What are the causes of generalized emphysema?

Causes of Generalized Emphysema

The primary causes of generalized emphysema are cigarette smoking and alpha-1 antitrypsin (AAT) deficiency, with cigarette smoke being the most common cause worldwide. 1

Major Etiologic Factors

Cigarette Smoking

• Cigarette smoking is the most common cause of emphysema globally, inducing chronic inflammatory responses and oxidative stress in the lungs that lead to alveolar destruction. 1, 2
• Cigarette smoke causes emphysema through four distinct mechanisms: oxidative stress, inflammation, protease-induced degradation of the extracellular matrix, and enhanced alveolar epithelial and endothelial cell apoptosis. 2, 3
• Oxidants in cigarette smoke inactivate AAT by converting the active site Met358 to methionine sulfoxide, reducing the association constant for neutrophil elastase by approximately 2,000-fold. 1
• Cigarette smoke recruits inflammatory cells, particularly neutrophils, which contribute to greater neutrophil elastase load in the airways. 1

Alpha-1 Antitrypsin Deficiency

• AAT deficiency is one of the most common genetically conditioned causes of emphysema, though it remains underdiagnosed in clinical practice. 1, 4
• Fewer than 60% of individuals with severe AAT deficiency develop significant airflow limitation, suggesting that AAT deficiency alone is often insufficient to induce emphysema without additional factors. 1
• The PIZZ phenotype carries the highest risk, with serum AAT levels of 20-45 mg/dl (compared to normal PIMM levels of 150-350 mg/dl). 1
• A serum level of less than 11 μM is associated with increased risk for emphysema development. 1
• Z AAT inhibits neutrophil elastase at a slower rate than normal M AAT (4.5 versus 9 M⁻¹ second⁻¹), providing qualitatively less functional protection. 1

Other Inhaled Noxious Particles and Gases

• Occupational exposures and biomass fuel smoke contribute to emphysema development, particularly in non-smoking populations. 1, 4
• A documented case involved a 52-year-old non-smoking farmer who developed generalized emphysema after 37 years of spraying orchards, demonstrating occupational chemical exposure as a causative factor. 4
• Air pollution represents an additional environmental risk factor for emphysema development. 2

Pathogenic Mechanisms

Protease-Antiprotease Imbalance

• Emphysema develops when elastin fiber repair mechanisms are overwhelmed by massive elastase attack from inflammatory reactions. 1
• The protease-antiprotease imbalance is central to pathogenesis, with neutrophil elastase destroying alveolar structures when AAT protection is inadequate. 1

Combined Risk Factors

• The combination of cigarette smoking and AAT deficiency creates synergistic risk, as smoking further impairs already compromised AAT function both quantitatively and qualitatively. 1
• Cigarette smoke and proteinases both impair lung elastin resynthesis, preventing normal repair mechanisms. 1
• Leukotriene B4 released from alveolar macrophages acts as a neutrophil chemotactic factor, perpetuating inflammation in AAT-deficient individuals. 1

Clinical Pitfalls

A critical diagnostic pitfall is the failure to test for AAT deficiency in patients with early-onset emphysema or emphysema in non-smokers. 4 The case literature demonstrates diagnostic delays of up to 10 years between symptom onset and diagnosis, representing missed opportunities for lifestyle modification and targeted treatment. 4

Diagnostic testing for AAT deficiency should be performed in all patients with:

• Emphysema or symptomatic COPD identified at an early age (typically before age 45). 4
• Generalized emphysema pattern on imaging. 4
• Emphysema in non-smokers or minimal smoking history. 4
• Family history of emphysema or liver disease. 1