What is the management of Alpha 1 anti-trypsin (A1AT) deficiency?

Management of Alpha-1 Antitrypsin Deficiency

Who Should Be Tested

Test all adults with COPD, adult-onset asthma with persistent airflow obstruction (FEV1/FVC <0.7), or unexplained bronchiectasis for A1AT deficiency. 1 The Canadian Thoracic Society 2025 guidelines emphasize that delayed diagnosis (averaging 5.3 years after symptom onset) leads to worse overall survival and transplant-free survival, making early identification critical. 1

Testing Approach

• Initial screening: Measure serum A1AT level in patients with moderate clinical suspicion 1

  • If A1AT ≥23 mmol/L (≥1.2 g/L): severe deficiency ruled out (except rare dysfunctional variants) 1
  • If A1AT <23 mmol/L: proceed to genetic testing 1

• High clinical suspicion: DNA sequencing of SERPINA1 gene exons 2-5 is the gold standard, as it avoids misclassification from variable A1AT levels or limited PCR-based genotyping 1

• Also test: First-degree relatives of identified patients 1

Augmentation Therapy Criteria

Offer intravenous A1AT augmentation therapy to patients meeting ALL of the following criteria: 1, 2

• Severe A1AT deficiency (serum level <11 mmol/L or <0.57 g/L) 1, 2
• Documented SERPINA1 deficiency genotypes (typically Pi*ZZ) 1
• FEV1 <80% predicted 1, 2
• Documented emphysema on imaging 1
• Never-smoker OR former smoker (smoke-free ≥6 months) 1, 2
• On optimal COPD pharmacotherapy 1

Evidence Strength by Disease Severity

The American Thoracic Society/European Respiratory Society guidelines note that augmentation therapy evidence is strongest for moderate airflow obstruction (FEV1 35-60% predicted), with less clear benefits in severe (FEV1 <35%) or mild (FEV1 >60%) obstruction. 1 However, the 2025 Canadian guidelines use the broader FEV1 <80% threshold based on updated evidence. 1

Do NOT offer augmentation therapy to: 1

• Current smokers (must achieve cessation first—smoking reduces life expectancy to <20 years after diagnosis) 2
• Patients without documented emphysema 1

Standard COPD Management (Required for ALL Patients)

Regardless of A1AT levels, all patients require comprehensive COPD management: 1, 2

• Bronchodilators: Inhaled beta-agonists and anticholinergics 1
• Inhaled corticosteroids: Particularly for bronchial hyperreactivity 1
• Antibiotics: Early aggressive treatment for ALL purulent exacerbations (infection increases elastolytic burden) 1
• Supplemental oxygen: When meeting conventional criteria (including air travel) 1
• Pulmonary rehabilitation: For functional impairment 1
• Vaccinations: Annual influenza, pneumococcal, and hepatitis B 1, 2

Critical Preventive Measures

Smoking cessation is the single most important intervention and must be achieved before considering augmentation therapy. 2 The Lung Health Study demonstrated significantly reduced FEV1 decline in successful quitters. 1

Additional preventive strategies: 1

• Avoid secondhand smoke, occupational dusts, fumes, vaping, and inhaled cannabis 1
• Minimize respiratory irritant exposure (may require job change) 1
• Maintain exercise, healthy diet, and pulmonary hygiene 1

Monitoring During Treatment

• Annual spirometry: Assess FEV1 decline rate 2
• CT imaging: Monitor emphysema progression 2
• Liver function tests: Regular assessment in elderly patients, even without symptoms 1
• Liver ultrasound: Periodic assessment for cirrhosis/hepatoma risk 1
• CT abdomen: In patients ≥50 years with decompensated cirrhosis (α-fetoprotein is insensitive) 1

Special Populations

Heterozygotes (PiMZ, PiSZ): Lower risk than PiZZ but still require smoking cessation emphasis and standard COPD therapy. 2 Smoking and pack-years correlate with greater emphysema in PiSZ patients. 1

Lung transplant recipients: Insufficient evidence for routine augmentation therapy, but favor treatment during acute rejection or infection episodes when free elastase activity increases. 1

Lung volume reduction surgery: Limited evidence in A1AT deficiency shows possible benefit but shorter duration than A1AT-replete COPD; robust selection criteria remain elusive. 1

Common Pitfalls

• Therapeutic nihilism: Low-quality augmentation therapy evidence has contributed to under-testing, but identification still enables critical preventive measures and family screening 1
• Relying on clinical picture alone: Delayed diagnosis is not related to specific clinical characteristics—systematic testing is essential 1
• Missing rare variants: Standard PCR genotyping may miss dysfunctional A1AT variants with normal serum levels; DNA sequencing is superior 1