Treatment for Alpha-1 Antitrypsin (A1AT) Deficiency
Alpha-1 antitrypsin augmentation therapy is conditionally recommended for patients with COPD who have documented emphysema, FEV1 <80% predicted, severely reduced A1AT levels (<11 mmol/L or <0.57 g/L), and documented SERPINA1 genotypes associated with A1AT deficiency. 1
Diagnostic Approach
Before initiating treatment, proper diagnosis is essential:
- Testing for A1AT deficiency is conditionally recommended in all individuals with COPD at diagnosis, those with adult-onset asthma with persistent airflow obstruction, and individuals with unexplained bronchiectasis 1
- For patients with high clinical suspicion (early-onset COPD <40 years, COPD with low tobacco exposure <10 pack-years, basal pan-lobular emphysema, family history of COPD or A1AT deficiency), both serum A1AT levels and genetic testing with DNA sequencing of SERPINA1 gene are recommended 1
- For moderate clinical suspicion, initial measurement of serum A1AT levels should be performed, with genetic testing if levels are <23 mmol/L (1.2 g/L) 1
Treatment Algorithm
1. Augmentation Therapy
Indicated for patients who meet ALL the following criteria:
- Never or previously smoked (must be smoke-free for at least 6 months) 1
- FEV1 <80% predicted 1
- Documented emphysema 1
- Documented SERPINA1 genotypes associated with A1AT deficiency 1
- Severely reduced functional A1AT level (<11 mmol/L or <0.57 g/L) 1, 2
- Not received a lung transplant 1
2. Standard COPD Management
All patients with A1AT deficiency should receive optimal standard COPD care:
- Bronchodilators for symptomatic relief, even when objective bronchodilator responsiveness may be lacking 1
- Inhaled steroids for those with bronchial hyperreactivity 1
- Aggressive antibiotic treatment for respiratory infections, with macrolides potentially reducing neutrophil inflammation 1
- Oxygen therapy for those with hypoxemia 1
3. Preventive Measures
- Smoking cessation is critical - early cessation significantly reduces FEV1 decline 1
- Influenza and pneumococcal vaccinations 1
- Minimize exposure to respiratory irritants (second-hand smoke, dusts, fumes) 1
- Consider occupational changes if frequent exposure to respiratory irritants occurs 1
- Hepatitis testing and vaccination (especially for patients with liver disease) 1
- Pulmonary rehabilitation 1
- Self-management education 1
Efficacy and Limitations
- Augmentation therapy increases antigenic and functional levels of A1AT in both serum and lung epithelial lining fluid 2
- Therapy has been shown to preserve CT scan lung density and potentially reduce mortality 1
- However, the effect on pulmonary exacerbations and progression of emphysema has not been conclusively demonstrated in randomized controlled trials 2
- The clinical benefit of increased blood levels of A1AT at recommended doses has not been definitively established 2
Special Considerations
- Genetic testing is particularly important as some variants (like Pi*F) may have normal A1AT levels but dysfunctional protein 1
- Due to variability in A1AT protein serum levels, SERPINA1 sequencing is recommended before starting augmentation therapy 1
- Early diagnosis and treatment are crucial as delayed diagnosis (average 5.3 years after first clinical manifestations) is associated with worse overall survival 1
- Family screening should be considered for relatives of individuals identified with abnormal A1AT genes 1
Emerging Treatments
Research is ongoing for alternative treatment approaches:
- Inhaled and oral delivery methods for augmentation therapy 1
- Gene therapies targeting correction of A1AT protein misfolding 1, 3
- RNA editing approaches that may modify the underlying genetic defect 3
Alpha-1 antitrypsin deficiency remains underdiagnosed despite being one of the most common inherited conditions (affecting about 1 in 2000 to 5000 people) 4. Early diagnosis and prompt initiation of augmentation therapy are essential to slow the progression of lung disease in affected patients.