Secretory diarrhea will not
referring to the many clinical complications that may decrease substantially during a fast and has a low
occur after resection of varying lengths of the small bowel. osmolality gap. Osmotic diarrhea will generally decrease
Rarely, these complications may be due to congenital during a fast and has a high (>50 mosmol/L) osmolality
abnormalities of the small bowel. Most commonly in gap. Celiac sprue, chronic pancreatitis, lactase deficiency,
adults, short bowel syndrome occurs in mesenteric vas- and Whipple’s disease all cause an osmotic diarrhea.
cular disease, primary mucosal or submucosal disease
(Crohn’s disease), and operations without preexisting 16. The answer is E.
small bowel disease such as trauma. Multiple factors con- (Chaps. 15 and 16) Cobalamin malabsorption may occur
tribute to diarrhea and steatorrhea including gastric acid due to disease at multiple anatomic sites extending from
hypersecretion, increased bile acids in the colon due to the stomach to the ileum. In the past, the Schilling test
absent or decreased reabsorption in the small bowel, and was utilized to assess cobalamin absorption, but this test
lactose intolerance due to increased gastric acid secre- is not currently commercially available. Cobalamin is
tion. Nonintestinal symptoms may include renal calcium primarily present in meat, but dietary deficiency is rare
oxalate calculi due to an increase in oxalate absorption by except in strict vegans. Dietary cobalamin is bound in the
the large intestine with subsequent hyperoxaluria. This stomach to R-binder protein that is synthesized in sali-
may be due to increased fatty acids in the colon that bind vary glands and stomach. The cobalamin–R binder com-
calcium, and thus calcium in the gut is not free to bind plex requires an acid medium. Therefore, achlorhydria
708 Review and Self-Assessment
of any cause may result in the inability for splitting of granulomas are only found in about half of surgical
cobalamin from food and binding to R-binder pro- resections. Flat villi are not always present in either dis-
tein. Cobalamin absorption has an absolute require- ease and are more commonly found in isolation with
ment for intrinsic factor, which allows uptake by specific celiac disease.
receptors in the ileum. Intrinsic factor is produced and
released by gastric parietal cells. Thus pernicious anemia, 19. The answer is D.
the autoimmune atrophy of parietal cells, is a cause of (Chap. 17) There are a number of dermatologic manifesta-
cobalamin malabsorption. Pancreatic protease enzymes tions of inflammatory bowel disease (IBD), and each type
lyse the cobalamin–R binder protein complex to release of IBD has a particular predilection for different dermato-
cobalamin in the proximal intestine where it is bound to logic conditions. This patient has pyoderma gangrenosum.
intrinsic factor for ileal absorption. Thus a deficiency Pyoderma gangrenosum can occur in up to 12% of patients
of pancreatic enzymes, such as in chronic pancreatitis, with ulcerative colitis and is characterized by a lesion that
can lead to cobalamin malabsorption. Finally, cobalamin- begins as a pustule and progresses concentrically to sur-
intrinsic factor is absorbed via an intact epithelium in the rounding normal skin. The lesions ulcerate with violaceous,
ileum. Inflammation (Crohn’s disease) or absence (surgical heaped margins and surrounding erythema. They are typi-
removal) of ileum will cause cobalamin malabsorption. cally found on the lower extremities. Often the lesions are
The large intestine is not involved in cobalamin absorp- difficult to treat and respond poorly to colectomy; similarly,
tion; thus ulcerative colitis confined to the large intestine pyoderma gangrenosum is not prevented by colectomy.
will not cause malabsorption. Treatment commonly includes IV antibiotics, glucocorti-
coids, dapsone, infliximab, and other immunomodulatory
17. The answer is D. agents. Erythema nodosum is more common in Crohn’s
(Chap. 17) The incidence of inflammatory bowel disease disease, and attacks correlate with bowel symptoms. The
is highly influenced by ethnicity, location, and environ- lesions are typically multiple red hot, tender nodules mea-
mental factors. Both conditions have their highest inci- suring 1–5 cm and are found on the lower legs and arms.
dence in the United Kingdom and North America, and Psoriasis is more common in ulcerative colitis. Finally,
the peak incidence has a bimodal distribution of age of pyoderma vegetans is a rare disorder in intertriginous areas
presentation: 15–30 years and 60–80 years. The incidence reported to be a manifestation of inflammatory bowel dis-
of both ulcerative colitis and Crohn’s disease is high- ease in the skin.
est among persons of the Ashkenazi Jewish population.
Prevalence decreases progressively in non-Jewish white, 20. The answer is D.
African-American, Hispanic, and Asian populations. (Chap. 17, Cochrane Database Syst Rev 2007 Oct 17;
Cigarette smoking is associated with a decreased inci- [4]) Despite being described as a clinical entity for over
dence of ulcerative colitis, but may cause Crohn’s disease. a century, the etiology of IBD remains cryptic. Current
Oral contraceptive use is associated with a slightly higher theory is related to an interplay between inflammatory
incidence of Crohn’s disease, but not ulcerative colitis. stimuli in genetically predisposed individuals. Recent
Monozygotic twins are highly concordant for Crohn’s studies have identified a group of genes or polymor-
disease, but not ulcerative colitis. phisms that confer risk of IBD. Multiple microbio-
logic agents, including some that reside as “normal”
18. The answer is C. flora, may initiate IBD by triggering an inflammatory
(Chap. 17) Chronic bloody diarrhea associated with response. Anaerobic organisms (e.g., Bacteroides and
weight loss and systemic symptoms in a young person Clostridia spp.) may be responsible for the induction
is highly suggestive of inflammatory bowel disease. Her of inflammation. Other organisms, for unclear rea-
surgical findings suggest discontinuous lesions, which is sons, may have the opposite effect. These “probiotic”
typical of Crohn’s disease. Ulcerative colitis, in contrast, organisms include Lactobacillus spp., Bifidobacterium spp.,
typically affects the rectum and proceeds caudally from Taenia suis, and Saccharomyces boulardii. Shigella, Esch-
there without normal mucosa until the area of inflam- erichia, and Campylobacter spp. are known to promote
mation terminates. The presence of strictures and fissures inflammation. Studies of probiotic therapy in adults
further supports the diagnosis of Crohn’s disease, as these and children with IBD have shown potential benefit
are not features of ulcerative colitis. Microscopically, both for reducing disease activity.
ulcerative colitis and Crohn’s disease may have crypt
abscess and, although Crohn’s disease is more often trans- 21. The answer is D.
mural, full thickness disease may be present in ulcerative (Chap. 17) Methotrexate, azathioprine, cyclosporine,
colitis. The hallmark of Crohn’s disease is granulomas that tacrolimus, and anti-tumor necrosis factor (TNF) antibody
may be present throughout the bowel wall and involve are reasonable options for patients with CD, depending
the lymph nodes, mesentery, peritoneum, liver, and on the extent of macroscopic disease. Pneumonitis is a
pancreas. Although pathognomonic for Crohn’s disease, rare but serious complication of methotrexate therapy.
Review and Self-Assessment 709
of 90–97%. Findings often include a thickened appendix common, and the stool contains large quantities of fecal
with periappendiceal stranding and often the presence leukocytes and fecal lactoferrin. Other pathogens that
of a fecalith. Free air is uncommon, even in the case of cause inflammatory diarrhea are most Salmonella species,
a perforated appendix. Nonvisualization of the appendix Campylobacter jejuni, enterohemorrhagic Escherichia coli,
on CT is associated with surgical findings of a normal and Clostridium difficile.
appendix 98% of the time. Colonoscopy has no role in Penetrating diarrhea is caused by either Salmonella
the diagnosis of acute appendicitis. typhi or Yersinia enterocolitica. The site of inflammation in
penetrating diarrhea is the distal small bowel. In pen-
35 and 36. The answers are C and D, respectively. etrating diarrhea, these organisms penetrate the intestinal
(Chap. 22) The patient presents with several months of wall and multiply within Peyer’s patches and intestinal
epigastric abdominal pain that is worse after eating. His lymph nodes before disseminating into the bloodstream.
symptoms are highly suggestive of peptic ulcer disease, Clinically, penetrating diarrhea presents as enteric fever
with the worsening pain after eating suggesting a duode- with fever, relative bradycardia, abdominal pain, leukope-
nal ulcer. The current presentation with acute abdomen nia, and splenomegaly.
and free air under the diaphragm diagnoses perforated
viscus. Perforated gallbladder is less likely in light of the 38 and 39. The answers are B and D, respectively.
duration of symptoms and the absence of the significant (Chap. 23) Traveler’s diarrhea is common among indi-
systemic symptoms that often accompany this condition. viduals traveling to Asia, Africa, and Central and South
As the patient is relatively young with no risk factors for America, affecting 25 to 50% of travelers to these
mesenteric ischemia, necrotic bowel from an infarction areas. Most traveler’s diarrhea begins within 3 to 5 days
is highly unlikely. Pancreatitis can have a similar presenta- after arrival and is self-limited, lasting 1 to 5 days. Most
tion, but a pancreas cannot perforate and liberate free air. individuals acquire traveler’s diarrhea after consuming
Peritonitis is most commonly associated with bacterial contaminated food or water. Although some organisms
infection, but it can be caused by the abnormal presence have a geographic association, enterotoxigenic and
of physiologic fluids, for example, gastric contents, bile, enteroaggregative Escherichia coli are found worldwide
pancreatic enzymes, blood, or urine, or by foreign bodies. and are the most common causes of traveler’s diarrhea.
In this case peritonitis most likely is due to the presence In Asia, Campylobacter jejuni is also common. This pre-
of gastric juice in the peritoneal cavity after perforation sentation would be uncommon for Shigella spp. because
of a duodenal ulcer has allowed these juices to leave the it most frequently causes bloody diarrhea. Norovirus is
gut lumen. associated with a more profuse diarrhea. It has been the
causative organism in large outbreaks on cruise ships.
37. The answer is B. Giardia lamblia is a parasite that is responsible for 5% or
(Chap. 23) Acute infectious diarrhea remains a leading less of traveler’s diarrhea. The approach to treatment of
cause of death worldwide, especially among children traveler’s diarrhea should be tailored to the severity of
younger than 5 years of age. The major categories of the patient’s symptoms. In general, most cases are self-
acute diarrheal illness include noninflammatory, inflam- limited. As long as an individual is able to maintain
matory, and penetrating diarrhea. Vibrio cholerae causes adequate fluid intake, no specific therapy may be required
diarrhea through production of an enterotoxin, which is if there are no more than one or two unformed stools
characteristic of noninflammatory diarrhea. After inges- daily without distressing abdominal symptoms, bloody
tion of a large volume (105–106) of organisms, V. chol- stools, or fever. In this scenario, the patient is not having
erae attaches to the brush border of the small intestinal a large number of stools, but in the presence of distress-
enterocytes and produces cholera toxin. The primary ing abdominal symptoms, use of bismuth subsalicylate or
clinical characteristic of diarrheal illness caused by toxin loperamide is recommended. If loperamide is used, an
production is profuse watery diarrhea that is not bloody. initial dose of 4 mg is given followed by 2 mg after pas-
Fecal leukocytes are typically not present in noninflam- sage of each unformed stool. Antibacterial therapy is only
matory diarrhea. However, a mild increase in fecal lacto- recommended if there is evidence of inflammatory diar-
ferrin can be seen because this test is more sensitive for rhea (bloody stools or fever) or there are more than two
the presence of mild inflammation. Other pathogens that unformed stools daily. The antibacterial agent of choice is
are common causes of noninflammatory diarrhea are usually a fluoroquinolone. Ciprofloxacin given as a single
enterotoxigenic Escherichia coli, Bacillus cereus, Staphylococ- dose of 750 mg or 500 mg three times daily for 3 days
cus aureus, and viral diarrhea, among others. is typically effective. In Thailand, Campylobacter jejuni is a
The site of inflammation in inflammatory diarrhea is common agent and has a high degree of fluoroquinolone
typically the colon or distal small bowel. In inflammatory resistance. For travelers to Thailand who require antibiot-
diarrhea, there is invasion of leukocytes into the wall ics, azithromycin is recommended with an initial dose of
of the intestines. The prototypical pathogen of inflam- 10 mg/kg on the first day followed by 5 mg/kg on days
matory diarrhea is Shigella dysenteriae. Bloody stools are 2 and 3 if diarrhea persists.
712 Review and Self-Assessment
40. The answer is C. Vancomycin is reserved for patients with severe infection
(Chap. 23) Acute bacterial food poisoning occurring 1 either initially or with recurrence. Fecal transplantation,
to 6 hours after ingestion of contaminated food is most intravenous immunoglobulin, and oral nitazoxanide are
commonly caused by infection with Staphylococcus aureus all potential therapies for patients with multiple recur-
or Bacillus cereus. S. aureus is associated with ingestion of rences.
ham, poultry, potato or egg salad, mayonnaise, or cream
pastries that have been allowed to remain at room tem- 45. The answer is E.
perature after cooking. B. cereus is classically associated (Chap. 24) Clindamycin, ampicillin, and cephalosporins
with contaminated fried rice. The symptoms of bacte- (including ceftriaxone) were the first antibiotics associ-
rial food poisoning begin abruptly with nausea, vomit- ated with Clostridium difficile–associated disease and still
ing, abdominal cramping, and diarrhea. However, fever is are. More recently, broad-spectrum fluoroquinolones,
not a common finding and should cause one to consider including moxifloxacin and ciprofloxacin, have been
other etiologies of vomiting and diarrhea. associated with outbreaks of C. difficile, including out-
breaks in some locations of a more virulent strain that
41. The answer is C. has caused severe disease among elderly outpatients. For
(Chap. 23) The patient most likely has food poisoning unclear reasons, β-lactams other than the later genera-
caused by contamination of the fried rice with Bacillus tion cephalosporins appear to carry a lesser risk of disease.
cereus. This toxin-mediated disease occurs when heat- Penicillin–β-lactamase combination antibiotics appear to
resistant spores germinate after boiling. Frying before have lower risk of C. difficile–associated disease than the
serving may not destroy the preformed toxin. The emetic other agents mentioned. Cases have even been reported
form of illness occurs within 6 hours of eating and is self- associated with metronidazole and vancomycin admin-
limited. No therapy is necessary unless the patient devel- istration. Nevertheless, all patients initiating antibiotics
ops severe dehydration. This patient currently has no should be warned to seek care if they develop diarrhea
symptoms consistent with volume depletion; therefore, that is severe or persists for more than 1 day because
she does not need intravenous fluids at present. Sarcoid- all antibiotics carry some risk for C. difficile–associated
osis does not predispose patients to infectious diseases. disease.
is usually caused by skin organisms, most commonly grounds from primary (spontaneous) peritonitis. It is
Staphylococcus spp. The organisms migrate into the peri- often overlooked because classic peritoneal signs are almost
toneal fluid via the device. There may not be a tunnel or always lacking, and it is uniformly fatal in the absence of
exit-site infection. Peritonitis is the most common rea- surgery. Suspicion for this diagnosis should occur when
son for discontinuing CAPD. Y-connectors and diligent ascites shows a protein greater than 1 g/dL, lactate dehy-
technique decrease the risk of CAPD. In contrast to PBP drogenase (LDH) greater than serum LDH, glucose level
and similar to spontaneous bacterial peritonitis (SBP), below 50 mg/dL, or a polymicrobial Gram stain. When
the onset of symptoms is usually acute with diffuse pain this diagnosis is suspected, abdominal radiography is
and peritoneal signs. The dialysate will be cloudy with indicated to rule out free air, and prompt surgical con-
greater than 100 WBC/μL and greater than 50% neutro- sultation is warranted. Unlike with primary (spontane-
phils. Dialysate should be placed in blood culture media ous) bacterial peritonitis, in cases of secondary perito-
and often is often positive with one organism. Finding nitis, antibiotics should include anaerobic coverage and
more than one organism in culture should prompt an often antifungal agents. This patient requires intravenous
evaluation for SBP. Empirical intraperitoneal coverage fluid because he has hypotension and tachycardia caused
for CAPD peritonitis should be directed against staph- by sepsis. Drotrecogin alfa has been shown to reduce
ylococcal species based on local epidemiology. If the mortality in patients with sepsis, but it is not indicated
patient is severely ill, intravenous antibiotics should be in patients with thrombocytopenia, cirrhosis, and ascites.
added. If the patient does not respond within 4 days,
catheter removal should be considered. 50. The answer is B.
