Alpha-1 Antitrypsin Deficiency is Associated with Early Onset of Pulmonary Disease
Alpha-1 antitrypsin deficiency is primarily associated with early onset of pulmonary disease, specifically emphysema, which can develop as early as the third or fourth decade of life. 1
Pathophysiology and Clinical Presentation
Alpha-1 antitrypsin (AAT) is a critical protease inhibitor that primarily targets neutrophil elastase, an enzyme that degrades elastin and other components of the lung matrix. When AAT is deficient:
- The imbalance between elastase and anti-elastase activity leads to progressive, irreversible destruction of lung tissue 2
- Panacinar emphysema with basal predominance is seen in all adult patients with severe AAT deficiency 1
- Even in an 11-year-old child with AAT deficiency who died from liver complications, uniform panacinar emphysema was found at autopsy 1
Clinical Manifestations of Pulmonary Disease
Symptomatic obstructive lung disease in AAT deficiency typically presents between ages 32-41 years in individuals with a smoking history, which is significantly earlier than non-genetic COPD 1. Key pulmonary manifestations include:
- Dyspnea on exertion (84% of patients)
- Wheezing during respiratory infections (76%) and independent of infections (65%)
- Chronic cough (42%)
- Increased cough and phlegm production (50%)
The National Heart, Lung, and Blood Institute Registry data shows that 72% of deaths in AAT-deficient patients were due to emphysema, highlighting the predominance of pulmonary complications 1.
Diagnostic Findings
Pulmonary involvement in AAT deficiency has characteristic imaging findings:
- HRCT shows panacinar emphysema with predominant lower lobe distribution 3
- CT quantitation of emphysema is more sensitive than pulmonary function tests for detecting disease progression 3
- Pulmonary function tests typically show:
- Reduced FEV1 with normal or reduced FVC
- Obstructive impairment (reduced FEV1/FVC ratio)
- Hyperinflation with increased residual volume and total lung capacity 1
Risk Factors and Disease Progression
Smoking significantly accelerates disease progression in AAT-deficient individuals:
- Even in patients with normal lung function, there is evidence of lung inflammation with 3-fold higher neutrophil counts and 2-fold increase in protease levels 4
- This inflammatory phenotype correlates with declining lung function, suggesting that the disease process begins before clinical symptoms appear 4
Diagnostic Testing Recommendations
The Canadian Thoracic Society recommends targeted testing for AAT deficiency in:
- Individuals with early-onset COPD (before 40 years of age)
- Patients with low tobacco exposure (<10 pack-years) who develop COPD
- Those with panlobular emphysema
- Patients with a family history of COPD 1
Treatment Considerations
Alpha-1 proteinase inhibitor (A1-PI) therapy is the only available treatment that addresses the underlying disease etiology:
- Evidence from the RAPID/RAPID Extension trials confirms that A1-PI therapy slows disease progression 2
- Early introduction of treatment may delay time to death, lung transplantation, or severe respiratory complaints 2
- There is limited evidence that A1-PI therapy provides a gain of more than five life-years 2
Common Pitfalls in Diagnosis
AAT deficiency is significantly underdiagnosed despite being one of the most common inherited conditions (affecting about 1 in 2000-5000 people) 5. Common diagnostic pitfalls include:
- Misdiagnosis as asthma due to the presence of wheezing and bronchodilator responsiveness 1
- Delayed diagnosis due to lack of awareness about the condition
- Relying solely on AAT protein serum levels without genetic testing 1
To avoid these pitfalls, the American Thoracic Society recommends testing for AAT deficiency in all patients with COPD, unexplained liver disease, and adults with bronchiectasis without evident etiology 1.