What is the management of Alpha 1 antitrypsin deficiency?

Management of Alpha-1 Antitrypsin Deficiency

Augmentation therapy with intravenous alpha-1 antitrypsin (AAT) is recommended for patients with severe AAT deficiency (serum levels <11 μmol/L or <0.57 g/L), documented emphysema, and FEV1 <80% predicted to slow lung function decline and reduce mortality. 1

Diagnosis and Testing

Targeted Testing Strategy

• Test for AAT deficiency in patients with:
  • COPD with emphysema, especially with early onset (<45 years)
  • Unexplained bronchiectasis
  • Adult-onset asthma with persistent airflow obstruction
  • Family history of AAT deficiency

Diagnostic Approach

1. Initial screening: Serum AAT level
2. Confirmatory testing: SERPINA1 gene sequencing (preferred over protein phenotyping)
3. CT scan to document presence and extent of emphysema

Treatment Algorithm

1. Augmentation Therapy

• Indications:

  • Severe AAT deficiency (serum levels <11 μmol/L or <0.57 g/L)
  • FEV1 <80% predicted
  • Documented emphysema on CT scan
  • Non-smoking status for at least 6 months 1

• Dosing:

  • Standard regimen: 60 mg/kg body weight administered intravenously weekly 1
  • Goal: Maintain serum AAT levels above protective threshold (>15 μmol/L)

• Efficacy:

  • Slows decline in lung function (FEV1 decline of 53 ml/year in treated vs. 75 ml/year in untreated patients) 1
  • Most beneficial in patients with moderate emphysema (FEV1 31-65% predicted) 1
  • Reduces mortality in patients with AAT deficiency 1
  • Slows loss of lung density as measured by CT scan 1

2. Standard COPD Management

• Bronchodilators (LAMA, LABA, or combination)
• Inhaled corticosteroids when appropriate
• Pulmonary rehabilitation
• Oxygen therapy when indicated
• Vaccinations (influenza, pneumococcal, COVID-19)
• Prompt treatment of exacerbations

3. Lifestyle Modifications

• Smoking cessation (absolute requirement)
• Avoidance of occupational and environmental exposures
• Nutritional support (small, frequent meals if weight loss is present)
• Regular exercise within limitations

Special Considerations

Monitoring

• Regular pulmonary function tests (every 6-12 months)
• CT scans to assess emphysema progression
• Monitoring for adverse reactions to augmentation therapy

Adverse Effects of Augmentation Therapy

• Generally well-tolerated with low incidence of serious adverse events
• Mild reactions may include fever, chills, and dyspnea (reported in approximately 5% of patients) 1
• Anaphylactic reactions are rare but have been reported 1

Liver Disease Management

• Regular monitoring of liver function tests
• Hepatology referral for patients with evidence of liver involvement

Pitfalls and Caveats

1. Delayed Diagnosis: AAT deficiency is often underdiagnosed or misdiagnosed as asthma or COPD, delaying appropriate treatment.

2. Smoking Status: Augmentation therapy is significantly less effective in current smokers. Smoking cessation is mandatory before initiating therapy.

3. Treatment Timing: Initiating augmentation therapy in patients with advanced disease (FEV1 <30% predicted) may provide limited benefit compared to those with moderate disease.

4. Genetic Heterogeneity: While Pi*ZZ is the most common genotype causing severe deficiency, other rare variants can also cause disease and may be missed with limited genotyping.

5. Therapeutic Gap: Current augmentation therapy addresses only the lung manifestations, not the liver or skin manifestations of AAT deficiency.

6. Administration Burden: Weekly intravenous infusions represent a significant burden for patients, potentially affecting adherence and quality of life.

The evidence supporting augmentation therapy comes primarily from observational studies and limited randomized controlled trials, but the consistent findings of slowed lung function decline and reduced mortality provide compelling support for its use in appropriately selected patients with AAT deficiency and emphysema.