eMedicine Specialties > Pulmonology > Obstructive Airways Diseases

Emphysema

Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital
Contributor Information and Disclosures

Updated: Jun 14, 2006

Introduction

Background

The word emphysema is derived from Greek and means "to blow into," hence "air containing" or "air inflated." The term emphysema was initially applied to air within the tissues (ie, subcutaneous emphysema). In 1721, Ruysch described large air spaces in lung specimens of humans as emphysema. In 1799, Matthew Bailey subsequently provided the first clear illustration and description of emphysema as enlarged air spaces. Laennec contributed considerably to the understanding of emphysema and recognized that emphysema is associated with chronic bronchitis. In 1939, Cournand introduced the notion that emphysema causes airflow obstruction.

Emphysema is defined as abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of the walls and without obvious fibrosis. The 3 described morphological types of emphysema are centriacinar, panacinar, and paraseptal.

The first type, centriacinar emphysema, begins in the respiratory bronchioles and spreads peripherally. Also called centrilobular emphysema, this form is associated with long-standing cigarette smoking and predominantly involves the upper half of the lungs.

The second type is panacinar emphysema, which destroys the entire alveolus uniformly and is predominant in the lower half of the lungs. This type of emphysema generally is observed in patients with homozygous alpha1-antitrypsin (AAT) deficiency. In people who smoke, focal panacinar emphysema at the lung bases may accompany centriacinar emphysema.

The third type, distal acinar emphysema (also known as paraseptal emphysema), preferentially involves the distal airway structures, alveolar ducts, and alveolar sacs. The process is localized around the septae of the lungs or pleura. Although airflow frequently is preserved, the apical bullae may lead to spontaneous pneumothorax. Giant bullae occasionally cause severe compression of adjacent lung tissue.

Pathophysiology

Emphysema commonly presents with chronic bronchitis, and the pathological changes occur not only in the lung parenchyma but also in the large and small airways. Chronic bronchitis is characterized by mucous gland enlargement, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucus plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis. These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

Emphysema, on the other hand, is characterized by focal destruction limited to the airspaces distal to the respiratory bronchioles. Both emphysematous destruction and small airway inflammation often are found in combination in individual patients. When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the mechanism of airflow limitation. By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the airflow limitation. Although air flow obstruction in emphysema is virtually irreversible, bronchoconstriction due to inflammation accounts for a limited amount of reversibility.

Pathogenesis

Pathologically, various lesions may be found in the airways of emphysematous lungs. Some are the lesions of chronic bronchitis; others affect the small airways. The vascular changes develop simultaneously. Abnormal longitudinal muscle appears in the intima of arterioles and arteries; these may show intimal fibrosis and thickening of the muscular media. Enlargement of bronchial arteries and veins occurs in some patients. Bronchial venous enlargement may cause shunting of systemic venous blood to the left atrium.

Cigarette smoking

Cigarette smoking leads to neutrophil activation and retention in the lung parenchyma. A number of neutrophil-derived and macrophage-derived enzymes known as proteinases and elastases (ie, proteolytic enzymes) can destroy various components of the extracellular matrix of the lung and cause emphysema. In addition, neutrophils produce serine proteinases. Macrophages synthesize various metalloproteinases and cysteine proteinases.

Proteinase/antiproteinase hypothesis

Normally, the locally synthesized plasma proteinase inhibitors, especially AAT, permeate the lung tissue and prevent proteolytic enzymes from digesting structural proteins of the lungs. Lung destruction results from an excess of proteinase release in the lungs, a reduction in the antiproteinase defense within the lung, or a combination of both increased proteinase burden and decreased proteinase inhibitor capacity. Therefore, emphysema is the product of an imbalance between the proteinases and antiproteinases in favor of proteinases.

