Emphysema

2021
Definition
Emphysema and chronic bronchitis are airflow-limited states contained
within the disease state known as
chronic obstructive pulmonary disease (COPD). [1]
Emphysema is pathologically defined as an abnormal permanent
enlargement of air spaces distal to the terminal bronchioles, accompanied
by the destruction of alveolar walls and without obvious fibrosis. [1]
Risk factor
Genetic risk factor: alpha-1-antitrypsin (AAT) deficiency (also known as alpha-1 antiprotease deficiency)

○ a glycoprotein member of the serine protease inhibitor family

○ synthesized in the liver and is secreted into the blood stream
○ 394–amino acid, single-chain protein
○ to neutralize neutrophil elastase in the lung interstitium and to protect the lung parenchyma from
elastolytic breakdown. If not inactivated by AAT, neutrophil elastase destroys lung connective tissue
leading to emphysema.
■ inherited as an autosomal codominant condition
■ located on the long arm of chromosome 14
■ expresses different phenotypes (serum protease inhibitor phenotype notated Pi type).
■ homozygous for the Z allele - Pi ZZ (more than 90%)
■ usually of northern European descent
■ serum levels well below the reference range levels at about 20% of the normal level (2.5 to 7
mmol/L)

But, lifetime nonsmokers who are homozygous for the Z allele rarely develop emphysema.

Cigarette smoking is the most important risk factor for emphysema development in individuals with AATD.
Risk factor

● Tobacco smoke is a key factor

● exposure to air pollutants in the
home and workplace, genetic
factors, and respiratory
infections also play a role
● exposure to biomass cooking of
liquids and fuels, including wood,
crops, animal dung, and coal
● poor ventilation of the home and
dependent family members’
(children and elderly persons)
Pathopysiology
Once innate respiratory defenses of the lung’s epithelial cell barrier and mucociliary transport
system are infiltrated by foreign/invading antigens (noxious cigarette ingredients)

The responding inflammatory immune cells (polymorphonuclear cells, eosinophils, macrophages,

CD4 positive and CD8 positive lymphocytes) transport the antigens to the bronchial associated
lymphatic tissue layer (BALT). These cells release chemotactic factors/pro-inflammatory cytokines
that amplify the inflammation.

The inflammation is further amplified by oxidative stress and protease production.

●Oxidants are produced from cigarette smoke and released from inflammatory cells.
●This protease is elastase, released by macrophages, and responsible for breakdown of the
lung’s fragile elastic lamina (of which elastin is a structural protein component).
Pathopysiology

The repair process of airway remodeling exacerbates emphysema’s anatomical

derangements with key characters such as vascular endothelial growth factor
(VEGF).

It is these structural changes of mucus hyperplasia, bronchiolar edema, and smooth

muscle hypertrophy and fibrosis in smokers’ airways that result in the small airways
narrowing of less than two millimeters.
Morphology
The described morphological pathology of region-specific emphysema remains in three
types:
●Centriacinar emphysema - most common type, mainly localized to the proximal
respiratory bronchioles with focal destruction and predominantly found in the upper
lung zones.
●Panacinar emphysema - destroys the entire alveolus uniformly, in the lower half of the
lungs, observed in patients with homozygous (Pi ZZ) alpha1-antitrypsin (AAT) deficiency
●Paraseptal emphysema - preferentially involves the distal airway structures, alveolar
ducts, and alveolar sacs; localized around the septae of the lungs or pleura; the apical bullae
Morphology
CENTRILOBULAR EMPHYSEMA
PANLOBULAR EMPHYSEMA
PARASEPTAL EMPHYSEMA
Etiology
● Smoking is by far the single most clearly established environmental risk factor for emphysema/chronic
bronchitis. Eight out of 10 cases of COPD are caused by smoking.
● Chronic occupational exposure to inhaled mineral dusts, metal fumes, organic dusts (e.g. wood, grains),
diesel exhaust fumes, and/or chemical gases or vapors is estimated to be the cause of 19.2% of COPD in
smokers and 31.1% of COPD in individuals with no history of smoking.
● Alpha-1 antitrypsin deficiency (AATD), which results in damage to the delicate gas exchange region of
the lungs (alveoli), eventually leading to emphysema in individuals as young as 30 years of age. Among
patients with COPD, up to 3% are estimated to have AATD.
● Emphysema occurs in approximately 2% of persons who use intravenous drugs.
● Human immunodeficiency virus (HIV) infection was found to be an independent risk factor.
● Hypocomplementemic vasculitis urticaria syndrome (HVUS)
● Cutis laxa, a disorder of elastin
● Marfan syndrome is an autosomal dominant inherited disease of type I collagen
● Ehlers-Danlos syndrome refers to a group of inherited connective-tissue disorders with manifestations
● Salla disease is an autosomal recessive storage disorder
Epidemiology
Chronic lower respiratory disease, primarily COPD, is the third leading cause of death in the United States and the
fourth leading cause of death worldwide, although it may become the fourth global cause of death in 2020.