(Chap. 26) Helicobacter pylori is thought to colonize about
48. The answer is D. 50% (30% in developed countries and >80% in devel-
(Chap. 25) The computed tomography scan shows a large oping countries) of the world’s population. The organ-
complex liver abscess in the right lobe. Liver abscesses ism induces a direct tissue response in the stomach, with
may arise from hematogenous spread, biliary disease (most evidence of mononuclear and polymorphonuclear
common currently), pylephlebitis, or contiguous infec- infiltrates in all of those with colonization regardless of
tion in the peritoneal cavity. Fever is the only common whether or not symptoms are present. Gastric ulceration
physical finding in liver abscess. Up to 50% of patients and adenocarcinoma of the stomach arise in association
may not have symptoms or signs to direct attention to with this gastritis. MALT is specific to H. pylori infec-
the liver. Nonspecific symptoms are common, and liver tion and because of prolonged B-cell activation in the
abscess is an important cause of fever of unexplained ori- stomach. Although H. pylori does not directly infect the
gin in elderly patients. The only reliably abnormal serum intestine, it does diminish somatostatin production,
studies are elevated alkaline phosphatase or WBC in 70% indirectly contributing to the development of duode-
of patients. Liver abscess may be suggested by an elevated nal ulcers. Gastroesophageal reflux disease is not caused
hemidiaphragm on chest radiograph. The most common by H. pylori colonization. Recent studies have demon-
causative organisms in presumed biliary disease are gram- strated that colonization by some strains of H. pylori may
negative bacilli. Anaerobes are not common unless pel- be protective for the development of adenocarcinoma of
vic or other enteric sources are suspected. Fungal liver the esophagus and premalignant lesions such as Barrett’s
abscesses occur after fungemia in immunocompromised esophagus (odds ratio, 0.2–0.6).
patients receiving chemotherapy, often presenting symp-
tomatically with neutrophil reconstitution. Drainage, 51. The answer is E.
usually percutaneous, is the mainstay of therapy and is (Chap. 26) It is impossible to know whether the patient’s
useful initially diagnostically (Figure 25-3). continued dyspepsia is attributable to persistent Helico-
bacter pylori as a result of treatment failure or to some
49. The answer is C. other cause. A quick noninvasive test to look for the
(Chap. 25) It is important to distinguish between pri- presence of H. pylori is a urea breath test. This test can
mary (spontaneous) and secondary peritonitis. Primary be done as an outpatient and gives a rapid, accurate
peritonitis is a result of long-standing ascites, usually as a response. Patients should not have received any proton
result of cirrhosis. The pathogenesis is poorly understood pump inhibitors or antimicrobials in the meantime. Stool
but may involve bacteremic spread or translocation across antigen test is another good option if urea breath testing
the gut wall of usually only a single species of pathogenic is not available. If the urea breath test is positive more
bacteria. Secondary peritonitis is caused by rupture of a than 1 month after completion of first-line therapy,
hollow viscous or irritation of the peritoneum caused by second-line therapy with a proton pump inhibitor,
a contiguous abscess or pyogenic infection. It typically bismuth subsalicylate, tetracycline, and metronidazole
presents with peritoneal signs and in most cases repre- may be indicated. If the urea breath test result is nega-
sents a surgical emergency. Secondary peritonitis in a tive, the remaining symptoms are unlikely attributable to
patient with cirrhosis is difficult to distinguish on clinical persistent H. pylori infection. Serology is useful only for
714 Review and Self-Assessment
diagnosing infection initially, but it can remain positive and 55. The answer is D.
therefore misleading in those who have cleared H. pylori. (Chap. 28) Shigellosis remains a cause of dysentery in the
Endoscopy is a consideration to rule out ulcer or upper developing world and sporadic cases caused by fecal–oral
gastrointestinal malignancy but is generally preferred after contamination occur in the developing and developed
two failed attempts to eradicate H. pylori. Figure 26-2 out- world. The human intestinal tract is the most prevalent res-
lines the algorithm for management of H. pylori infection. ervoir for the bacteria. Clinical illness from Shigella infec-
tion can be caused by a very small inoculum. Shigellosis
52. The answer is A. typically evolves through four phases: incubation, watery
(Chap. 26) Helicobacter pylori is a disease of overcrowd- diarrhea, dysentery, and the postinfectious phase. The
ing. Transmission has therefore decreased in the United incubation period is usually 1 to 4 days, and the dysentery
States as the standard of living has increased. It is predi- follows within hours to days. The dysentery syndrome
cated that the percentage of duodenal ulcers caused by is indistinguishable from other invasive enteropathogens
factors other than H. pylori (e.g., use of nonsteroidal anti- (including Campylobacter spp.), and inflammatory bowel
inflammatory drugs) will increase over the upcoming disease is also in the differential diagnosis. Because the
decades. Controversial but increasing evidence suggests organism is enteroinvasive, antibiotic therapy is indicated.
that H. pylori colonization may provide some protection Ciprofloxacin is generally recommended unless there is
from recent emerging gastrointestinal disorders, such as no or proven resistance. Ceftriaxone, azithromycin, piv-
gastroesophageal reflux disease (and its complication, mecillinam, and some recent quinolones are also effective.
esophageal carcinoma). Therefore, the health implica- Shigella infection typically does not cause life-threatening
tions of H. pylori eradication may not be simple. dehydration. Antimotility agents are not recommended
because they are thought to prolong the systemic symp-
53. The answer is A. toms and may increase the risk of toxic megacolon and
(Chap. 26) In vitro, Helicobacter pylori is susceptible to a hemolytic uremic syndrome. There is currently no com-
wide variety of antibiotics. However, monotherapy is no mercially available vaccine for Shigella infection.
longer recommended because of inadequate antibiotic
delivery to the colonization niche and the development 56. The answer is A.
of resistance. All current regimens include a proton pump (Chap. 29) Campylobacter spp. are motile, curved gram-
inhibitor (omeprazole or equivalent), H2 blocker (raniti- negative rods. The principal diarrheal pathogen is Cam-
dine or equivalent), and/or bismuth. Regimens includ- pylobacter jejuni. This organism is found in the gastroin-
ing quinolones may not be advisable because of common testinal tract of many animals used for food production
resistance and the risk of developing Clostridium difficile and is usually transmitted to humans in raw or under-
colitis. Current regimens have an eradication rate of 75 to cooked food products or through direct contact with
80%. (See Table 26-2.) infected animals. More than half of cases are caused by
insufficiently cooked contaminated poultry. Campylo-
54. The answer is E. bacter infection a common cause of diarrheal disease in
(Chap. 27) Salmonella enteritidis is one of the causes of the United States. The illness usually occurs within 2 to
nontyphoidal salmonellosis (NTS) along with Salmonella 4 days after exposure to the organism in food or water.
typhimurium and other strains. Enteric (typhoid) fever Biopsy of an affected patient’s jejunum, ileum, or colon
is caused by Salmonella typhi or Salmonella paratyphi. reveals findings indistinguishable from those of Crohn’s
Recent cases of gastroenteritis caused by NTS have been disease and ulcerative colitis. Although the diarrheal
associated with undercooked or raw eggs. In contrast to illness is usually self-limited, it may be associated with
S. typhi and S. paratyphi, which only have human res- constitutional symptoms, lasts more than 1 week, and
ervoirs, the NTS can colonize livestock accounting for recurs in 5 to 10% of untreated patients. Complications
outbreaks related to contaminated water (fresh produce, include pancreatitis, cystitis, arthritis, meningitis, and
undercooked ground meat, dairy products). The gastro- Guillain-Barré syndrome. The symptoms of Campylo-
enteritis caused by NTS is indistinguishable clinically for bacter enteritis are similar to those resulting from infec-
other enteric pathogens. The diarrhea is nonbloody and tion with Salmonella typhi, Shigella spp., and Yersinia spp.;
may be copious. The disease is typically self-limited in all of these agents cause fever and the presence of fecal
healthy hosts, and antibiotic therapy is not recommended leukocytes. The diagnosis is made by isolating Campylo-
because it does not change the course of disease and pro- bacter organisms from the stool, which requires selective
motes resistance. Therapy may be necessary for neonates media. Escherichia coli (enterotoxigenic), Norwalk agent,
or debilitated elderly patients who are more likely to and rotavirus are generally not associated with the find-
develop bacteremia. Bacteremia occurs in fewer than 10% ing of fecal leukocytes. About 5 to 10% of untreated
of cases. Metastatic infections of bone, joint, and endo- patients with Campylobacter enteritis develop recurrences
vascular devices may occur. There is no vaccine for NTS. that may be clinically and pathologically confused with
Oral and parenteral vaccines for S. typhi are available. inflammatory bowel disease.
Review and Self-Assessment 715
57. The answer is A. diarrhea outbreaks in the United States. They spread via
(Chap. 29) As is true with all acute diarrheal diseases, fecal–oral spread and have a low inoculum necessary for
adequate volume resuscitation is central to treatment. disease. In temperate regions, they tend to occur in cold
Many patients with mild Campylobacter enteritis will resolve weather months. The incubation period is less than 3
spontaneously, and not all patients clearly benefit from days, typically 24 hours. The onset of disease is rapid.
therapy. In the presence of high or persistent fever, Fever, myalgias, and headache are common. The diar-
bloody diarrhea, severe diarrhea, worsening symptoms, rhea is nonbloody without fecal leukocytes. The disease
or symptoms persisting for more than 1 week, antibiotics is self-limited, and therapy is supportive.
are recommended. A 5- to 7-day course of erythromy-
cin, azithromycin (and other macrolides), or ciprofloxa- 60. The answer is B.
cin is effective. Drug resistance to fluoroquinolones and (Chap. 31) Nearly all children worldwide are infected
tetracycline is increasing. Antimotility agents are not rec- with rotavirus by age 5 years. In the developing world,
ommended because they have been associated with the it remains a major cause of diarrheal death caused by
development of serious complications, including toxic volume depletion. Repeated infections occur with each
megacolon and hemolytic uremic syndrome. Tinidazole subsequent episode of lesser severity. Therefore, severe
and metronidazole are used to treat a variety of nonbacte- disease is uncommon in adolescents and adults who may
rial diarrhea syndromes, including giardiasis and amoebiasis. develop disease, particularly after contact with ill children.
Metronidazole is also used for Clostridium difficile–associated The disease typically has an abrupt onset with vomiting
colitis. usually preceding diarrhea. Fever occurs in approximately
one-third of cases. Stools usually do not contain blood,
58. The answer is B. mucus, or inflammatory material. The disease is usu-
(Chap. 30) Cholera remains a worldwide problem with ally self-limited in 3 to 7 days. Because rotavirus is a
sporadic cases usually related to contact with fecally con- major cause of childhood hospitalization and morbid-
taminated water or seafood. Humans are the only known ity in the United States, vaccination is recommended
reservoir of Vibrio cholera. Most cases are reported in Africa for all U.S. children. Vaccination has less efficacy in the
or Asia. After a century, cholera returned to Haiti after developing world because of a higher frequency of mal-
recent natural disasters and breakdown of public health nutrition, co-infection, and comorbidities, but is rec-
measures. The watery diarrhea of cholera is mediated by ommended by the World Health Organization for all
a specific cholera toxin that binds to small intestine epi- children worldwide.
thelium to cause profuse fluid secretion. The diarrhea of
cholera is painless, nonbloody, and watery with mucus 61. The answer is E.
and few inflammatory cells. The term “rice-water” diar- (Chap. 32) Entamoeba histolytica is a common pathogen
rhea refers to the appearance of water after soaking rice. in areas of the world with poor sanitation and crowding.
Morbidity and mortality from cholera are from profound Transmission is oral–fecal, and the primary manifestation
volume depletion. Rehydration is essential to therapy. is colitis, often heme positive. Liver abscess is a common
Major improvements in care came from the develop- complication, occurring after the organism crosses the
ment of oral rehydration solutions that take advantage colonic border and travels through the portal circulation,
of glucose–sodium co-transport in the small intestine. subsequently lodging in the liver. At the time of pre-
These solutions allowed effective rehydration in resource sentation with liver abscess, the primary gastrointestinal
limited settings where intravenous rehydration was not infection has usually cleared, and organisms cannot be
practical. Diagnosis is by culture or point-of-care antigen identified in the stool. Suggestive imaging with a positive
detection dipstick assay. Antibiotics are not necessary for serologic test result for E. histolytica is diagnostic. When
cure, but they diminish the duration and volume of fluid a patient has a diagnostic imaging procedure, a positive
loss and hasten the clearance of the organism from stool. amebic serology result is highly sensitive (>94%) and
A single dose of doxycycline is effective in adults in areas highly specific (>95%) for diagnosis of amebic liver
where there is not resistance. Ciprofloxacin or azithro- abscess. Treatment for amebic liver abscess is generally
mycin may be alternatives. with metronidazole. Luminal infection can be treated
with paromomycin or iodoquinol. Campylobacter is a
59. The answer is B. major cause of foodborne infectious diarrhea. Although
(Chap. 31) The Norwalk virus is the prototype calici- usually self-limited, it may cause serious enteritis and
virus that causes human disease. The calicivirus family, inflammatory diarrhea but not liver abscess.
many of which cause gastroenteritis and diarrhea, par-
ticularly in children, includes norovirus and sapovirus. 62. The answer is C.
