What causes mild centrilobular emphysema besides smoking?

Causes of Mild Centrilobular Emphysema Beyond Smoking

The most important non-smoking cause of centrilobular emphysema is alpha-1 antitrypsin (AAT) deficiency, particularly in individuals with severe genetic variants (PIZZ, PInull-null, or PI*SZ phenotypes), though occupational and environmental exposures to dusts, fumes, and gases also contribute independently to emphysema development. 1

Genetic Causes

Alpha-1 Antitrypsin Deficiency

AAT deficiency is the only established genetic disorder that causes emphysema and COPD, and should be tested in any patient with early-onset emphysema or emphysema without significant smoking history 1, 2, 3:

• PI*ZZ phenotype: Individuals with serum AAT levels <35% of normal (below 11 μM) have significantly increased risk for emphysema even without smoking 1, 2
• PI*SZ phenotype: Serum levels range from 9-23 μM and confer moderately increased risk regardless of whether levels are above or below 11 μM 1
• PI*null-null variant: Complete absence of AAT protein in serum 2
• PI*MZ heterozygotes: May develop emphysema with additional environmental stressors, though risk is lower than homozygous variants 1

In nonsmokers with severe AAT deficiency, emphysema risk exists but is substantially lower than in those who smoke, with some never-smokers maintaining normal life expectancy 1

Occupational and Environmental Exposures

Occupational exposures to dusts, fumes, and gases independently cause emphysema and are underappreciated risk factors 1:

• Mineral dust exposure: Significantly reduces FEV1 (31% predicted vs 40% predicted in unexposed individuals) and increases chronic cough and breathlessness 1
• Cotton mill work: Endotoxin exposure is a risk factor, particularly in PI*MZ individuals 1
• Grain working and mining: Associated with increased COPD risk 1
• Indoor air pollution: Biomass cooking and heating with wood, animal dung, crop residues, and coal in poorly ventilated dwellings increases risk 1

These exposures act independently of smoking and show no interaction with tobacco use in causing airflow limitation 1

Early Life and Developmental Factors

Abnormal lung growth and development accounts for approximately 50% of COPD cases 1:

• Reduced maximal attained lung function from childhood factors identifies individuals at increased risk 1
• "Childhood disadvantage factors" are as important as heavy smoking in predicting adult lung function 1
• Severe childhood respiratory infections are associated with reduced lung function and increased respiratory symptoms in adulthood 1

Other Contributing Factors

Asthma and Airway Hyperresponsiveness

• Asthma is a risk factor for developing chronic airflow limitation and COPD 1
• Airway hyperresponsiveness without clinical asthma diagnosis independently predicts COPD development 1

Infections

• HIV infection accelerates smoking-related emphysema and COPD onset 1
• Tuberculosis is identified as both a risk factor and potential comorbidity for COPD 1

Passive Smoking

• Environmental tobacco smoke contributes to respiratory symptoms and COPD by increasing total burden of inhaled particles and gases 1
• Smoking during pregnancy affects fetal lung growth and development 1

Clinical Implications

Testing for AAT deficiency should be performed in 1:

• All patients with COPD or emphysema, particularly with early onset (before age 45)
• Patients with emphysema without significant smoking history
• Individuals with asthma characterized by incompletely reversible airflow obstruction
• Siblings and first-degree relatives of AAT-deficient individuals
• Patients with unexplained liver cirrhosis

Centrilobular emphysema typically shows upper lobe predominance, distinguishing it from the panlobular pattern with lower lobe predominance seen in severe AAT deficiency 4. However, minimal centrilobular emphysema can occur in the upper lobes even in AAT deficiency 1.

Important Caveats

• While smoking remains the dominant cause of centrilobular emphysema, approximately 50% of COPD cases develop from abnormal lung growth rather than accelerated decline 1
• The protease-antiprotease imbalance underlying emphysema can result from genetic deficiency, environmental exposures, or inflammatory processes 3, 5
• Occupational exposures are frequently overlooked but contribute substantially to disease burden 1