Alpha-1 antitrypsin deficiency (AATD) is among the most prevalent potentially fatal genetic disorders in the U.S.,
and occurs approximately equally in men and women.

The incidence of AADT among whites is estimated between 1/2500 and 1/3000.

Among patients with COPD, up to 3% have AATD. The overwhelming majority of individuals with AATD have not
been diagnosed; approximately 10% of the individuals in the United States estimated to have AATD have received
a diagnosis.

Alpha-1 antitrypsin deficiency (AATD) has been identified in virtually all populations but is most common in
individuals of Scandinavian, British, Spanish and Portuguese descent.
Prognosis
A correlation has been established between radiographic severity of emphysema and mortality.

COPD and higher serum alpha-1 antitrypsin levels also have a worse systemic inflammation status
and higher 10-year mortality.

Comorbidities are common with COPD and have a significant impact on prognosis. Lung cancer,
Gastroesophageal reflux (GERD), Osteoporosis, anxiety, depression, Other frequent comorbidities
(metabolic syndromes, cardiovascular disease, hypertension and bronchiectasis).
History
● Dyspnea
● Chronic cough, "smoker's cough,
● Sputum production, clear-to-white sputum in the morning
● A history of exposure to risk factors
● Most patients seek medical attention late in the course of their disease, usually
ignoring smoldering symptoms that start gradually and progress over the
course of years.
● Patients will adapt and modify their lifestyles
● A multiyear history (fifth decade of life)
● Wheezing
AAT-deficient patients present earlier than other COPD patients, usually in their
fourth or fifth decade of life, with severe AAT deficiency mainly affecting the
lungs and the liver.
Physical examination
Longer to exhale than it does to inhale

Measurement of the forced expiratory time maneuver (a forced expiratory time more than 6 seconds
indicates severe expiratory airflow obstruction); FEV1/FVC ratio - the spirometry portion of pulmonary
function testing

The physical signs are quite sensitive and specific in severe disease - tachypnea and dyspnea with mild
exertion

The RR increases in proportion to disease severity

In end-stage emphysema: cyanosis, elevated jugular venous pressure, atrophy of limb musculature, and
peripheral edema due to the development of PHT, right-to-left shunting, and/or right heart failure

Thoracic examination: a 2:1 increase in anterior to posterior diameter (“barrel chest”), diffuse or focal
wheezing, diffusely diminished breath sounds, hyperresonance upon percussion, prolonged expiration,
and/or hyperinflation on chest radiographs
Differential diagnoses
Congestive heart failure: wheezing - is often difficult to differentiate from emphysema. A history
of orthopnea, paroxysmal nocturnal dyspnea, the presence of fine basal crackles, typical findings
on chest radiographs

Bronchiectasis: chronic production of copious purulent sputum, coarse crackles, clubbing upon
physical examination, abnormal findings on chest radiographs and CT scans

Bronchiolitis obliterans: in younger persons who do not smoke, in persons with collagen-
vascular diseases. A CT scan - areas of mosaic attenuation without evidence of generalized
emphysema

Chronic asthma: the important distinction is a significant bronchodilator response and normal
diffusion (ie, diffusing capacity of lung for carbon monoxide [DLCO]) on pulmonary function tests
Laboratory studies
Arterial blood gas analysis
Hematocrit: Chronic hypoxemia may lead to polycythemia.
Serum bicarbonate: Chronic respiratory acidosis leads to compensatory metabolic alkalosis. In
the absence of blood gas measurements, serum bicarbonate levels are useful for following
disease progression.
Sputum evaluation: mucoid and the predominant cells are macrophages. With an exacerbation,
the sputum becomes purulent, with excessive neutrophils and a mixture of organisms visualized
through Gram staining (Streptococcus pneumoniae and Haemophilus influenzae)
AATD-related emphysema: liver ultrasound, laboratory testing of AST, ALT, GGT, albumin, bilirubin,
INR, and platelets
AATD Testing: All individuals with COPD regardless of age or ethnicity should be tested for
AATD. The diagnosis of severe AAT deficiency is confirmed when the serum level falls below the
protective threshold value (ie, 3-7 mmol/L).
Proteinase inhibitor (Pi) typing and/or AAT genotyping; expanded genotyping for rare AAT alleles
and gene sequencing- Confirmatory testing
Imaging studies
Chest radiographs
●flattened
diaphragms
●increased
retrosternal space
●hyperlucency of the
lung parenchyma
 High-resolution CT (HRCT)
scanning

● emphysematous bullae in
the upper lobes
Pulmonary function test - spirometry
Total lung capacity, functional residual capacity, and residual volume are
increased. The vital capacity is decreased.