Most adults worldwide have antibodies to these viruses. (Chap. 33) Of the listed protozoa, only Giardia infection
However, they are a major cause of morbidity through- can be diagnosed with stool ova and parasite examina-
out the world and a frequent cause of nonbacterial tion. Stool antigen immunoassay can be used to diagnose
716 Review and Self-Assessment
Giardia and Cryptosporidium spp. Fecal acid-fast testing immunodeficiency, such as advanced HIV infection.
may be used to diagnose Cryptosporidium, Isospora, and Outbreaks in immunocompetent hosts are caused by
Cyclospora spp. Microsporidia require special fecal stains ingestion of oocysts. Infectious oocysts are excreted in
or tissue biopsy for diagnosis. human feces, causing human-to-human transmission.
Waterborne transmission of oocysts accounts for disease
63. The answer is D. in travelers and common-source outbreaks. Oocysts resist
(Chap. 33) Trichomoniasis is transmitted via sexual con- killing by routine chlorination of drinking and recre-
tact with an infected partner. Many men are asymptom- ational water sources. Infection may be asymptomatic in
atic but may have symptoms of urethritis, epididymitis, immunocompetent and immunosuppressed hosts. Diar-
or prostatitis. Most women have symptoms of infec- rhea is typically watery and nonbloody and may be asso-
tion that include vaginal itching, dyspareunia, and mal- ciated with abdominal pain, nausea, fever, and anorexia.
odorous discharge. These symptoms do not distinguish In immunocompetent hosts, symptoms usually subside
Trichomonas infection from other forms of vaginitis, in 1 to 2 weeks without therapy. In advanced AIDS
such as bacterial vaginosis. Trichomoniasis is not a self- with CD4 counts below 100/μL, severe symptoms may
limited infection and should be treated for symptomatic develop, leading to significant electrolyte and volume
and public health reasons. Wet-mount examination for loss. Nitazoxanide is approved for treatment of Crypto-
motile trichomonads has a sensitivity of 50 to 60% in sporidium but to date has not been shown to be effective
routine examination. Direct immunofluorescent anti- in HIV-infected patients. The best available therapy for
body staining of secretions is more sensitive and can also these patients is antiretroviral therapy to reduce immune
be performed immediately. Culture is not widely avail- suppression. Tinidazole and metronidazole are used to
able and takes 3 to 7 days. Treatment should consist treat giardiasis and trichomoniasis, not cryptosporidiosis.
of metronidazole either as a single 2-g dose or 500-mg
doses twice daily for 7 days; all sexual partners should 66. The answer is B.
be treated. Trichomoniasis resistant to metronidazole has (Chap. 34) Strongyloides is the only helminth that can
been reported and is managed with increased doses of replicate in the human host, allowing autoinfection.
metronidazole or with tinidazole. Humans acquire Strongyloides when larvae in fecally con-
taminated soil penetrate the skin or mucous membranes.
64. The answer is E. The larvae migrate to the lungs via the bloodstream;
(Chap. 33) Giardiasis is diagnosed by detection of parasite break through the alveolar spaces; ascend the respiratory
antigens in the feces or by visualizing cysts or trophozo- airways; and are swallowed to reach the small intestine,
ites in feces or small intestine. There is no reliable serum where they mature into adult worms. Adult worms may
test for this disease. Because a wide variety of pathogens penetrate the mucosa of the small intestine. Strongyloi-
are responsible for diarrheal illness, some degree of diag- des is endemic in Southeast Asia, sub-Saharan Africa,
nostic testing beyond the history and physical examina- Brazil, and the Southern United States. Many patients
tion is required for definitive diagnosis. Colonoscopy does with Strongyloides are asymptomatic or have mild gas-
not have a role in diagnosing Giardia infection. Giardiasis trointestinal symptoms or the characteristic cutaneous
can persist in symptomatic patients and should be treated. eruption, larval currens, as described in this case. Small
Severe symptoms such as malabsorption, weight loss, bowel obstruction may occur with early heavy infection.
growth retardation, and dehydration may occur in pro- Eosinophilia is common with all clinical manifestations.
longed cases. Additionally, extraintestinal manifestations In patients with impaired immunity, particularly gluco-
such as urticarial, anterior uveitis, and arthritis have been corticoid therapy, hyperinfection or dissemination may
associated with potential giardiasis. A single oral 2-g dose occur. This may lead to colitis, enteritis, meningitis,
of tinidazole is reportedly more effective than a 5-day peritonitis, and acute renal failure. Bacteremia or gram-
course of metronidazole with cure rates above 90% for negative sepsis may develop because of bacterial trans-
both. Paromomycin, an oral poorly absorbed amino- location through disrupted enteric mucosa. Because of
glycoside, can be used for symptomatic patients during the risk of hyperinfection, all patients with Strongyloides
pregnancy, but its efficacy for eradicating infection is not infection, even asymptomatic carriers, should be treated
known. Clindamycin and albendazole do not have a role with ivermectin, which is more effective than alben-
in treatment of giardiasis. Refractory disease with persis- dazole. Fluconazole is used to treat candidal infections.
tent infection can be treated with a longer duration of Mebendazole is used to treat trichuriasis, enterobiasis
metronidazole. (pinworm), ascariasis, and hookworm. Mefloquine is
used for malaria prophylaxis.
65. The answer is D.
(Chap. 33) Cryptosporidium typically causes a self-limited 67. The answer is B.
diarrheal illness in immunocompetent patients but may (Chap. 34) Ascaris lumbricoides is the longest nematode
cause severe debilitating disease in patients with severe (15–40 cm) parasite of humans. It resides in tropical
Review and Self-Assessment 717
and subtropical regions. In the United States, it is found in cholestatic causes of liver disease. Nausea often occurs
mostly in the rural Southeast. Transmission is through in severe disease and can be accompanied by vomiting.
fecally contaminated soil. Most commonly, the worm Right upper quadrant pain is a less common symptom
burden is low, and it causes no symptoms. Clinical dis- and indicates stretching of the liver capsule.
ease is related to larval migration to the lungs or to adult
worms in the gastrointestinal tract. The most common 71. The answer is B.
complications occur because of a high gastrointestinal (Chap. 35) Women are more susceptible to the effects
adult worm burden, leading to small bowel obstruc- of alcohol on the liver. On average, drinking about two
tion (most often in children with a narrow-caliber small drinks daily can lead to chronic liver disease in women,
bowel lumen) or migration leading to obstructive com- whereas in men it is about three drinks daily. In indi-
plications such as cholangitis, pancreatitis, or appendicitis. viduals with alcoholic cirrhosis, the average daily alcohol
Rarely, adult worms can migrate to the esophagus and be intake is usually much higher, however, and heavy drink-
orally expelled. During the lung phase of larval migra- ing for more than 10 years is typical before the onset of
tion (9–12 days after egg ingestion), patients may develop liver disease.
a nonproductive cough, fever, eosinophilia, and pleuritic
chest pain. Eosinophilic pneumonia syndrome (Löffler’s 72. The answer is D.
syndrome) is characterized by symptoms and lung infil- (Chap. 36) It is important to understand the patterns
trates. Meningitis is not a known complication of asca- of laboratory abnormalities that indicate liver disease
riasis but can occur with disseminated strongyloidiasis in is present. One way to consider laboratory evaluation
an immunocompromised host. of liver disease is to consider three general categories
of tests: tests based on excretory function of the liver,
68. The answer is A. tests of biosynthetic activity of the liver, and coagula-
(Chap. 34) Ascariasis should always be treated, even in tion factors. The most common tests of liver function
asymptomatic cases, to prevent serious intestinal com- fall under the category of tests based on the detoxifica-
plications. Albendazole, mebendazole, and ivermectin tion and excretory function of the liver. These include
are effective. These agents should not be administered to serum bilirubin, urine bilirubin, ammonia, and enzyme
pregnant women. Pyrantel is safe in pregnancy. Metro- levels. Bilirubin can exist as a conjugated and an uncon-
nidazole is used for anaerobic bacterial and Trichomonas jugated form. The unconjugated form is often referred
infections. Fluconazole is mostly used to treat Candida to as the indirect fraction. Elevations in the unconju-
infections. Diethylcarbamazine (DEC) is first-line ther- gated form of bilirubin are not related to liver disease,
apy for active lymphatic filariasis. Vancomycin has no but are most commonly seen in hemolysis and a number
effect on nematodes. of benign genetic conditions such as Gilbert’s syndrome.
In contrast, conjugated hyperbilirubinemia almost always
69. The answer is E. indicates disease of the liver or biliary tract. Conjugated
(Chap. 34) This patient’s most likely diagnosis is anisa- bilirubin is water soluble and is excreted in the urine, but
kiasis. This is a nematode infection in which humans are unconjugated bilirubin is not. Rather, it binds to albu-
an accidental host. It occurs hours to days after ingest- min in the blood. Therefore, bilirubinuria implies liver
ing eggs that previously settled into the muscles of fish. disease as well. Among the serum enzymes, it is useful
The main risk factor for infection is eating raw fish. Pre- to consider those that are associated with hepatocellu-
sentation mimics an acute abdomen. History is critical lar injury or those that reflect cholestasis. Alanine and
because upper endoscopy is both diagnostic and curative. aspartate aminotransferases are the primary enzymes that
The implicated nematodes burrow into the mucosa of indicate hepatocyte injury. Alkaline phosphatase is the
the stomach, causing intense pain, and must be manu- most common enzyme elevated in cholestasis, but bone
ally removed by endoscope or, on rare occasion, surgery. disease also causes increased alkaline phosphatase. In some
There is no medical agent known to cure anisakiasis. cases, one needs additional information to determine if
the alkaline phosphatase is liver or bone in origin. Other
70. The answer is A. tests that would be elevated in cholestatic liver disease are
(Chap. 35) The most common and most characteristic 5′-nucleotidase and γ-glutamyl transferase. The primary
symptom of liver disease is fatigue. Unfortunately, it is test of synthetic function is measurement of serum albu-
also very nonspecific with little specific diagnostic util- min. Coagulation factors can be directly measured, but
ity. The fatigue in liver disease seems to improve in the impaired production of coagulation factors in liver disease
morning and worsen throughout the day, but it can be is primarily inferred from elevations in prothrombin time.
intermittent. Jaundice is the hallmark of liver disease and
is much more specific. Jaundice, however, is typically a 73 and 74. The answers are E and D, respectively.
sign of more advanced disease. Itching is also typically a (Chap. 37) This patient is presenting with an asymptomatic
symptom of more advanced disease and is more common and mild elevation in unconjugated hyperbilirubinemia
718 Review and Self-Assessment
that has occurred during a time of increased stress, the patient has risk factors for hepatitis A, B, and C infec-
fatigue, and likely decreased caloric intake. This presen- tion, including having had sex with men and a prior his-
tation is characteristic of Gilbert’s syndrome (option E), tory of injection drug use. All acute viral hepatitis presents
an inherited disorder of bilirubin conjugation. In Gil- with a similar clinical pattern, although incubation periods
bert’s syndrome, there is a mutation of the UGT1A1 vary after exposure. The most common initial symptoms
gene that encodes bilirubin UDP-glucuronosyltransfer- are fatigue, anorexia, nausea, vomiting, myalgias, and head-
ase that leads to a reduction in activity on the enzyme to ache. These symptoms precede the onset of jaundice by
10–35% of normal. This enzyme is of critical importance about 1–2 weeks. Once jaundice develops, the prodromal
in the conjugation of bilirubin. Most of the time, there symptoms regress. On physical examination, there is usually
is no apparent jaundice, as the reduced ability to conju- obvious icterus with an enlarged and tender liver. Spleno-
gate bilirubin is not reduced to a degree that leads to an megaly can occur. AST and ALT are elevated with peak
elevation of bilirubin. However, during times of stress, levels that are quite variable between 400–4000 U/L, and
fatigue, alcohol use, decreased caloric intake, or intercur- alkaline phosphatase levels are increased to a much lesser
rent illness, the enzyme can become overwhelmed, lead- degree. Hyperbilirubinemia (levels from 5 to 20 mg/dL)
ing to a mild hyperbilirubinemia. Typical bilirubin levels occurs with primarily increased levels of conjugated bili-
are less than 4.0 mg/dL unless the individual is ill or fast- rubin. Thus, it is important to recognize the patterns of
ing. Diagnosis usually occurs during young adulthood, antibody production in the viral hepatitides. Hepatitis A
and episodes are self-limited and benign. If a liver biopsy is an RNA virus that presents with acute hepatitis and is
were to be performed, hepatic histology would be nor- transmitted by the fecal-oral route. In the acute state, the
mal. No treatment is necessary as there are no long-term IgM would be elevated, which is not seen in this sce-
consequences of Gilbert’s syndrome, and patient reas- nario. Hepatitis B virus is a DNA virus with three com-
surance is recommended. Other inherited disorders of mon antigens that are tested serologically to determine the
bilirubin conjugation are Crigler-Najjar syndrome types time course of the illness. These antigens are the surface
I and II. Crigler-Najjar syndrome type I is a congenital antigen, the core antigen, and the e antigen, which is a
disease characterized by more dramatic elevations in bili- nucleocapsid protein produced from the same gene as the
rubin as high as 20–45 mg/dL that is first diagnosed in core antigen but is immunologically distinct. Several dis-
the neonatal period and is present throughout life. This tinct patterns can be observed. In acute hepatitis B, the
rare disorder was once fatal in early childhood due to the core IgM, surface antigen, and e antigens are all positive,
development of kernicterus. However, with photother- which is what is seen in this case. At this point, the patient is
apy, individuals are now able to survive into adulthood, highly infectious with viral shedding in body fluids, includ-
although neurologic deficits are common. Crigler-Najjar ing saliva. In a late acute infection, core IgG may be posi-
syndrome type II is similar to type I, but the elevations in tive at the same time as surface- and e-antigen positivity. In
bilirubin are less. Kernicterus is rare. This is due to the chronic hepatitis B, this same pattern of serologies is seen.
fact that there is some residual function of the bilirubin If a patient has a prior infection without development of
UDP-glucuronosyltransferase enzyme (<10%), which is chronic hepatitis, the core IgG and surface antibody is posi-
totally absent in type I disease. Hemolysis is another fre- tive. However, when immunity is obtained via vaccination,
quent cause of elevated unconjugated bilirubin. Hemoly- only the surface antibody (SAb) is positive; the e antigen
sis can be caused by many factors including medications, and surface antigen will be negative since the patient was
autoimmune disorders, and inherited disorders, among never infected. The variety of antigen-antibody positivities
others. However, the normal hematocrit, LDH, and that can result are outlined in Table 38-5. Acute hepati-
haptoglobin eliminate hemolysis as a possibility. Dubin- tis C often is detectable with contemporary immunoassays
Johnson syndrome is another congenital hyperbiliru- early in the disease when the aminotransferases are positive.