Role of inflammation in COPD

In contrast to the eosinophil, which is the most prominent inflammatory cell in asthma, the cellular composition of the airway inflammation in COPD is predominantly mediated by the neutrophils. Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, thus unleashing tissue destruction. Severity of airflow obstruction has correlated with greater induced sputum neutrophilia that is also more prevalent in patients with chronic cough and sputum production and is associated with an accelerated decline in lung function.

Macrophages also play an important role through macrophage-derived matrix metalloproteinases (MMPs). Cigarette smoke causes neutrophil influx and is required for the secretion of MMPs, therefore suggesting that both neutrophils and macrophages are required for the development of emphysema. Studies have also shown that T lymphocytes, particularly CD8+, in addition to the macrophages, play an important role in the pathogenesis of smoking-induced airflow limitation. To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation occurs in surgical specimens from patients without COPD versus patients with mild or severe emphysema.

Alpha1-antitrypsin deficiency

AAT is a glycoprotein member of the serine protease inhibitor family that is synthesized in the liver and is secreted into the blood stream. The main purpose of this 394–amino acid, single-chain protein is to neutralize neutrophil elastase in the lung interstitium and to protect the lung parenchyma from elastolytic breakdown. Severe AAT deficiency predisposes to unopposed elastolysis with clinical sequela of early onset of panacinar emphysema.

Deficiency of AAT is inherited as an autosomal codominant condition. The gene is located on the long arm of chromosome 14 and has been sequenced and cloned. The most common type of severe AAT deficiency occurs in individuals who are homozygous for the Z-type protein. Homozygous individuals (PIZZ) have serum levels well below the reference range levels (reference range is 20-53 mmol/L). The risk of emphysema occurs below a threshold of 11 mmol/L.

Frequency

United States

Four to 6% of male adults and 1-3% of female adults are estimated to have emphysema.

Current estimates suggest that 60,000-100,000 Americans have severe AAT deficiency, but only 4% have been identified. The major risk factor for developing emphysema among PIZZ individuals is cigarette smoking, which accelerates the onset of dyspnea by 19 years.

International

Few data are available on the prevalence of chronic obstructive pulmonary disease (COPD) worldwide, but it is likely higher than in the United States. In addition, the rates are rising as more than 1.2 billion humans are exposed to the ravages of cigarette smoking.

Based on pooled data from a number of studies, global prevalence of COPD was 7.5%, chronic bronchitis alone was 6.4%, and emphysema alone was 1.8%. The prevalence from 26 spirometric estimates was 8.9%. The most common spirometric definitions were those of the Global Initiative for Obstructive Lung Disease (GOLD). Thus, the prevalence of physiologically defined COPD in adults aged 40 years and older is approximately 9-10%.

Mortality/Morbidity

In recent decades, the death rates in the United States have been rising. COPD is now the fourth most common cause of death, accounting for nearly 4.5% of all deaths. Furthermore, COPD may be a contributory factor in another 4.3% of deaths.

Sex

Estimates show that 4-6% of white male adults and 1-3% of white female adults have emphysema or COPD. Men have a higher mortality rate than women.

Clinical

History

Most patients with emphysema have smoked at least 20 cigarettes per day for 20 or more years before the common symptoms of cough and dyspnea develop.

• Commonly, patients present in their fifth decade of life with productive cough or acute chest illness. The cough usually is worse in the morning and produces small amounts of colorless sputum from concomitant chronic bronchitis.
• Breathlessness, the most significant symptom, does not occur until the sixth decade of life. By the time forced expiratory volume in 1 second (FEV₁) has fallen to 30% of predicted, the patient is breathless on minimal exertion.
• Wheezing may occur in some patients, particularly during exertion and exacerbations.
• With disease progression, the intervals between acute exacerbations become shorter; cyanosis and right heart failure may develop.
• Alpha1-antitrypsin deficiency
  • Severe AAT deficiency mainly affects the lungs and the liver. Liver dysfunction dominates the clinical picture in the first decade of life. The patients who are homozygous (ie, PIZZ) develop emphysema with the following distinctive features: early presentation ( <50 y), predilection for the lung bases, and panacinar morphological pattern.
  • Bronchiectasis and asthma also are associated with AAT deficiency.

