Causes of Emphysema in Non-Smokers
Alpha-1 antitrypsin (AAT) deficiency is the primary genetic cause of emphysema in non-smokers and must be tested in any patient presenting with emphysema without significant smoking history. 1
Alpha-1 Antitrypsin Deficiency - The Primary Genetic Cause
AAT deficiency is the only established genetic disorder that causes emphysema and COPD, and represents the most important consideration in non-smoking patients with emphysema. 1
Key Phenotypes and Risk Levels
PI*ZZ phenotype (serum AAT levels <35% of normal) carries the highest risk for emphysema development even without smoking, with nonsmoking PI*ZZ individuals showing FEV1 decline of 47 ml/year compared to 70 ml/year in smokers 2
PI*SZ phenotype has moderately increased risk regardless of AAT levels being above or below 11 μM 1
PI*MZ heterozygotes may develop emphysema when exposed to additional environmental stressors, though risk is lower than homozygous variants 1
Nonsmoking PI*ZZ patients can have median life expectancy of 69 years (similar to normal population), but demonstrate wide variance in lung function even among never-smokers 2
Clinical Testing Recommendations
Testing for AAT deficiency should be performed in: 1
- All patients with emphysema without significant smoking history
- Early-onset emphysema (typically before age 45)
- Siblings and first-degree relatives of AAT-deficient individuals
- Patients with asthma characterized by incompletely reversible airflow obstruction
- Patients with unexplained liver cirrhosis
Occupational and Environmental Exposures
Occupational exposures to dusts, fumes, and gases independently cause emphysema and are significantly underappreciated risk factors. 1
Specific High-Risk Exposures
Mineral dust exposure significantly reduces lung function and increases chronic cough and breathlessness 1
Cotton mill work, particularly endotoxin exposure, represents a major risk factor especially in PI*MZ individuals 1
Grain working and mining are associated with increased COPD risk 1
In nonsmoking PI*ZZ individuals over 50 years old, occupational exposure to airway irritants for at least 3 months was an independent determinant of lung function decline 2
Indoor air pollution from biomass cooking and heating increases emphysema risk 1
Employment for more than 10 years in agricultural environments and use of kerosene heaters were independent correlates of decreased lung function in nonsmoking AAT-deficient patients 2
Early Life and Developmental Factors
Abnormal lung growth and development accounts for approximately 50% of COPD cases, making this a critical and often overlooked cause. 1
Key Developmental Risk Factors
Reduced maximal attained lung function from childhood factors identifies individuals at increased risk for emphysema later in life 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
However, a prospective study of 103 Swedish children with AAT deficiency showed normal lung function when reaching adulthood, indicating childhood respiratory infections are not a major factor specifically for AAT-deficiency related emphysema 2
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
Among nonsmoking PI*ZZ individuals, symptoms of wheezing were identified as independent determinants of FEV1 decline, particularly in men over 50 years old 2
Infectious and Systemic Factors
HIV infection accelerates emphysema development even in the absence of smoking 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
Self-reported passive smoking increased risk for chronic bronchitis in AAT-deficient patients 2
However, some studies of AAT-deficient patients could not find an effect of passive smoking on emphysema development, suggesting conflicting evidence 2
Age and Sex Factors in Non-Smokers
Male sex was identified as an independent determinant of FEV1 decline in nonsmoking PI*ZZ individuals 2
Age over 50 years shows accelerated lung function decline in never-smokers with AAT deficiency, with greater rate of decline after 50 years compared to before 2
Most nonsmoking PI*ZZ individuals have normal lung function until 50 years of age, with great differences in lung function between individuals appearing after this age 2
Critical Clinical Pitfall
The most common pitfall is failing to test for AAT deficiency in patients with emphysema who have minimal or no smoking history. Diagnosis is often delayed for up to a decade, with patients seeing several clinicians before genetic testing is performed 3. The American Thoracic Society explicitly recommends testing all patients with COPD or emphysema, particularly with early onset, to avoid missing this treatable genetic condition 1.