binemia. However, it is a predominantly conjugated Thus, a positive HCV antibody could indicate acute hepa-
hyperbilirubinemia caused by a defect in biliary excre- titis C in this individual. However, given his clinical history
tion from hepatocytes. Obstructive choledocholithiasis is of prior injection drug use and inability to donate blood,
characterized by right upper quadrant pain that is often this likely indicates chronic hepatitis C infection. In some
exacerbated by fatty meals. The absence of symptoms or instances, ecstasy has been reported to cause drug-induced
elevation in other liver function tests, especially alkaline hepatitis, but given the viral serologies in this patient, this
phosphatase, also makes this diagnosis unlikely. would be unlikely.
highly unlikely with acute hepatitis C infection. Acet- that leads to transplantation. Acetaminophen is metab-
aminophen remains one of the major causes of fulminant olized in the liver through two pathways. The primary
hepatic failure and is managed by prompt administration pathway is a phase II reaction that produces nontoxic
of N-acetylcysteine. Budd-Chiari syndrome is character- sulfate and glucuronide metabolites. The minor pathway
ized by posthepatic thrombus formation. It often pres- occurs through a phase I reaction leading to the produc-
ents with jaundice, painful hepatomegaly, ascites, and tion of N-acetyl-p-benzoquinone-imine (NAPQI). This
elevated transaminases. metabolite is directly toxic to liver cells and can lead to
hepatocyte necrosis. With therapeutic use of acetamino-
82. The answer is A. phen, glutathione in the liver rapidly converts NAPQI
(Chap. 39) The liver is the primary site for the metabo- to a nontoxic metabolite that is excreted in the urine.
lism of many drugs and as such is susceptible to injury However, glutathione stores can become depleted in the
related to drugs and toxins. Indeed, the most common setting of a large acute ingestion, chronic alcoholism, or
cause of acute hepatic failure is drug-induced liver injury. the chronic ingestion of increased acetaminophen. In
In general, it is useful to think of chemical hepatotox- addition, because alcohol upregulates the first enzyme
icity within two broad categories: direct toxic effects in the metabolic pathway, NAPQI accumulates more
and idiosyncratic reactions. Drugs or toxins that cause a quickly in alcoholics. Given the known hepatotoxicity
direct toxic effect on the liver are either poisons them- of acetaminophen, the U.S. Food and Drug Adminis-
selves or are metabolized to toxic substances. With agents tration has recommended a maximum daily dose of no
that cause a direct toxic effect on hepatocytes, there is a more than 3.25 g, with lower doses in individuals who
predictable, dose-related pattern of injury, and the time use alcohol chronically. Acute ingestions of 10–15 g of
to effect is relatively short. The most common drug or acetaminophen is sufficient to cause clinical evidence
toxin causing direct hepatocyte toxicity is acetamino- of liver injury, and doses higher than 25 g can lead to
phen. In therapeutic doses, acetaminophen does not cause fatal hepatic necrosis. The course of illness with acute
liver injury. However, in higher doses, one of the metabo acetaminophen ingestion follows a predictable pattern.
lites of acetaminophen, N-acetyl-p-benzoquinone-imine Nausea, vomiting, abdominal pain, and shock occur
(NAPQI), can overwhelm the glutathione stores of the within 4–12 hours after ingestion. Liver enzymes and
liver that are necessary to convert NAPQI to a non- synthetic function are normal during this time. Within
toxic metabolite and lead to hepatocyte necrosis. Other 24–48 hours, these symptoms subside and are followed
medications or toxins that cause direct hepatocyte injury by evidence of hepatic injury. Maximal levels of amino-
are carbon tetrachloride, trichloroethylene, tetracycline, transferases can reach more than 10,000 U/L and may
and the Amanita phalloides mushroom. More commonly not occur until 4–6 days after ingestion. These patients
known as the deathcap mushroom, ingestion of a single must be followed carefully for fulminant hepatic fail-
mushroom can contain enough hepatotoxin to be lethal. ure with serious complications including encephalopa-
Idiosyncratic reactions are infrequent and unpredictable. thy, cerebral edema, marked coagulopathy, renal failure,
There is no dose dependency, and the timing of hepatic metabolic acidosis, electrolyte abnormalities, and refrac-
injury has little association with the duration of drug tory shock. Levels of acetaminophen are predictive of the
treatment. Many drugs produce idiosyncratic reactions, development of hepatotoxicity. The first level should be
and often it is difficult to known when an idiosyncratic measured no sooner than 4 hours after a known inges-
reaction will lead to more serious liver failure. Often, mild tion. Levels should be plotted on a nomogram that relates
increases in transaminase levels will occur, but over time acetaminophen levels to the time after ingestion. If at
adaptation leads to a return of liver enzymes to normal 4 hours the acetaminophen level is greater than 300 μg/
levels. In other instances, idiosyncratic reactions can lead mL, significant hepatotoxicity is likely. In the setting of
to fulminant hepatic failure. Although rare, serious hepatic overdose, it may be difficult to know the exact quantity
reactions can lead to medications being removed from and timing of the ingestion. For the patient presenting in
the market. It is now recognized that many idiosyncratic the clinical scenario in this question, her acetaminophen
reactions are related to metabolites leading to liver injury. level of greater than 300 μg/mL is quite concerning for a
However, it is likely that individual genetic variations in large ingestion, and treatment should be initiated imme-
liver metabolism are the primary cause, and these are not diately. The primary treatment for acetaminophen over-
predictable effects of the drug given our current state of dose is N-acetylcysteine. N-acetylcysteine acts to replete
knowledge. Common medications that can lead to idiosyn- glutathione levels in the liver and also provides a reser-
cratic drug reactions include halothane, isothane, isoniazid, voir of sulfhydryl groups to bind to the toxic metabolites.
HMG-CoA reductase inhibitors, and chlorpromazine. The typical dose of N-acetylcysteine is 140 mg/kg given
as a loading dose, followed by 70 mg/kg every 4 hours
83. The answer is B. for a total of 15–20 doses. This drug can also be given
(Chap. 39) Acetaminophen overdose is the most common by continuous infusion. Activated charcoal or cholestyr-
cause of acute liver failure and drug-induced liver failure amine should only be given if the patient presents within
Review and Self-Assessment 721
30 minutes after ingestion. Hemodialysis will not accel- levels at a single point in time do not definitively rule out
erate clearance of acetaminophen and will not protect the possibility that cirrhosis can develop. Progression to
the liver. Most patients with fulminant hepatic failure end-stage liver disease in individuals with chronic HCV
develop acute renal failure, often requiring hemodialysis. hepatitis is more likely in older individuals and in those
If a patient survives an acetaminophen overdose, there is with a longer duration of infection, advanced histologic
usually no chronic liver injury. stage and grade, genotype 1 infection, more complex
quasi-species diversity, concomitant other liver disease,
84. The answer is E. HIV infection, and obesity. Among these factors, the best
(Chap. 40) The patient in this scenario has evidence of prognostic indicator for the development of progres-
chronic active hepatitis B virus (HBV) infection. The sive liver disease is liver histology. Specifically, patients
presence of hepatitis B e antigen (HBeAg) is indicative who have moderate to severe inflammation or necro-
of ongoing viral replication, and individuals with HBeAg sis including septal or bridging fibrosis have the great-
positivity typically have high levels of HBV DNA on test- est risk of developing cirrhosis over the course of 10–20
ing. The spectrum of clinical infection in chronic hepa- years. Indications for therapy in those with HCV include
titis B is quite variable, and often individuals are asymp detectable levels of HCV RNA, portal or bridging fibro-
tomatic with elevated liver enzymes identified on test- sis on liver biopsy, or moderate to severe hepatitis on liver
ing for other reasons. Thus, the decision to treat chronic biopsy. Contraindications to treatment are age greater
HBV infection should not be based on clinical features. than 60 years, mild hepatitis on liver biopsy, and severe
Most experts recommend treatment of HBeAg-positive renal insufficiency. Standard therapy for HCV infection
chronic HBV infection with HBV DNA levels above 2 is pegylated interferon plus ribavirin. While genotypes
× 104 IU/mL if the ALT is elevated greater than twice 1 and 4 are less responsive to therapy than genotypes 2
the upper limit of normal. At present, many treatment and 3, the current research demonstrates a response rate
options are available for the treatment of HBV infection of at least 40% for genotypes 1 and 4. Interestingly, even
and fall broadly into two categories: nucleoside analogues in individuals who fail to show a virologic or biochemi-
and interferons. While lamivudine and interferon were cal response, 75% will have histologic improvement on
the first drugs used for the treatment of chronic HBV liver biopsy. The treatment course for genotypes 1 and
infection, these drugs have largely been supplanted by 4 is a minimum of 48 weeks, whereas genotypes 2 and
entecavir, tenofovir, and pegylated interferon as first-line 3 can be treated for as little as 24 weeks. Once treat-
therapy. When choosing among these agents, treatment ment has been started, a repeat HCV viral load should be
can be tailored to specific patient preferences. Pegylated assessed at 12 weeks. At this point, a 2-log drop in viral
interferon achieves more rapid clearance of HBeAg and load is expected. Failure to achieve this level of response
does not contribute to viral mutations. However, it is suggests that a sustained virologic response is unlikely to
associated with systemic side effects that many find intol- occur. With a drop of this magnitude, however, the likeli-
erable and requires weekly SC injections. In contrast, the hood of a sustained virologic response is about 66% at
oral agents often require a longer duration of therapy, the end of therapy, and if the viral load is undetectable at
are very well tolerated, and yield a more profound sup- 12 weeks, the chances of a sustained virologic response
pression of HBV DNA. However, mutations can occur is more than 80%.
with the use of these medications. Combination therapy
does not appear to be more effective than single-drug 86. The answer is C.
therapy. The patient’s husband should also be screened (Chap. 40) Three types of autoimmune hepatitis have
for hepatitis B given the continued viremia. been identified based on clinical and laboratory charac-
teristics. Type I autoimmune hepatitis is a disorder typi-
85. The answer is E. cally seen in young women. The clinical characteristics
(Chap. 40) Much information has been gained in recent can be variable from those of chronic hepatitis to fulmi-
decades about the progression and treatment of chronic nant hepatic failure, and many of the features are difficult
hepatitis C virus (HCV) infection. Chronic hepatitis to distinguish from other causes of chronic hepatitis. In
develops in about 85% of all individuals affected with some individuals, extrahepatic manifestations including
HCV, and 20–25% of these individuals will progress to fatigue, malaise, weight loss, anorexia, and arthralgias
cirrhosis over about 20 years. Among those infected with can be quite prominent. Liver enzymes are elevated but
HCV, about one-third of individuals will have normal may not correlate with the clinical severity of disease. In
or near-normal levels of aminotransferases, although liver more severe cases, elevations in serum bilirubin between
biopsy demonstrates active hepatitis in as much as one- 3 and 10 mg/dL can be seen. Hypoalbuminemia occurs
half of patients. Moreover, about 25% of individuals with in advanced disease, and hypergammaglobulinemia (>2.5
normal aminotransferase levels at one point in time will g/dL) is very common. The circulating antibody profile
develop elevations in these enzymes later, which can lead in autoimmune hepatitis depends to some extent on the
to progressive liver disease. Thus, normal aminotransferase type of hepatitis. Antinuclear antibodies are positive in a
722 Review and Self-Assessment
homogeneous staining pattern almost invariably in the epatitis, with a score greater than 21 being an indication
h
disease, and rheumatoid factor is also common. Peri- for treatment as well. This patient has a discriminate func-
nuclear antineutrophilic cytoplasmic antibody may be tion of 73, indicating very severe disease and a poor prog-
positive, but in an atypical fashion. Anti–smooth muscle nosis. Complete abstinence from alcohol is imperative.
antibodies and anti–liver/kidney microsomal antibodies Treatment with prednisone 40 mg daily (or prednisolone
are frequently seen, but these are nonspecific as other 32 mg daily) for 4 weeks should be initiated. Following the
causes of chronic hepatitis can lead to positivity of these initial period, a taper should be achieved over a period of
enzymes. Because of the lack of a specific autoimmune 4 weeks. Alternatively, pentoxifylline 400 mg three times
profile, the diagnostic criteria for autoimmune hepatitis daily for 4 weeks can also be used.
incorporate a variety of clinical and laboratory features.
Specific features that argue against this diagnosis include 89. The answer is C.
prominent alkaline phosphatase elevation, presence of (Chap. 42) The clinical presentation is consistent with a
mitochondrial antibodies, markers of viral hepatitis, his- cholestatic picture, which can present with painless jaun-
tory of hepatotoxic drugs or excess alcohol intake, and dice and pruritus. The pruritus can be prominent and
histologic evidence of bile duct injury or atypical biopsy is present in 50% of individuals at the time of diagno-
features including excess hepatic iron, fatty infiltration, sis. The pruritus is typically intermittent and worse in
and viral inclusions. Antimitochondrial antibodies are the evening. There is no other prominent association
typically seen in primary biliary cirrhosis. such as following hot baths or showers, which occurs in
polycythemia vera. Other causes of pruritus outside of
87. The answer is D. cholestasis include lymphoma and uncontrolled hypo-
(Chap. 40) In the course of acute hepatitis B, HBeAg or hyperthyroidism. However, the laboratory studies in
positivity is common and usually transient. Persistence of this patient clearly represent cholestasis with an eleva-
HBeAg in the serum for 3 months or longer indicates an tion in alkaline phosphatase and bilirubin. The clinical
increased likelihood of development of chronic hepatitis characteristics are more commonly seen in primary bili-
B. In chronic hepatitis B, the presence of HBeAg in the ary cirrhosis compared to primary sclerosis cholangitis,
serum indicates ongoing viral replication and increased as the patient is a middle-aged female with positive anti-
infectivity. It is also a surrogate for inflammatory liver mitochondrial antibodies. In contrast, primary sclerosing
injury but not fibrosis. The development of antibody to cholangitis is associated with positive perinuclear anti-
HBeAg (anti-HBe) is indicative of the nonreplicative neutrophil cytoplasmic antibodies in 65% of patients, and
phase of HBV infection. During this phase, intact virions 50% of individuals with primary sclerosing cholangitis
do not circulate and infectivity is less. Currently, quanti- have a history of ulcerative colitis.
fication of HBV DNA with polymerase chain reaction
allows risk stratification as fewer than 103 virions/μL is 90. The answer is B.
the approximate threshold for liver injury and infectivity. (Chap. 42) Esophageal varices develop in the setting of
portal hypertension associated most commonly with cir-
88. The answer is C. rhotic liver disease. In recent years, patients with cirrhosis
(Chap. 41) This patient presents with severe acute alco- have been commonly screened for varices by endoscopy,
holic hepatitis. In its earliest form, alcoholic liver disease as about 33% will have varices on examination. More-
is marked by fatty infiltration of the liver. In more acute over, it is estimated that one-third of individuals with
alcoholic hepatitis, there is hepatocyte injury with balloon varices will develop bleeding. As this patient does not
degeneration and necrosis. Many cases of alcoholic hepa- have medical care, it is unknown whether he has vari-
titis are asymptomatic. However, as in this case, the severe ces, but with the large volume of bleeding the patient
manifestations can include fever, jaundice, spider nevi, and has experienced, the treating physician should assume
abdominal pain that can mimic an acute abdomen in its that the patient has variceal bleeding and act accordingly.
severity. On laboratory examination, the AST is typically The first step in the treatment of any individual with
elevated more than the ALT, although the total trans- acute gastrointestinal bleeding is to ensure appropriate
aminase levels are rarely greater than 400 U/L. Hyper- large-bore IV access, preferably in a large central vein
bilirubinemia can be quite marked, with lesser elevation in or the antecubital fossae, and begin volume resuscitation.
alkaline phosphatase. Hypoalbuminemia and coagulopathy Volume resuscitation should be initiated with normal
are poor prognostic indicators. A discriminate function saline, and blood products should be administered when
(DF) can be calculated as (4.6 × the prolongation of pro- available. Once volume resuscitation has been initiated,
thrombin time above control) + serum bilirubin. A DF emergent consultation with GI for endoscopic evalua-
greater than 32 is associated with a poor prognosis and is tion should be obtained. Endoscopic treatment should
an indication for the treatment of acute alcoholic hepati- include esophageal band ligation, but in the acute set-
tis. The Model for End-Stage Liver Disease (MELD) score ting, sclerotherapy may be used to control local bleeding
can also be used for prognostication in acute alcoholic with band ligation occurring at a future point in time.
