What is the management for alpha 1 anti-trypsin (A1AT) deficiency?

Management of Alpha-1 Antitrypsin (A1AT) Deficiency

The management of Alpha-1 Antitrypsin deficiency should focus on preventing lung disease progression through smoking cessation, avoiding environmental pollutants, and implementing augmentation therapy with intravenous A1AT for patients with FEV1 <80% of predicted and evidence of emphysema. 1

Diagnosis and Testing

• Testing for A1AT deficiency is strongly recommended for symptomatic adults with emphysema, COPD, or asthma with incompletely reversible airflow obstruction 1
• Clinical features that should prompt suspicion of A1AT deficiency include:
  • Early-onset emphysema (age ≤45 years)
  • Emphysema without recognized risk factors
  • Emphysema with prominent basilar hyperlucency
  • Unexplained liver disease
  • Necrotizing panniculitis
  • Anti-proteinase 3-positive vasculitis
  • Family history of emphysema, bronchiectasis, liver disease, or panniculitis 1
• Diagnosis requires measurement of serum A1AT levels with confirmation by genetic testing (SERPINA1 sequencing) before starting augmentation therapy 1

Non-Pharmacological Management

Preventive Strategies

• Smoking cessation is critical and should be prioritized as the most important intervention 1

  • Early cessation is particularly important in those with homozygous phenotype
  • Pharmacologic aids for smoking cessation should be offered to committed smokers

• Avoid exposure to respiratory irritants:

  • Second-hand tobacco smoke
  • Occupational dusts and fumes
  • Consider job change if frequent exposure occurs 1

• Preventive vaccinations:

  • Influenza vaccine annually
  • Pneumococcal vaccination 1
  • Hepatitis B vaccination (recommended for patients with overt liver disease) 1

Pulmonary Rehabilitation

• Pulmonary rehabilitation improves endurance, reduces dyspnea, and reduces hospitalizations 1
• Higher exercise work rates are often well-tolerated by A1AT-deficient patients who are typically younger with fewer comorbidities than other COPD patients 1

Pharmacological Management

Standard COPD Therapies

• Bronchodilators:

  • Most patients with A1AT deficiency and obstructive lung disease benefit symptomatically from bronchodilators even without objective bronchodilator responsiveness 1
  • Use to lessen dyspnea with exertion, but monitor for overuse 1

• Inhaled corticosteroids:

  • Consider in patients with evidence of bronchial hyperreactivity
  • May reduce bronchial inflammation and potentially slow FEV1 loss over time 1

• Antibiotics:

  • Use promptly in patients with evidence of bronchitis or upper respiratory infection
  • Consider macrolides for their anti-inflammatory properties, but be aware of potential bacterial resistance 1
  • Longer courses may be needed for those with bronchiectasis 1

• Oxygen therapy:

  • Supplemental oxygen for patients who desaturate during exercise to increase exercise capacity 1
  • Long-term oxygen therapy for severe hypoxemia according to standard criteria 1

Augmentation Therapy

• Recommended for individuals with:

  • Severe A1AT deficiency (serum levels <11 μmol/L or <0.57 g/L)
  • FEV1 <80% of predicted
  • Evidence of emphysema on CT scan 1

• Dosing:

  • Standard dose is 60 mg/kg body weight administered intravenously once weekly 2
  • This regimen has been shown to raise Alpha1-PI levels in both serum and epithelial lining fluid 2

• Clinical benefits:

  • Augmentation therapy has been shown to reduce the decline in lung density on CT scans 1
  • The effect on FEV1 decline may be more pronounced in patients with moderate airflow obstruction (FEV1 30-65% predicted) 3

• Limitations:

  • The clinical efficacy in influencing the course of pulmonary emphysema or frequency of exacerbations has not been conclusively demonstrated in adequately powered randomized controlled trials 2

Management of Comorbidities

• Depression and anxiety:

  • Monitor for early signs of depression such as loss of appetite
  • Consider selective serotonin reuptake inhibitors for both depression and anxiety disorders 1
  • Short-acting benzodiazepines may help manage panic but monitor for side effects 1
  • Non-pharmacologic relaxation techniques may be beneficial 1

• Nutritional support:

  • Address weight loss and malnutrition which are common in emphysema
  • Consider smaller, more frequent meals to reduce dyspnea from abdominal bloating 1

Special Considerations

• Liver disease:

  • Test for hepatitis serology in all patients with A1AT deficiency 1
  • Monitor for development of cirrhosis and hepatocellular carcinoma, especially in never-smokers who may have higher risk of liver complications 1

• Necrotizing panniculitis:

  • A rare complication of Pi*ZZ phenotype that presents with necrotic lesions in subcutis and dermis 1
  • May respond to augmentation therapy 1

Emerging Therapies

• New approaches to treating A1AT deficiency beyond augmentation therapy are under investigation:
  • Correction of A1AT protein misfolding
  • Increasing autophagy of polymerized A1AT protein
  • RNA interference and editing
  • Gene transfer therapies 1, 4

Monitoring Disease Progression

• Regular pulmonary function testing to monitor FEV1 decline
• CT scan lung density measurements may provide more sensitive assessment of emphysema progression 1
• Monitor for liver disease progression, especially in never-smokers 1

Prognosis

• In smokers who cannot stop smoking, life expectancy is less than 20 years after diagnosis 1
• FEV1 decline is most rapid when between 30-65% of predicted value 1
• Among non-index patients who are never-smokers, normal life expectancy has been observed 1
• Two-year mortality of 50% occurs at an FEV1 of 15% of predicted 1