What is the treatment for alpha-1 antitrypsin deficiency?

Treatment of Alpha-1 Antitrypsin Deficiency

All patients with alpha-1 antitrypsin deficiency require comprehensive standard COPD management, and augmentation therapy should be conditionally added for those with severe deficiency (A1AT <11 μmol/L or <0.57 g/L), documented emphysema on CT, FEV1 <80% predicted, and who are non-smokers or former smokers (smoke-free ≥6 months). 1, 2, 3

Standard COPD Management (Required for All Patients)

All patients with A1AT deficiency and respiratory disease must receive optimal conventional therapy regardless of whether they qualify for augmentation therapy 1, 3:

• Bronchodilators for symptomatic relief, even when objective bronchodilator responsiveness is lacking 1, 3
• Inhaled corticosteroids for patients with bronchial hyperreactivity 1, 3
• Antibiotics for early treatment of all purulent exacerbations due to increased elastolytic burden risk 3
• Systemic corticosteroids for brief courses during acute exacerbations 3
• Pulmonary rehabilitation for patients with functional impairment 1, 3
• Supplemental oxygen when indicated by standard criteria 4
• Vaccinations: annual influenza, pneumococcal, and hepatitis B 2, 3

Smoking Cessation (Absolute Priority)

Smoking cessation is the single most critical intervention and must be achieved before considering augmentation therapy. 2, 3

• Smokers with A1AT deficiency have a life expectancy <20 years after diagnosis 2
• Patients must be smoke-free for at least 6 months before augmentation therapy initiation, as continued smoking accelerates emphysema progression and negates the protective benefits of augmentation therapy 1
• Early cessation significantly reduces FEV1 decline 1

Augmentation Therapy Eligibility Criteria

Augmentation therapy is conditionally recommended only when ALL of the following criteria are met 1, 2, 3:

Required Criteria:

• Severe A1AT deficiency: serum A1AT level <11 μmol/L (<0.57 g/L) 2, 3, 5
• Documented SERPINA1 deficiency genotypes (typically PiZZ, Pinull-null, or Pi*SZ) confirmed by genetic testing 1, 3
• Documented emphysema on high-resolution CT chest (particularly basilar-predominant panacinar emphysema) 1, 3
• FEV1 <80% predicted on post-bronchodilator spirometry 1, 2
• Non-smoker or former smoker (smoke-free ≥6 months) 1, 2, 3
• On optimal conventional COPD therapy as outlined above 1

Absolute Contraindications:

• Active smoking 1, 3
• IgA deficiency with anti-IgA antibodies 1
• Lack of documented emphysema on imaging 1

Augmentation Therapy Dosing and Administration

The standard dose is 60 mg/kg intravenously weekly, which is the FDA-approved on-label dosing 1, 5

• The goal is to maintain serum A1AT levels above 11 μmol/L, though the clinical benefit of this threshold has not been conclusively proven 5
• Augmentation therapy increases both serum and lung epithelial lining fluid A1AT levels 5

Evidence for Augmentation Therapy Efficacy

The strongest evidence for benefit comes from patients with moderate emphysema (FEV1 31-65% predicted) 1:

• German-Danish study showed yearly FEV1 decline of -53 mL in treated versus -75 mL in untreated groups (p<0.02) 1
• NHLBI Registry demonstrated mortality benefit (OR 0.79, p<0.02) specifically in the subgroup with FEV1 35-49% predicted 1
• Meta-analysis showed augmentation therapy slows CT density decline by 0.79 g/L/year versus placebo (p=0.002) 6

Critical Evidence Gaps:

• The efficacy of augmentation therapy has not been demonstrated in adequately powered randomized controlled trials for hard clinical endpoints 5
• It is unknown whether augmentation therapy benefits patients without impaired FEV1 or whether earlier therapy would fully prevent lung function decline 1
• Benefits for patients with asthma with persistent airway obstruction and/or bronchiectasis but without CT evidence of emphysema are unknown 1

Monitoring During Treatment

Annual assessments are required 3:

• Spirometry to track FEV1 decline 3
• CT chest to monitor emphysema progression using lung density measurements 3
• Liver function tests to monitor for liver disease (A1AT deficiency can cause cirrhosis) 3

Special Populations

Heterozygous states (PiMZ, PiSZ) are at lower risk than Pi*ZZ but still require management focused on smoking cessation and standard COPD therapy 2

Patients with normal A1AT levels but dysfunctional protein variants require genetic testing for identification, as serum levels alone are insufficient 1, 3

Critical Pitfalls to Avoid

• Do not assume A1AT deficiency diagnosis alone justifies augmentation therapy—emphysema must be documented on CT 1
• Do not start augmentation therapy in active smokers—it is futile and contraindicated 1, 3
• Do not withhold standard COPD therapy—augmentation is adjunctive, not a replacement 1, 3
• Do not rely on serum levels alone—genetic testing is required to confirm specific variants 1, 3
• Do not overlook liver disease—monitor liver function tests and consider ultrasound/CT for cirrhosis screening 3