DLCO is decreased in proportion to the severity of emphysema.

Lung mechanics and gas exchange worsen during acute exacerbations.

As many as 30% of patients have an increase in FEV1 of 15% or more

after inhalation of a bronchodilator.
Treatment
The goal of therapy is to relieve symptoms, prevent disease progression, improve exercise
tolerance and health status, prevent and treat complications and exacerbations, and reduce
mortality.
Smoking cessation intervention
These stages are (1) precontemplation, (2) contemplation, (3) preparation, (4) action, and (5)
maintenance.
Smoking intervention programs include self-help, group, physician-delivered, workplace, and
community programs.
Patient education, A target date to quit, Follow-up support, Relapse prevention, Advice for healthy
lifestyle changes, Social support systems, Adjuncts to treatment (ie, pharmacological agents).
“5-A” approach to counseling: /The US Preventive Services Task Force guideline /

●Ask about tobacco use.

●Advise to quit through personalized messages.
●Assess willingness to quit.
●Assist with quitting.
●Arrange follow-up care and support.
Nicotine replacement therapies

A person who smokes and who requires the first cigarette within 30 minutes of
waking is likely to be highly addicted and would benefit from nicotine
replacement therapy.
●Nicotine polacrilex is a chewing gum
●Transdermal nicotine patches
●The use of an antidepressant medication, bupropion at 150 mg
●Varenicline is approved for smoking cessation. This agent is a partial agonist
selective for alpha4, beta2 nicotinic acetylcholine receptors.
Medical management
Bronchodilators alone: SABA (beta2-agonists and anticholinergic agents), LABA (long-acting
beta agonists and oral phosphodiesterase inhibitors such as theophylline)
In combination with anti-inflammatory drugs (eg, corticosteroids, phosphodiesterase-4 inhibitors)
Supportive care (eg, oxygen therapy, ventilatory support, pulmonary rehabilitation, palliative
care)
Antibiotics: The patients who benefited most from antibiotic therapy were those with
exacerbations that were characterized by at least two of the following: increases in dyspnea,
sputum production, and sputum purulence (The Winnipeg criteria).
Mucolytic agents: Although mucolytic agents have been shown to decrease cough and chest
discomfort, they have not been shown to improve dyspnea or lung function.
Oxygen therapy: for use during sleep
Diet: Nutritional support is an important part of comprehensive care.
Alpha1-antitrypsin deficiency
The treatment strategies for alpha1-antitrypsin (AAT) deficiency involve:
●reducing the neutrophil elastase burden
●primarily by smoking cessation
●augmenting the levels of AAT:
○ to increase endogenous production of AAT by the liver (ie, danazol, tamoxifen)
○ administration of purified AAT by periodic intravenous infusion or by
inhalation
Tamoxifen may be beneficial in persons with the Pi ZZ phenotype.
Intravenous augmentation therapy is the only available approach that can increase
serum levels to greater than 11 mmol/L, the protective threshold. Replacement is
administered weekly (60 mg/kg), biweekly (120 mg/kg), or monthly (250 mg/kg).
Surgical Care
Bullectomy

Giant bullae may compress adjacent lung tissue, reducing the blood flow and ventilation to the relatively healthy
lung. Removal of these bullae may result in expansion of compressed lungs and improvement of lung function.

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) attempts to decrease hyperinflation by surgically resecting the most diseased
parts of the lung. This improves airflow by increasing the elastic recoil of the remaining lung and the mechanical
efficiency of the respiratory muscles to generate expiratory pressures.

Lung volume reduction surgery is not recommended for patients with AATD-related emphysema.

Endobronchial valve placement

Endobronchial valve placement through bronchoscopy is under investigation as an alternative to LVRS. These valves
are unidirectional and allow exhalation but do not allow inhalation.

Lung transplantation

Lung transplantation provides improved quality of life and functional capacity but does not result in survival benefit.
The patients selected to receive transplants should have a life expectancy of 2 years or less.
References
https://emedicine.medscape.com/

https://www.osmosis.org/

https://www.uptodate.com/
Thank you for your attention!