Review and Self-Assessment 723
If emergent endoscopy is not an option, placement of a from hepatic irradiation and high-dose chemotherapy in
Sengstaken-Blakemore or Minnesota tube to tampon- preparation for hematopoietic stem cell transplantation.
ade bleeding should be employed. In addition, vasocon- It is not a typical complication of liver transplantation.
stricting agents are used to decrease splanchnic blood Although echocardiography is a useful tool for assess-
flow. While vasopressin was initially the agent of choice, ing left and right ventricular function, findings may be
cardiovascular ischemia can occur with the high doses unimpressive in patients with constrictive pericarditis. A
used in GI bleeding. The currently preferred agents are high index of suspicion for constrictive pericarditis (e.g.,
octreotide or somatostatin by continuous infusion. Non- prior episodes of pericarditis, mediastinal irradiation)
specific beta blockers such as propranolol or nadolol are should lead to a right-sided heart catheterization with
used for the primary or secondary prevention of variceal demonstration of “square root sign,” which is the limita-
bleeding, but are not prescribed in the acute setting as tion of right heart filling pressure in diastole that is sug-
these agents could worsen hypotension. gestive of restrictive cardiomyopathy. Cardiac magnetic
resonance imaging may also be helpful in determining
91. The answer is A. which patients should proceed to cardiac surgery.
(Chap. 42) The cornerstone of the management of ascites
is sodium restriction to less than 2 g daily. A common 93. The answer is B.
misconception is to institute a fluid restriction as well. (Chap. 42) The presence of cirrhosis in an elderly woman
However, this is neither effective nor necessary. With a with no prior risk factors for viral or alcoholic cirrho-
sodium restriction to 2 g daily, most mild ascites can be sis should raise the possibility of primary biliary cirrhosis
managed quite well. If sodium restriction alone fails to (PBC). It is characterized by chronic inflammation and
correct ascites, then initiation of diuretics is required. fibrous obliteration of intrahepatic ductules. The cause is
Spironolactone at a dose of 100–200 mg daily is the ini- unknown, but autoimmunity is assumed, as there is an
tial diuretic used for ascites and can be titrated as high association with other autoimmune disorders, such as
as 400–600 mg daily if tolerated. Loop diuretics can be autoimmune thyroiditis, CREST syndrome, and the sicca
added to spironolactone. The typical agent is furosemide syndrome. The vast majority of patients with symptomatic
beginning at 40–80 mg daily with the maximum doses disease are women. The antimitochondrial antibody test
being about 120–160 mg daily. Care must be taken to (AMA) is positive in over 90% of patients with PBC and
avoid renal dysfunction with loop diuretics, and higher only rarely is positive in other conditions. This makes it
doses may not be tolerated. If ascites is refractory to the most useful initial test in the diagnosis of PBC. Since
these treatments, transjugular intrahepatic portosystemic there are false positives, if AMA is positive a liver biopsy is
shunts (TIPS) can be considered. This procedure creates performed to confirm the diagnosis. The 24-hour urine
a portocaval shunt be introducing an expandable metal copper collection is useful in the diagnosis of Wilson’s dis-
stent from the hepatic veins through the substance of the ease. Hepatic failure from Wilson’s disease typically occurs
liver into the portal veins, creating a direct portocaval before age 50. Hemochromatosis may result in cirrhosis.
shunt. Thus, TIPS decreases portal pressures to decrease It is associated with lethargy, fatigue, loss of libido, discol-
ascites and the risk of variceal bleeding. However, hepatic oration of the skin, arthralgias, diabetes, and cardiomy-
encephalopathy typically worsens following TIPS. opathy. Ferritin levels are usually increased, and the most
suggestive laboratory abnormality is an elevated transfer-
92. The answer is A. rin saturation percentage. Although hemochromatosis is
(Chap. 42) Severe right-sided heart failure may lead to a possible diagnosis in this case, PBC is more likely in
chronic liver injury and cardiac cirrhosis. Elevated venous light of the clinical scenario. Although chronic hepatitis B
pressure leads to congestion of the hepatic sinusoids and and hepatitis C are certainly in the differential diagnosis
of the central vein and centrilobular hepatocytes. Cen- and must be ruled out, they are unlikely because of the
trilobular fibrosis develops, and fibrosis extends outward patient’s history and lack of risk factors.
from the central vein, not the portal triads. Gross exami-
nation of the liver shows a pattern of “nutmeg liver.” 94. The answer is D.
Although transaminases are typically mildly elevated, (Chap. 44) This patient presents with nonalcoholic fatty
severe congestion, particularly associated with hypoten- liver disease (NAFLD) that has progressed to cirrho-
sion, may result in dramatic elevation of AST and ALT sis. It is now commonly thought that many individu-
50- to 100-fold above normal. Budd-Chiari syndrome, als previously identified as having cryptogenic cirrhosis
or occlusion of the hepatic veins or inferior vena cava, had NAFLD as a cause of end-stage liver disease. With
may be confused with congestive hepatopathy. How- the rising prevalence of obesity in the United States and
ever, the signs and symptoms of congestive heart failure Europe, NAFLD is expected to continue to rise. At pres-
are absent in patients with Budd-Chiari syndrome, and ent, the prevalence of NAFLD is estimated between to be
these patients can be easily distinguished clinically from 14–20%. Of these individuals, 30–40% with nonalcoholic
those with heart failure. Venoocclusive disease may result steatohepatitis will develop advanced fibrosis and 10–15%
724 Review and Self-Assessment
will develop outright cirrhosis. Most patients diagnosed Ursodeoxycholic acid can be used in some instances to
with NAFLD are asymptomatic with incident note of dissolve gallstones. It acts to decrease the cholesterol
elevated liver enzymes found on testing for other reasons. saturation of bile and also allows the dispersion of cho-
The ALT is typically slightly higher than the AST, and lesterol from stones by producing a lamellar crystalline
both enzymes are only mildly elevated. In most instances phase. It is only effective, however, in individuals with
the ALT and AST are only 1.5–2 times the upper limit of radiolucent stones measuring less than 10 mm.
normal. NAFLD often accompanies other components
of the metabolic syndrome, with insulin resistance being 96. The answer is D.
a common link between these disorders. The diagnosis (Chap. 45) A practitioner needs to have a high index
of NAFLD requires a careful history and examination of suspicion for acalculous cholecystitis in critically ill
to rule out other disorders. Alcohol intake should be patients who develop decompensation during the course
less than 20 g/d. Comprehensive testing should include of treatment for the underlying disease and have no other
serologies for viral hepatitis, iron studies, ceruloplasmin, apparent source of infection. Some predisposing condi-
α1 antitrypsin levels, and autoimmune serologies. Liver tions for the development of acalculous cholecystitis
biopsy most commonly shows macrovesicular steatosis include serious trauma or burns, postpartum following
with a mixed inflammatory infiltrate in a lobular dis- prolonged labor, prolonged parenteral hyperalimentation,
tribution. The fibrosis that occurs has a characteristic and the postoperative period following orthopedic and
perivenular and perisinusoidal distribution. In cirrhotic other major surgical procedures. The clinical manifesta-
patients, steatosis may not be seen, but can recur follow- tions of acalculous cholecystitis are identical to calculous
ing transplant. The only known effective treatment for disease, but the disease is more difficult to diagnose. Ultra-
NAFLD is weight loss and exercise. Thiazolidinediones sonography and CT scanning typically only show biliary
are currently being studied given their effects on insulin sludge, but they may demonstrate large and tense gallblad-
resistance. In addition, ongoing research into statins and ders. Hepatobiliary scintigraphy often shows delayed or
ursodeoxycholic acid is being undertaken, but no spe- absent gallbladder emptying. Successful management relies
cific medication can be recommended at this point for on accurate and early diagnosis. In critically ill patients, a
patients with NAFLD. percutaneous cholecystostomy may be the safest immedi-
ate procedure to decompress an infected gallbladder. Once
95. The answer is B. the patient is stabilized, early elective cholecystectomy
(Chap. 45) In the National Health and Nutrition Exami- should be considered. Metronidazole to provide anaerobic
nation Survey, the prevalence of gallstone disease in the coverage should be added, but this would not elucidate or
United States was 7.9% in men and 16.6% in women. adequately treat the underlying condition.
While the disease is quite prevalent, not all patients with
gallstone disease require cholecystectomy. It is estimated 97. The answer is C.
that 1–2% of patients with asymptomatic gallstone dis- (Chap. 45) Gallstones are very common, particularly in
ease will develop complications that will require surgery Western countries. Cholesterol stones are responsible for
yearly. Therefore, it is important to know which patients 80% of cases of cholelithiasis; pigment stones account for
with asymptomatic gallstones require referral for surgery. the remaining 20%. Cholesterol is essentially water insol-
The first factor to consider is whether the patient has uble. Stone formation occurs in the setting of factors that
symptoms that are caused by gallstones and whether they upset cholesterol balance. Obesity, cholesterol-rich diets,
are frequent enough and severe enough to necessitate sur- high-calorie diets, and certain medications affect the
gery. Commonly called biliary colic, the classic symptoms biliary secretion of cholesterol. Intrinsic genetic muta-
of gallstone disease are right upper quadrant pain and full- tions in certain populations may affect the processing
ness that begins suddenly and can last as long as 5 hours. and secretion of cholesterol in the liver. Pregnancy results
Nausea and vomiting can accompany the episode. Vague in both an increase in cholesterol saturation during the
symptoms of epigastric fullness, dyspepsia, and bloating third trimester and changes in gallbladder contractility.
following meals should not be considered biliary colic. Pigment stones are increased in patients with chronic
A second factor that would be considered in recommend- hemolysis, cirrhosis, Gilbert’s syndrome, and disruptions
ing a patient for cholecystectomy is whether the patient in the enterohepatic circulation. Although rapid weight
has a prior history of complications of gallstone disease loss and low-calorie diets are associated with gallstones,
such as pancreatitis or acute cholecystitis. A final factor there is no evidence that a high-protein diet confers an
that would lead to the recommendation for cholecys- added risk of cholelithiasis.
tectomy is the presence of anatomical factors that would
increase the likelihood of complications such as a porce- 98. The answer is C.
lain gallbladder or congenital abnormalities of the biliary (Chap. 46) In the United States, over 6000 individuals
tract. Individuals with very large stones (>3 cm) would undergo liver transplants yearly. However, the demand
also need to be considered carefully for cholecystectomy. for organs far outpaces the supply with a waiting list
Review and Self-Assessment 725
of over 16,000 individuals. The most common reasons achieved for an acceptable period of time, transplantation
for liver transplant are alcoholic cirrhosis and chronic can be considered. Indeed, alcoholic cirrhosis accounts
hepatitis C infection. When evaluating someone for liver for a substantial proportion of the patients who undergo
transplantation, it is important to ensure that the patient liver transplantation.
is an appropriate candidate. For individuals with alco-
holic cirrhosis, sustained abstinence and recovery need 100. The answer is A.
to be demonstrated, although the recidivism rate is as (Chap. 48) The most common cause of acute pancreati-
high as 25% after transplantation. Absolute contraindi- tis in the United States is gallstones causing common
cations to liver transplant include uncontrolled infec- bile duct obstruction. Although bile duct obstruction
tion, active substance or alcohol abuse, extrahepatobili- may be demonstrated on technetium HIDA scan, right
ary malignancy (excluding nonmelanoma skin cancer), upper quadrant ultrasound is preferred for ease, demon-
metastatic malignancy to the liver, AIDS, or life-threat- stration of gallstones in the gallbladder, and demonstra-
ening or advance systemic disease. Cholangiocarcinoma tion of obstructed bile duct. Alcohol is the second most
almost invariably recurs following liver transplantation. common cause, followed by complications of endoscopic
Thus, it is now considered a contraindication to trans- retrograde cholangiopancreatography (ERCP). Hyper-
plant. While primarily performed in children, living triglyceridemia accounts for 1–4% of cases with tri-
donor transplantation is increasingly being considered glyceride levels usually greater than 1000 mg/dL. Other
in adults given the poor availability of cadaveric organs. potential causes of pancreatitis include trauma, postop-
In living donor transplantation, typically the right lobe erative states, drugs such as valproic acid, anti-HIV medi-
of the liver is taken from a suitable healthy donor. Cur- cations, estrogens, and sphincter of Oddi dysfunction.
rently, living donor transplantation accounts for 4% of Additionally, there are a number of rare causes that have
all liver transplants. It is certainly not without risk. The been described. The most judicious first step in evalua-
average healthy donor will be medically disabled for at tion is to test for gallstones and pursue more rare causes
least 10 weeks, and the risk of death for the donor is after the most common cause has been ruled out.