Physical

The sensitivity of the physical evaluation in mild-to-moderate disease is relatively poor; however, the physical signs are quite sensitive and specific for severe disease. Patients with severe disease experience tachypnea and respiratory distress with simple activities.

• The respiratory rate increases in proportion to disease severity. Use of accessory respiratory muscles and paradoxical indrawing of lower intercostal spaces are evident.
• In advanced disease, cyanosis, elevated jugular venous pressure (JVP), and peripheral edema can be observed.
• Measurement of the forced expiratory time (FET) maneuver is a simple bedside test; FET greater than 6 seconds indicates severe expiratory airflow obstruction.
• Thoracic examination reveals hyperinflation (ie, barrel chest), wheezing, diffusely decreased breath sounds, hyperresonance on percussion, and prolonged expiration.

Causes

Cigarette smoking is by far the single most clearly established environmental risk factor for emphysema. The prevalence and incidence of emphysema are increased in relation to smoking by 2.8 times. Mortality rates from emphysema are increased substantially in people who smoke for more than 20 pack years. Emphysema also develops in patients who have AAT deficiency syndrome. The other causes of emphysema are described below.

• Persons who use intravenous drugs
  • Emphysema occurs in approximately 2% of persons who use intravenous drugs and is attributed to pulmonary vascular damage that results from the insoluble filler (eg, cornstarch, cotton fibers, cellulose, talc) contained in methadone or methylphenidate.
  • The bullous cysts found in association with IV use of cocaine or heroin occur predominantly in upper lobes. In contrast, methadone and methylphenidate injections are associated with basilar and panacinar emphysema.
• Immune deficiency syndromes
  • Apical and cortical bullous lung damage occurs in patients who have autoimmune deficiency syndrome and Pneumocystis carinii infection. Reversible pneumatoceles are observed in 10-20% of patients with this infection.
  • Human immunodeficiency virus (HIV) infection is associated with development of emphysemalike disease, to which malnutrition, direct cytotoxicity, and enhanced cytokine or elastase release contribute.
• Vasculitis syndrome
  • Hypocomplementemic vasculitis urticaria syndrome (HVUS) may be associated with obstructive lung disease.
  • Other symptoms
    • Angioedema
    • Nondeforming arthritis
    • Sinusitis
    • Conjunctivitis
    • Pericarditis
  • Emphysema develops in more than one half of patients.
• Connective tissue disorders
  • Cutis laxa is a disorder of elastin that is characterized most prominently by the appearance of premature aging. The disease usually is congenital, with various forms of inheritance (ie, dominant, recessive). Precocious emphysema has been described in association with cutis laxa as early as the neonatal period or infancy. The pathogenesis of this disorder includes a defect in the synthesis of elastin or tropoelastin.
  • Marfan syndrome is an autosomal dominant inherited disease of type I collagen characterized by abnormal length of the extremities, subluxation of the lenses, and cardiovascular abnormality. Pulmonary abnormalities, including emphysema, have been described in approximately 10% of cases.
  • Ehlers-Danlos syndrome refers to a group of inherited connective tissue disorders with manifestations that include hyperextensibility of the skin and joints, easy bruisability, and pseudotumors.
• Salla disease
  • Salla disease is an autosomal recessive storage disorder described in Scandinavia; the disease is characterized by intralysosomal accumulation of sialic acid in various tissues.
  • The most important clinical manifestations are severe mental retardation, ataxia, and nystagmus.
  • Precocious emphysema has been described and likely is secondary to impaired inhibitory activity of serum trypsin.
• HIV is a risk factor of premature development of emphysema. These patients also smoke cigarettes heavily and present in the fifth decade of life with the clinical symptoms of emphysema.

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