0.2–0.4%. Individuals receiving all forms of liver trans-
plant have demonstrated increasing survival over the 101. The answer is A.
past decades. The current 5-year survival rate is more (Chap. 48) Physical examination in acute pancreatitis
than 60%. Following transplantation, however, rejection, commonly shows an uncomfortable patient often with
infection, and recurrence of primary disease can occur. low-grade fever, tachycardia, and hypotension. Abdomi-
For chronic hepatitis B infection, reinfection of the nal tenderness and muscle rigidity are often present to
transplant frequently occurs, but this may be reduced to varying degrees. Cullen’s sign is a faint blue discolor-
as little as 35% with post-transplantation treatment with ation around the umbilicus that may occur as the result
hepatitis B immunoglobulin. For hepatitis C, reinfection of hemoperitoneum. Turner’s sign is blue-red-purple
is universal and is associated with the development of or green-brown discoloration of the flanks from tissue
allograft cirrhosis in 20–30% of patients within 5 years. catabolism of hemoglobin. Both of these signs indicate
Autoimmune diseases can also recur in the transplanted the presence of severe necrotizing pancreatitis.
liver, although it can be difficult to differentiate between
the autoimmune disease and rejection. Wilson’s disease 102. The answer is E.
and α1 antitrypsin deficiency, however, do not recur fol- (Chap. 48) The BISAP (Bedside Index of Severity in
lowing transplantation. Acute Pancreatitis) score has recently replaced Ranson’s
criteria and APACHE II severity scores as the recom-
99. The answer is E. mended modality to assess the severity of pancreatitis
(Chap. 46) The patient has advanced cirrhosis with a high due to the cumbersome nature of the prior scores and
risk of mortality, as evidenced by his episode of spon- the requirement of prior scores to collect large amounts
taneous bacterial peritonitis. His diabetes and remote of clinical and laboratory data over time. Furthermore,
skin cancer (since it was a basal cell carcinoma, not mela- the APACHE II and Ranson’s scoring mechanisms
noma) are not absolute contraindications for liver trans- did not have acceptable positive and negative predic-
plantation, but active alcohol abuse is. The other absolute tive values in predicting severe acute pancreatitis. The
contraindications to transplantation are life-threatening BISAP score incorporates five variables in determining
systemic disease, uncontrolled infections, preexisting severity: BUN greater than 35 mg/dL, impaired mental
advanced cardiac or pulmonary disease, metastatic malig- status, presence of SIRS, age above 60 years, and pleural
nancy, and life-threatening congenital malignancies. effusion on radiography. The presence of three or more
Ongoing drug or alcohol abuse is an absolute contrain- of these factors is associated with substantially increased
dication, and patients who would otherwise be suitable risk for in-hospital mortality. Additional risk factors
candidates should immediately be referred to appropriate initially predicting severity include BMI of 30 or above
counseling centers to achieve abstinence. Once that is and comorbid disease.
726 Review and Self-Assessment
normal tests of pancreatic exocrine function and normal time. An ERCP or magnetic resonance cholangiopan-
abdominal radiography. In small-duct disease, the pro- creatography (MRCP) may be considered to evaluate for
gression to steatorrhea is rare, and the pain is responsive a possible stricture that is amenable to therapy. However,
to treatment with pancreatic enzymes. The character- sphincterotomy is a procedure performed via ERCP that
istic findings on CT and abdominal radiograph of this may be useful in treating pain related to chronic pan-
patient are characteristic of chronic pancreatitis, and no creatitis and is not indicated in the patient. Angiography
further workup should delay treatment with pancreatic to assess for ischemic bowel disease is not indicated as
enzymes. Treatment with pancreatic enzymes orally will the patient’s symptoms are not consistent with intestinal
improve maldigestion and lead to weight gain, but they angina. Certainly, weight loss can occur in this setting, but
are unlikely to fully resolve maldigestive symptoms. Nar- the patient usually presents with complaints of abdomi-
cotic dependence can frequently develop in individuals nal pain after eating and pain that is out of proportion
with chronic pancreatitis due to recurrent and severe with the clinical examination. Prokinetic agents would
bouts of pain. However, as this individual’s pain is mild, likely only worsen the patient’s malabsorptive symptoms
it is not necessary to prescribe narcotics at this point in and are not indicated.
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INDEX
Bold numbers indicate the start of the main discussion of the topic; numbers with “f” and “t” refer to figure and table pages, respectively.
ABCG5/G8 hemitransporter, Abdominal wall disorders, 4, 38 spastic, 118f
458–459 Abdominoperineal resection, 564 subtypes of, 118f
Abdomen Abetalipoproteinemia treatment of, 31, 117–118
auscultation of, 71 diarrhea in, 49 Achlorhydria, 154, 177–178
inspection of, 71 pathophysiology of, 162 Acid-base imbalance, 619
palpation of, 71 small-intestinal mucosal biopsies in, Acidemia, 500
Abdominal bruits, 537 166, 167t Acinar cell
Abdominal mass, 521 Abortion, septic, 288 injury, pancreatitis and, 499
Abdominal pain, 2 Abscess pancreas and, 499
acute pancreatitis and, 499 anorectal, 220–221, 221f Acrocyanosis of digits, 645
in appendicitis, 231–232, 232t liver. See Liver abscess Acromegaly, 9
approach to the patient, 5–7 periapical, 9 Actinomycosis, 12t, 18
autoimmune pancreatitis and, 509 perinephric, 260–261 Activated charcoal, 40
differential diagnosis of, 6t psoas, 261 Active energy expenditure, 615
in gastrointestinal disease, 83, 83t renal, 260–261 Active transport, 158
hepatocellular carcinoma and, Absorption Acupressure, 36, 88
536–537 of carbohydrates, 162–163, Acustimulation, 88
history in, 5–6 163t Acute anaphylaxis, 45
imaging in, 7 disorders of, 156–178 Acute care settings
in intestinal ischemia, 225 impaired, 81 dietary intake and, 582–583
in intestinal obstruction, 228 of lipids, 160t, 160–162, 161f enteral nutrition in, 615
in irritable bowel syndrome, 204–205 nutrient, 157 parenteral nutrition in, 615
in malabsorption syndromes, 176t of proteins, 163–164 Acute cholecystitis, 501
mechanisms of Acalculous cholecystitis, 724 Acute intermittent porphyria, 457
abdominal wall disorders, 3t, 4 Acanthamoeba, 311–312, 312f Acute intestinal obstruction, 501
inflammation of parietal Acanthocytosis, 162 Acute mesenteric vascular occlusion,
peritoneum, 2, 3t Acarbose, 148 501
metabolic, 3t, 5 ACE inhibitors, 656 Acute myelomonocytic leukemia,
neurogenic, 3t, 5 Acetaminophen 14t, 17
obstruction of hollow viscera, hepatotoxicity caused by, 67, 387t, Acute necrotizing pancreatitis, 504–505,
2–4, 3t 389–392, 392f, 449f 703, 726
toxic, 3t metabolism of, 389, 391 Acute pancreatitis, 481
vascular disturbances, 3t, 4 overdosage/poisoning with, abdominal pain in, 5, 6t
in peptic ulcer disease, 136–137 391–392, 392f, 698–699, 720 AIDS infection and, 507
in peritonitis, 254 Acetylcholine approach to the patient, 490–495
referred, 3t, 4–5 in neural control of gastrointestinal causes of, 498t
Abdominal radiography system, 42 complications and course of,
in gallbladder disease, 463, in swallowing, 28 503–506
463t, 464f Achalasia, 82, 117, 686, 705 diagnosis of, 491t–492t, 500–503
in pancreatic disease evaluation, classic, 118f differential diagnosis for,
491t, 493 clinical features of, 117 501–503
Abdominal swelling/distention, 70 diagnosis of, 117, 118f general considerations, 497
in appendicitis, 232 differential diagnosis of, 117 laboratory data and, 499–500
causes of, 70 dysphagia in, 29–30 necrotizing, 258
history in, 71 with esophageal compression, pathogenesis of, 499
imaging in, 71, 72f 118f treatment for, 504–506
in intestinal obstruction, 228 LES relaxation impairment in, Acute respiratory distress syndrome
physical examination in, 71 117–118, 118f (ARDS), 499
729
730 Index
Bacteria Benign small bowel tumors, 532–533 Bile salt uptake systems, 458–459
adherence of, 238 Benzodiazepines, for nausea and Bile salt–induced diarrhea, after
colonic, 41–42 vomiting, 36, 36t cholecystectomy, 469
toxin production by, 239 Benzphetamine, 640 Biliary atresia, 470, 476
Bacterial endocarditis, 19 Bereavement, 76 Biliary cirrhosis, 435, 435–437
Bacterial infections, liver transplantation Beriberi, 587 primary, 435–436
and, 482t, 483 Bernstein test, 39 clinical features of, 435–437
Bacterial overgrowth syndrome, Beta-adrenergic antagonists (beta blockers) diagnosis of, 69, 335t, 436
173–174, 177 cyclic vomiting syndrome treated laboratory evaluation of, 436
diagnosis of, 52, 173–174 with, 36 pathology of, 435
diarrhea in, 49, 173 variceal bleeding treated with, 58, 440 prevalence of, 435
etiology of, 173 xerostomia caused by, 18 treatment of, 436
pathogenesis of, 173 Bevacizumab, 532 secondary, choledocholithiasis and, 471
small-intestinal, 39, 167t Bicarbonate, 496 Biliary colic
steatorrhea in, 173 Bicarbonate salts, 619 abdominal pain in, 3, 5
treatment of, 174 Bile acute pancreatitis, 501
Bacteria-mediated endocytosis, 269 composition of, 458–459 in gallbladder disease, 464
Bacteroides fragilis, 257 esophageal epithelium affected by, 121 indigestion in, 38
female genital tract, 257 in gallbladder, 458 nausea and vomiting in, 33
intraperitoneal abscess, 257 limey, cholecystitis and, 468 treatment of, 39
liver abscess, 259 production of, 458–460 Biliary dyskinesia, postcholecystectomy,
peritonitis, 255 secretion of, 458–459 469
Balamuthia, 312 Bile acid(s), 459 Biliary ectasia, congenital, 470
Balantidium coli/balantidiasis, 318 conjugated, 159 Biliary hypoplasia, 470
Balloon expulsion test, 55–56 enterohepatic circulation of, Biliary obstruction, 92f, 100
Balloon tamponade, 440 158–160, 159f, 159t, 459 Biliary sludge, 460–462
Balsalazide, 195, 196t functions of, 158, 159f, 159t Biliary tree tumors, 535
Bardet-Biedl syndrome (BBS), 629 malabsorption of, 48, 53 Biliary tumors, 544
Bariatric surgery, 641f, 641–642, 655 primary, 158 Biliopancreatic diversion, 641
Barium radiography reabsorption of, 159t, 159–160 Biliopancreatic diversion with duodenal
in constipation, 54 secondary, 158 switch, 641, 641f
in dysphagia, 31 secretion of, 159 Biliprotein, 63
in malabsorption syndromes, 165, 166f synthesis of, 158 Bilirubin
in nausea and vomiting, 35 Bile acid diarrhea, 159t, 159–160 alcoholic liver disease and, 429t
in peptic ulcer disease, 137, 138f Bile acid pool, 459 biliary excretion of, 349
in ulcerative colitis, 186 Bile duct conjugated, 63, 345t, 348–349
Barrett’s esophagus/metaplasia, 519 common, 458 conjugation of
dysplasia in, 121 imaging of, 100–101 hereditary defects in, 351t,
endoscopic findings in, 89, 90f, 103, obstruction of, 725 351–353
120f, 122 Bile duct disease, 470–474 impaired, 350
esophageal cancer and, 37, 120f, 122 choledocholithiasis, 470–473 delta fraction, 63
gastroesophageal reflux disease and, congenital anomalies, 470 extrahepatic disposition of, 349
37, 103 extrinsic compression, 473 in gut, 349
histopathology of, 122, 122f hemobilia, 473 hepatocellular uptake of, 348–349
Basal metabolic rate, 626 hepatobiliary parasitism, 473 metabolism of, 62–63, 348–349
Bedside Index of Severity in Acute sclerosing cholangitis, 473–474 production of, 62–63, 349–350
Pancreatitis, 503, 703, 725 strictures, 473 serum, 62
Behavioral therapy, 639 trauma-related, 473 isolated elevation of, 65, 65t
Behçet’s syndrome Bile duct stones, 92, 92f in liver function evaluation, 66,
diarrhea in, 50 Bile flow 340–341, 341f, 345t
oral manifestations of, 10, 13t regulation of, 458 measurement of, 63
Bell’s palsy, 18 sphincter of Oddi in, 459–460 normal value, 62–63
Benign liver tumors, 545, 545–546 Bile leak, from duct of Luschka, 93f transfer from blood to bile, 348f,
Benign recurrent cholestasis, 69 Bile reflux gastropathy, 148 348–349
Benign recurrent intrahepatic Bile salt excretory protein, 356 unconjugated, 62–63, 341, 345t
cholestasis, 354t, 355 Bile salt export pump, 459 urine, 63–64, 341, 345t
734 Index
Colonoscopy, 90, 91f–92f bile duct evaluations, 472t C-reactive protein (CRP)
acute ulcerative colitis evaluations, pancreatic disease evaluations, 491t, 494 metabolic syndrome and, 654
186, 186f Computed tomography enterography, in ulcerative colitis, 185
adenomatous polyp, 524 188–189, 189f Creatinine-height index, 602
colitis evaluations, 90, 91f Condyloma acuminata, 534 Cretinism, 9
colorectal cancer and, 530 Confluent necrosis, 368 CRH. See Corticotropin-releasing
constipation evaluations, 54 Congestive heart failure hormone
diarrhea evaluations, 46, 53 anorexia nervosa and, 645 Cricopharyngeal bar, 29
gastrointestinal bleeding evaluations, Framingham Study, 632 Crigler-Najjar syndrome, 340, 477,
61 Conjugated bile acids, 159 718
gastrointestinal disease evaluations, Connective tissue disorders, 501 clinical features of, 351t, 351–352
85, 86t Connective tissue metabolism, 592 jaundice in, 65
hereditary nonpolyposis colon cancer Constipation, 53 subtypes of, 65, 351t, 351–352
evaluations, 526 approach to the patient, 54, 54f Critical illness
intestinal ischemia evaluations, definition of, 53–56 cholestasis and, 69
226 epidemiology of, 41 REE and, 615
large-bowel cancer, for asymptomatic etiology of, 53t, 53–54 requiring ICU, SNS and, 612
patients, 528 idiopathic, 53 Crohn’s disease, 90f, 179, 533, 708
nausea and vomiting evaluations, in irritable bowel syndrome, appendicitis versus, 234
35 204–205 barium contrast small-intestinal
virtual, 107, 107f outlet abnormalities as cause of, 82 radiologic examinations in,
Colorectal cancer, 524 prevalence of, 41 166f
aspirin and, 527 psychosocial factors in, 53 cancer risks, 203
clinical features, 528–530 rectal prolapse and, 216 cardiopulmonary manifestations of,
Crohn’s disease and, 201–202 severe, 54–56 195
family history of, 106t treatment of, 56 clinical features of, 187–190, 188f,
hereditary factors and syndromes, Contact lenses, 312 190f
525t, 525–526 Continuous ambulatory peritoneal colitis in, 187–188
incidence, 524 dialysis, 256, 692, colorectal disease, 201–202
inflammatory bowel disease and, 712–713 complications of, 189
202f, 202–203 Continuous positive airway pressure, contrast-enhanced MDCT in,
metastases, 530–531 655 188–189, 189f
molecular pathogenesis of, 524 Copper, 599 diarrhea in, 50
personal history of, 106t Core liver biopsy, HCC and, 539 differential diagnosis of, 190–193,
presenting symptoms, 528 “Corkscrew” esophagus, 119, 119f 191t, 288
prognostic factors, 528–530 Coronary heart disease, 651 disorders associated with, 180
risk factors, 524t Coronary ischemia, 18 endoscopic features of, 188f,
screening for Coronavirus infections, 44 188–189, 190f
endoscopic, 105f, 105–107, 106t, Corpus luteum cyst rupture, 233 epidemiology of, 179t, 179–180,
107f Corrosive esophagitis, 125–126 180t
rationale for, 527 Corticotropin-releasing hormone, 629 etiology of, 180
strategies in, 106t Cortisol, 629 exogenous factors in, 183
spread patterns for, 528–530 COX. See Cyclooxygenase gastroduodenal ulcer in, 37
staging of, 528–530 COX-2 inhibitors, 129 gastrointestinal bleeding in, 59
survival factors, 529–530, 530t in NSAID-induced ulceration genetic factors in, 180t, 180–182,
treatment, 530–532 prevention, 144 181t
Combination chemotherapy in peptic ulcer disease, 58 hepatobiliary disease in, 194
esophageal cancer and, 520 Coxsackievirus infections ileocolitis in, 187
with radiation, for gastric herpangina, 11t immune regulation in, 180, 182
adenocarcinoma, 523 oral manifestations of, 11t jejunoileitis in, 187
Common bile duct, 458 CPAP. See Continuous positive airway laboratory evaluation of, 188f,
Computed tomography pressure 188–189, 190f
acute appendicitis evaluations, CPC. See Capsular polysaccharide macroscopic features of, 184f,
232, 233f complex 184–185
acute intestinal obstruction Craniopharyngioma, obesity and, metabolic bone disorders in,
evaluations, 228, 229f 629–630 194–195
Index 739
Hepatitis B virus vaccine, 339, 698, 719 genome of, 359t, 363–364 abdominal swelling with, 71
in adults, 383t global features of, 370–371 in liver disease, 334
in hemodialysis patients, 383t laboratory evaluation of, 373–377 Hepatopulmonary syndrome, 335
in infants and children, 383t pathology of, 368 Hepatorenal syndrome, in cirrhosis, 444
postexposure prophylaxis use of, prognosis of, 378 Herbal medicines/supplements, 396
382–383 prophylaxis for, 383 Hereditable gastrointestinal polyposis
Hepatitis B x antigen, 358f, 360–361 transmission of, 369t, 371 syndromes, 525t, 525–526
Hepatitis C virus infection, 359t, 364, treatment of, 380 Hereditary chronic pancreatitis,
364f, 699, 721 Hepatitis E virus infection, 359t, 513–514
biopsy findings in, 447f 365–366 Hereditary hemochromatosis, 453t,
cholestasis in, 68 clinical features of, 359t, 369t, 373 453–454
chronic, 410–412 diagnosis of, 335t Hereditary nonpolyposis colon cancer,
alcoholic liver disease associated epidemiology of, 369t, 372–373 526, 547
with, 427t, 428 global features of, 372–373 Hereditary pancreatitis, 513
aminotransferase activity in, 412 laboratory evaluation of, 373–377 Hermansky-Pudlak syndrome, 180
biopsy findings in, 447f, 448f pathology of, 368 Hernia, paraesophageal, 114
cirrhosis due to, 411–412, 434 prophylaxis for, 384 Herpangina, 11t
clinical features of, 413 risk factors for, 333 Herpes labialis, 11t
laboratory evaluation of, 413 transmission of, 369t, 372–373 Herpes simplex virus infections
liver disease progression in, 412 treatment of, 380 as opportunistic infection, 33
mortality data, 412 Hepatobiliary disease, 632–633 diarrhea in, 44
prognosis of, 412 Hepatobiliary parasitism, 473 esophagitis, 125
treatment of, 413f, 413–423, 416t, Hepatocellular carcinoma, 82, 535 orofacial, 11t
417f, 419t–420t age-adjusted incidence of, 535t proctitis, 191t, 192
antiviral therapy, 418, approach to patient, 538–539 skin manifestations of, 11t
419t–420t, 421–423, 423 clinical features, 536–538 Herpes zoster
PEG IFN and ribavirin, 413–417 clinical presentation of, 537t abdominal pain caused by, 5
protease inhibitors, 417–418, 422 CLIP staging system, 537, 538t oral manifestations, 11t, 18
clinical features of, 359t, 369t, 373 diagnosis of, 335t, 539 postherpetic neuralgia, 18
complications and sequelae of, epidemiology, 535–536 Herpetic gastritis, 153
377–379 etiologic factors, 535–536 Heterotopic gastric mucosa, 117
diagnosis of, 335t, 375–376 evaluation of, 543 HEV. See Hepatitis E virus
epidemiology of, 369t, 371–372, 372t hemochromatosis with, 450f Hiatal hernia, 114
global features of, 371–372, 372t high-risk populations, 539 gastroesophageal reflux and, 37
HIV and, 422 history and physical examination, 543 sliding, 114
laboratory evaluation of, 373–377, incidence of, 535, 535t types of, 114
376t indigestion in, 38 Hiccups, 228
liver transplantation for, 477–478 liver diseases and, 539 High-amplitude propagated
pathogenesis of, 367 management choices for, 540f contractions, 42–43
pathology associated with, 368 OKUDA staging system, 537, 538t Highly active antiretroviral therapy, 396
prophylaxis for, 383–384 paraneoplastic syndromes in, 537 High-performance liquid
recurrence of, after liver pathologic diagnosis of, 539 chromatography (HPLC), 590
transplantation, 486 patient presentation, 543 Hilar cholangiocarcinoma, 544
risk factors for, 333, 372t risk factors, 536t Hinchey classification, of diverticulitis,
screening for, 371, 372t staging, 537–538 214, 214f, 215–216
transmission of, 369t, 371–372, 372t targeted therapies for, 543t Hindgut tumors, 561
treatment of, 380 transhepatic artery Hip fracture, 141
Hepatitis D virus infection, 359t, chemoembolization for, 541t Histamine H2 receptor antagonists
363–364 treatments for, 539–544, 540t adverse effects of, 140
chronic, 411 stages I and II, 539–542 gastrinomas treated with, 566
HBV infection with, 371, 411 stages III and IV, 542–543 gastritis treated with, 59
treatment of, 411 Hepatocellular disorders, 331t, 332, gastroesophageal reflux disease treated
clinical features of, 359t, 369t, 373 345t with, 39, 123
complications and sequelae of, 378 Hepatocytes, 330–331, 342, 345t, gastrointestinal disease treated with, 87
diagnosis of, 335t, 376 698, 720 peptic ulcer disease treated with,
epidemiology of, 369t, 370–371 Hepatomegaly, 537 139t, 139–140
750 Index
cholangiocarcinoma and, 544 Maternal thiamine deficiency, 587 epidemiology of, 650–651
in cholestasis, 67–68 Mazindol, 640 etiology of, 652–654
in liver disease, 336 McBurney’s point, 232 HDL cholesterol, 656
pancreatic cancer and, 548–549 MCT. See Medium-chain triglycerides NCEP:ATPIII criteria, 650t,
pancreatic disease and, 491t, 494, MDCT. See Multidetector computed 650–651
511, 511f tomography pathophysiology of, 652f
primary sclerosing cholangitis, 194, 437 Mebendazole risk factors, 651–652
Magnetic resonance elastography, 336 ascariasis treated with, 322 treatment of
Magnetic resonance imaging hookworm infection treated with, blood pressure, 656–657
in Crohn’s disease, 190f 323 diet, 655
in liver disease, 336 Mechanical ventilation, 620 HDL cholesterol, 656
Malabsorption, 156 Meckel’s diverticulum, 59, 61 impaired fasting glucose, 657
approach to the patient, 164–167, Meclizine, 35, 36t insulin resistance, 657
167f, 167t, 168f Mediterranean lymphoma, 533 LDL cholesterol, 655–656
bacterial overgrowth syndrome, Medium-chain triglycerides, 616 lifestyle, 655
173–174 Megacolon obesity, 655
classification of, 176t diagnosis of, 54 physical activity, 655
clinical features of, 164–165 treatment of, 56 triglycerides, 656
genetic factors in, 169 Megarectum, 56 Metabolites, 626
laboratory evaluation of, 164–165 α-Melanocyte stimulating hormone Metals, 588t
pathophysiology of, 176t (α-MSH), 628, 629f Metformin, 657
radiologic examination in, 165, 166f Melanoma, oral, 14t Methotrexate, 197, 688, 708–709
Schilling test in, 165 Melanosis coli, 54 α-Methyldopa, 393, 564
small-intestinal mucosal biopsy in, Melena, 57 Methylprednisolone, 36t
165–167, 167t, 168f MEN 1. See Multiple endocrine Metoclopramide
surgery-related, 148–149 neoplasia type 1 adverse effects of, 35
urinary d-xylose test in, 165 Menaquinone, 598 gastrointestinal reflux disease treated
Malaria, 6t Ménétrier’s disease, 175 with, 40
Maldigestion, 510 indigestion in, 38 nausea and vomiting treated with,
Malignancy, 567 nausea and vomiting in, 34 35, 36t
Mallenkot drain, 221 peptic ulcer disease and, 155 vasoactive intestinal peptidomas
Mallory-Weiss tears treatment of, 155 treated with, 569
gastrointestinal bleeding in, 57, 57t, Meningitis, 276 Metronidazole
97–98, 98f, 125 Meningoencephalitis, primary amebic, amebiasis treated with, 310, 310t
nausea and vomiting in, 34 311, 311f C. difficile infection treated with,
treatment of, 58, 125 Mental retardation, 630t 250–251, 251t
Malnutrition, 601 MEOS. See Microsomal ethanol D. fragilis infection treated with,
alcoholic liver disease and, 427t, 428 oxidizing system 319
and nutritional assessment, 601–609 6-Mercaptopurine, 197, 200f, 426 diarrhea treated with, 47
in cirrhosis, 444–445 Mercury exposure/poisoning, 15t Giardia infection treated with, 315
in malabsorption syndromes, 176t Mesalamine, 195–196, 196t, 201 H. pylori eradication using, 142, 142t,
secondary, 601 Mesenteric ischemia, 690, 710 267t
Malocclusion, 9 abdominal pain in, 6t hepatic encephalopathy treated with,
MAMC (Mid-arm muscle indigestion in, 38 444
circumference), 605 nausea and vomiting in, 32 peritonitis treated with, 256
Manganese, 600 Mesenteric lymphadenitis, 6t, 233 resistance to, 267
Manometry Mesenteric vascular occlusion, 501 Trichomonas vaginalis infection treated
anorectal, 55 Mesenteric venous thrombosis, with, 319
esophageal, 31, 38–39 223–224, 224t MI. See Myocardial infarction
intestinal, 35 Metabolic acidosis, 619–620 Micellar formation, 161
Marasmus, 601 Metabolic disturbances, 619t Micelles, 459
kwashiorkor, 602t Metabolic syndrome, 650 Microlithiasis, 108
Mastocytosis clinical features, 654–655 Micronodular cirrhosis, 536
small-intestinal mucosal biopsies in, associated diseases, 654 Micronutrient malnutrition, 604
167t signs and symptoms, 654 Microsomal ethanol oxidizing system,
systemic, 48 diagnosis of, 655 432
756 Index
Occult blood in stool, 524 nausea and vomiting secondary to, P gene, 360
Occult colorectal cancers, 527 33t, 34 Paget’s disease of bone, 9
Occult gallstone disease, 505 oral pigmentation secondary to, 14t Pain
Occult gastrointestinal bleeding, 57 Oral hypoglycemics, 34, 566 management, chronic pancreatitis
OCG. See Oral cholecystography Oral intake, 504 and, 512–513
Octreotide, 148, 561 Oral mucosa palliation, 522
anesthesia and, carcinoid crises and, age-related changes in, 20 pancreatic cancer and, 548
563 pigmented lesions, 14t–15t Palliation
carcinoid syndrome treated with, 53 vesicular, bullous, or ulcerative esophageal cancer and, 520
glucagonomas and, 567 lesions, 11t–14t of pain, external beam irradiation,
GRFomas, 570 white lesions, 15t–16t 522
insulinomas and, 567 Oral pancreatic enzymes, cobalamin Palmar erythema, 334, 432, 432f
metastatic disease and, 572 malabsorption, 511 Palpation, abdominal, 6
nausea and vomiting treated with, Oral rehydration solution PAM. See Primary amebic
35, 36t cholera managed with, 293–294, 295t meningoencephalitis
necrotizing acute pancreatitis and, composition of, 245, 283, 293–294, Pancreas
505 295t autoprotection of, 497
somatostatinoma syndrome and, 568 infectious diarrhea managed with, biopsy of, 491t, 495
variceal bleeding treated with, 58, 245, 245t exocrine secretion, 496
440 Shigella infections managed with, 283 gastrinomas and, 565–566
vasoactive intestinal peptidomas, 569 Organophosphates, 45 inflammation of, gallstones and,
Zollinger-Ellison syndrome treated Orlistat, 640 498
with, 151 Oropharyngeal disease, 29 stellate cells of, 509
Ocular disorders, 193–194 ORS. See Oral rehydration solution Pancreas divisum, 514
Ocular melanomas, 545 Orthodeoxia, 335 Pancreatic abscess, 507
Odynophagia, 27, 38, 113, 124, 519 Orthotopic liver transplantation Pancreatic ascites, 508
OKUDA staging system, HCC and, FL-HCC and, 544 Pancreatic calculi, 511f
537, 538t hepatocellular carcinoma and, Pancreatic cancer, 512, 547,
Oligomenorrhea, 648 539–541, 543 548f
Olsalazine, 195, 196t OSA. See Obstructive sleep apnea adjuvant therapy, 551t
OLTX. See Orthotopic liver Osler-Weber-Rendu syndrome, 59 clinical features, 548
transplantation Osmotic diarrhea, 156 diagnostic procedures, 548–549
Omega-3 fatty acids, 656 Osmotic laxatives, 49 early detection of, 548
Omeprazole Osteoarthritis, 18 epidemiology of, 547
action of, 140 Osteomyelitis extrahepatic cholestasis in, 69
formulations of, 140 psoas abscess in, 261 gastroparesis in, 33
gastroesophageal reflux disease treated Salmonella, 276 genetic considerations, 547–548
with, 39 Osteonecrosis incidence and etiology, 547
H. pylori eradication treated with, in inflammatory bowel disease, 195 metastatic, 551
142t, 143, 267t of jaw, 19, 25f obstruction due to, 99, 99f
peptic ulcer disease treated with, 58, Osteoporosis, 594 operable, treatment for, 549
139t, 140 Osteosarcoma, 10 risk factors for, 547
Oncogenes, 558 Outlet obstruction to defecation, 55 screening for, 548
Ondansetron, 35, 36t Ova and parasite examination, 46, 52 staging of, 549, 550f
Open access endoscopy, 108, 109f, 110f Ovarian cyst survival, 551t
Operative resection, esophageal cancer abdominal pain in, 7 treatment, 549–551
and, 520 twisted, 7 Pancreatic carcinoma, 505–506
Opioids, 34 Overlapping sphincteroplasty, for fecal Pancreatic cholera, 48
Opisthorchis viverrini, 544 incontinence, 219 Pancreatic disease, 490
Oral calculus, 24f–25f Oxalate absorption, 172 acute, 490
Oral carcinoma, 23f Oxaliplatin approach to the patient, 490–495
Oral cholecystography, 463 colorectal cancer and, 531–532 ascites in, 72
Oral contraceptives tumors and, metastatic to liver, 545 diagnosis of, 490–495, 491t–492t,
cholestasis secondary to, 68 Oxidative stress hypothesis, 652–653 493f, 494t
hepatotoxicity secondary to, 387t, Oxyntic cell, 127, 127f etiology of, 490
388, 394–395 Oxyntic gland, 127, 127f, 130, 131f indigestion in, 38
Index 759
Peptic ulcer disease, 127, 565 proton pump inhibitors, 139t, in peritoneal dialysis, 256
abdominal pain in, 6t, 136–137 140–141 postoperative, 256
acute pancreatitis, 501 sucralfate, 139t, 141 prevention of, 255
barium radiography in, 137, 138f surgery, 145–149, 146f primary, 234, 253–255, 692, 712
clinical features of, 127, 136–137 Zollinger-Ellison syndrome and, prognosis of, 235
conditions related to, 149 149–152 recurrence of, 255
diagnostic evaluation of, 137–138, Percutaneous ethanol injection, secondary, 234, 255–256, 693, 713
138f 540–541, 541 treatment of, 235, 255, 256
differential diagnosis of, 137 Percutaneous liver biopsy, 341f, 344 Pernicious anemia, 177, 178t, 521, 708
dyspepsia in, 144 Percutaneous transhepatic Peroxisomal catalase, 432
endoscopic findings in, 89, 103 cholangiography, 472t Peroxisome proliferator-activated
benign, 89f, 137, 138f Pergolide, 561 receptor gamma, 195
hemorrhage, 96, 96f Perianal disease, 187–188 Pesticides, 536
malignant, 89f Perianal skin tags, 193 PETs. See Pancreatic endocrine tumors
epidemiology of, 131 Periapical abscess, 9 Peutz-Jeghers syndrome, 14t, 547–548
etiology of, 131–134, 136t Periapical cyst, 9 Peyronie’s disease, 561
gastric physiology and, 127f–129f, Periapical disease, 9 pH, esophageal, 38–39
128–130 Periapical granuloma, 9 Phacomatoses, 557
gastritis and, 153 Pericarditis, 4, 6t Phagophobia, 27
gastrointestinal bleeding in, 57, 57t, Perineal descent, 43f, 55 Phantom pain, 18
96, 96f, 137 Perinephric abscess, 260–261 Phendimetrazine, 640
genetic factors in, 134–135 Periodontal disease, 9, 24f–25f Phenol exposure, 62
H. pylori-related, 57–58, 131–132, AIDS-related, 9 Phenothiazines, 569
262, 264f in elderly, 20 Phentermine, 640
history in, 136 localized juvenile, 9 Phenytoin
indigestion in, 37 prevention of, 9 gingival hyperplasia caused by, 10
Ménétrier’s disease and, 155 risk factors for, 9 hepatotoxicity caused by, 394
mortality data, 127 Periodontitis, 22f Photodynamic therapy, 545
NSAID-induced, 132 Periodontium, 8 Photosensitivity, 592
epidemiology of, 135 Peripheral edema, 334, 634 Phrygian cap, 460
pathophysiology of, 135, Peripheral neuropathy Phylloquinone, 598
135f in malabsorption syndromes, 176t Physical activity, 576
treatment of, 143–144, 144t pyridoxine and, 592 metabolic syndrome, treatment, 655
pathophysiology of, 131–132, 133f, Peripherally acting medications, 640 obesity and, 639
134f Peripherally inserted central catheters, Physical examination
perforation in, 137 617 hepatocellular carcinoma, 538
physical examination in, 136–137 Periportal necrosis, 397 in high-risk patient, 605, 606t
prevalence of, 127 Peristalsis, 27–29 Physical fitness, 635
prevention of recurrent bleeding in, Peristaltic sounds, 7 PICCs. See Peripherally inserted central
58 Peritoneal carcinomatosis, 72, 72f, 73 catheters
recurrence of, 147 Peritoneal dialysis, continuous Picobirnaviruses, 300f, 305
smoking and, 135 ambulatory, 256, 692, PID. See Pelvic inflammatory disease
stress-related mucosal injury, 152 712–713 Piecemeal necrosis, 397
treatment of, 139–149 Peritonitis, 234, 253, 690–691, 711 Pigment stones, 462t, 462–463
antacids, 139, 139t abdominal pain in, 2, 6, 6t, 254, 711 Pill esophagitis, 126
approach to the patient, 144–145, acute, 234–235 Pilocarpine, 18
145f ascites in, 72, 73 Pivmecillinam, 283t
bismuth-containing preparations, aseptic, 234 Plant proteins, 576
139t, 141 bacterial, 74, 253–255, 443 Plaque, dental, 8–9
cytoprotective agents, 139t, clinical features of, 234–235, Plasma
141–142 253–255 insulin levels in, 566
H. pylori eradication, 142t, continuous ambulatory peritoneal proinsulin levels in, 566–567
142–143 dialysis-related, 692, 712–713 VIPomas, 568
H2 receptor antagonists, 139t, diagnosis of, 254, 254f Platelet dysfunction, 592
139–140 etiology of, 234, 235t Platypnea, 335
prostaglandin analogues, 139t, 141 pathophysiology of, 254f Pleistophora spp., 317
Index 761
Reiter’s syndrome, 276 etiologic agent of, 302 incidence of, 274–275
Reiter’s syndrome. See Reactive global considerations, 304–305, 305f intraabdominal infections caused
arthritis immunity to, 304 by, 276
Rejection, in liver transplantation, 484 pathogenesis of, 303 meningitis caused by, 276
Renal abscess, 260–261 prevention of, 304 osteomyelitis caused by, 276
Renal cell carcinoma, 69 treatment of, 304 prevention of, 278
Renal colic, 501 Rotavirus vaccine, 304 transmission of, 275
Renin-producing PET, 570 Rotor syndrome, 66, 354t, 355 treatment of, 277t, 277–278
Reoviridae, 299t Roux-en-Y gastric bypass, 641 urinary tract infections caused by,
Reproductive disorders, 632 Rumination, 32, 112 276
Reproductive system, 645 RXR agonists, 594 pathogenesis of, 269–270
Resistin, 627, 654 Salpingitis, 6t, 7
Resting energy expenditure (REE), S genes, 358f, 360 Sapovirus, 299t
576, 615–616 Saccharomyces boulardii, 250, 251t Sarcoidosis
Restitution, 128 Sacroiliitis, 193 extrahepatic cholestasis, 69
Restrictive weight loss surgeries, Saliva indigestion, 38
641–642 characteristics of, 18 oral, 18
Restrictive-malabsorptive weight loss substitutes for, 18 Saturated fats, 656
surgeries, 641–642 Salivary duct obstruction, 18 Schatzki’s ring, 29–30, 104f, 110, 115,
Retinaldehyde (11-cis), 594 Salivary glands 124f, 685–686, 705
Retinoic acid, 594 anorexia nervosa and, 645 Schilling test, 165, 177–178, 178t
Retinoid receptors, 594 carcinoma, 19 Schizophrenia, 592
Retinoid-mediated gene transcription, diseases of, 18–19 Scintigraphy, 86
594 Salivary stone, 25f Scleral icterus, 62
Retinoids, 594 Salmonella spp. Scleroderma. See Systemic sclerosis
Retinol activity equivalent, 594 characteristics of, 269 Scleroderma esophagus, 126
Retinol-binding protein, 594, 608 clinical features of, 45t Scombroid poisoning, 45
Retroperitoneal burn, 499 enteric fever caused by. See Enteric Scopolamine, 35, 36t
RFA. See Radiofrequency ablation fever Scurvy, 582, 592
Rheumatoid arthritis, 18 food-related, 44 Secondary active transport, 158
Rheumatologic diseases, 193 gastroenteritis Secretin, 511
RIAs. See Radioimmunoassays appendicitis vs., 234 Secretin-pancreozymin test, 491t
Ribavirin, 413–417, 422 inflammatory bowel disease vs., Secretory diarrhea, 156
Riboflavin (Vitamin B2), 591 191, 191t Sedentary lifestyle, metabolic syndrome
Rice water stool, 293, 293f treatment of, 242t and, 651
Ricinoleic acid, 48 S. enteritidis, 275, 694, 714 Selective internal radiation therapy, 573
Rifampin, 65 S. paratyphi, 269–270 Selective serotonin reuptake inhibitors,
Rifaximin S. typhi, 269–271 209–210
diarrhea treated with, 47 S. typhimurium, 269 Selenium, 599
hepatic encephalopathy treated with, splenic abscess, 260 Self-esteem, 647
444 vaccines for, 274 Senna, 48
irritable bowel syndrome treated Salmonellosis, 269 Sentinel acute pancreatitis event
with, 210 etiology of, 269 hypothesis, 509
travelers’ diarrhea treated with, 245t nontyphoidal Sepsis, 609, 612
Right hemicolectomy, 564 antibiotic resistance in, 275 kwashiorkor and, 602
Rimonabant, 640 antibiotics for, 277t protein catabolism and, 603
Rings bacteremia caused by, 276 Sepsis with hypotension, catheter and,
B, 115, 115f clinical manifestations of, 275–276 620
esophageal, 115, 115f control of, 278 Serine protease inhibitor kasal type 1
Rosuvastatin, 656 diagnosis of, 276–277 (SPINK1), 499, 514
Rotavirus, 299t, 300f, 302, 695, 715 endovascular infections caused by, Serotonin, 561–562
clinical features of, 45t, 243t, 300t, 276 appetite regulation, 639
303–304 epidemiology of, 274–275 atypical carcinoid syndromes and,
diagnosis of, 46, 299t, 304 gastroenteritis associated with, 556f
epidemiology of, 243, 299t, 302–303, 275–276 foregut tumors and, 552
305f genital tract infections caused by, 276 typical carcinoid syndromes, 556f
764 Index
Spider angioma, 71, 334, 432, 433f Steatorrhea, 49, 53, 156, 159 Subacute thyroiditis, 18
Spinal cord disease/injury, 55 in bacterial overgrowth syndrome, Subdiaphragmatic abscess, 6t
Spiral enteroscopy, 91, 91f 173 Submucosal plexus, 42
Spironolactone, 74, 442 detection of, 164–165 Substance P, 28, 42, 561
Spleen etiology of, 160, 164–165, 169t Subtotal gastrectomy, 522
infarction of, 6t nonenteric coated enzymes and, 512 Sucralfate
rupture of, 6t pancreatic exocrine function action of, 141
Splenectomy, 260 assessment in, 167 adverse effects of, 141
Splenic abscess in protein-losing enteropathy, 175 gastroesophageal reflux disease treated
abdominal pain in, 6t, 260 in short bowel syndrome, 172 with, 40
clinical features of, 260 in Whipple’s disease, 174 peptic ulcer disease treated with,
etiology of, 260 Steatosis 139t, 141
treatment of, 260 hepatic, 194 Sudan III stain, 164
Splenomegaly macrovesicular, in nonalcoholic fatty Sudeck’s point, 223f, 223–224
abdominal swelling in, 71 liver disease, 455, 455t Sulfasalazine, 195, 196t
in cirrhosis, 441 Stents, 99, 99f Sulfonylureas, 634
hepatocellular carcinoma and, 537 Steroid hormones, 634 Sulindac, 68
in liver disease, 334 Stevens-Johnson syndrome (SJS), Sumatriptan, 36
Spur cell anemia, 65 13t, 22f Sunitinib, 524
Squamous cell carcinoma, of esophagus, Stomach Superficial gastritis, 153
518 function of, 80 Superior mesenteric artery occlusion,
SRI. See Systemic response to tumors of, 520 4, 33
inflammation Stomatitis, 176t Surgery
SSRIs. See Selective serotonin reuptake Stone extraction, 512 hepatocellular carcinoma treated
inhibitors Stool with, 540
Staging anion concentrations in, 157 insulinomas and, 567
colorectal cancer, 528–530, 530t electrolytes in, 157 obesity treated with, 641f, 641–642
gastric carcinoma, 522t fasting effects on, 156–157 pancreatic abscess and, 507
hepatocellular carcinoma, 537–538 occult blood in, 524 pancreatic cancer, 549
pancreatic cancer and, 549, 550f osmolality of, 157 somatostatinoma syndrome and, 568
Stagnant bowel syndrome, 173, 177 in pancreatic disease evaluation, 492t Surgical debridement, 506
Staphylococcus aureus infections retained, 71 Surgical debulking, 567
continuous ambulatory peritoneal vomiting of, 34 Surgical mortality, from bariatric
dialysis-related peritonitis, 256 Stool analysis, 52 surgery, 641
diarrhea in, 44, 45t Stool culture, 46 Surgical resection
food-borne, 44, 45t, 243, 244t, 691, Stool osmolality gap, 707 gastric adenocarcinoma and, 523
712 Stool-bulking agents, 208–209 hepatocellular carcinoma and, 540, 542
nausea and vomiting in, 33 Strawberry gums, 10 nonmetastatic carcinoid tumors and,
parotitis, 18 Streptococcus bovis bacteremia, 527 564
psoas abscess, 261 Streptozotocin, 572 PETs and, 566
splenic abscess, 260 Stress-related gastric mucosal injury, 59 Survival rate
Staphylococcus epidermis, 620 “String sign,” in Crohn’s disease, advanced pancreatic cancer and, 549,
STARR (stapled transanal rectal 187, 188 551, 551t
resection) procedure, 217, Stroke gastric adenocarcinoma and, 522–523
217f dental care after, 19 Swallowing
Starvation dysphagia in, 29 physiology of, 27–28, 28f
marasmus and, 602 Strongyloides stercoralis/strongyloidiasis, tests of, 31
metabolic rate and, 603 696, 716 Sweet’s syndrome, 193
protein catabolism and, 603 clinical features of, 321t, 323–324 Sympathomimetic adrenergic agents,
Statins, 656 diagnosis of, 324–325 640
hepatotoxicity caused by, 395 epidemiology of, 323 Syndrome X. See Metabolic syndrome
triglycerides and, 656 inflammatory bowel disease vs., Syndromes of obesity, comparison, 630t
Stauffer’s syndrome, 69 191t, 192 Syphilis
Steatohepatitis, nonalcoholic life cycle of parasite, 321t, 323, 324f abdominal pain in, 5
cirrhosis caused by, 434–435 treatment of, 321t, 325 congenital, 12t
diagnosis of, 335t Subacute necrosis, 368 secondary, 10, 12t
766 Index