What is the treatment for alpha 1 antitrypsin (A1AT) deficiency?

Treatment of Alpha-1 Antitrypsin Deficiency

All patients with A1AT deficiency and COPD require optimal standard COPD management (bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, oxygen therapy), with augmentation therapy added only for those meeting strict eligibility criteria: severe deficiency (A1AT <11 mmol/L or <0.57 g/L), documented emphysema on CT, FEV1 <80% predicted, confirmed SERPINA1 deficiency genotype, and smoke-free status for ≥6 months. 1, 2

Diagnostic Confirmation Required Before Treatment

Genetic testing with SERPINA1 gene sequencing is mandatory before initiating augmentation therapy, not just serum A1AT levels, because over 300 genetic variants exist and some produce normal circulating levels but dysfunctional protein. 1, 3, 4

• Severe deficiency threshold: serum A1AT <11 mmol/L (<0.57 g/L) 1, 2
• High-resolution CT chest must document emphysema presence (typically basilar panacinar pattern) 3, 4
• Post-bronchodilator spirometry establishing FEV1 <80% predicted 2, 3
• Smoking status verification—must be nonsmoker for minimum 6 months 1, 3

Standard COPD Management (Required for ALL Patients)

Every patient with A1AT deficiency-related COPD must receive comprehensive standard therapy regardless of augmentation therapy eligibility. 1, 2

• Bronchodilators for symptomatic relief (even without objective bronchodilator response) 2, 4
• Inhaled corticosteroids for those with bronchial hyperreactivity 2, 4
• Antibiotics for early treatment of all purulent exacerbations (increased elastolytic burden risk) 4
• Pulmonary rehabilitation for functional impairment 1, 3
• Supplemental oxygen when indicated by standard criteria 1
• Vaccinations: annual influenza, pneumococcal, hepatitis B 2, 3

Smoking Cessation (Absolute Priority)

Smoking cessation is the single most critical intervention and must be achieved before augmentation therapy consideration. 2, 4 Smokers with A1AT deficiency have life expectancy <20 years after diagnosis, and continued smoking negates all protective benefits of augmentation therapy. 2, 3

Augmentation Therapy Eligibility Criteria

The Canadian Thoracic Society (2025) conditionally recommends augmentation therapy only when ALL criteria are met: 1

• Severe A1AT deficiency: serum level <11 mmol/L (<0.57 g/L) 1, 2
• Documented SERPINA1 deficiency genotype (typically Pi*ZZ) 1
• CT-documented emphysema 3, 4
• FEV1 <80% predicted 1, 2
• Never smoker or former smoker (smoke-free ≥6 months) 1, 3
• On optimal standard COPD therapy 1, 3

Dosing and Administration

• 60 mg/kg weekly intravenous infusion of human plasma-derived A1AT 3, 5
• Therapy is lifelong once initiated 6, 5

Evidence for Augmentation Therapy Efficacy

The strongest evidence for benefit exists in patients with moderate emphysema (FEV1 31-65% predicted). 3

• German-Danish study: FEV1 decline -53 mL/year (treated) vs -75 mL/year (untreated), p<0.02 3
• NHLBI Registry: mortality benefit (OR 0.79, p<0.02) specifically in FEV1 35-49% predicted subgroup 3
• Evidence is weaker for severe airflow obstruction 3
• Critical evidence gap: unknown whether augmentation benefits patients without impaired FEV1 or prevents decline if started earlier 3

Monitoring During Treatment

Annual assessments are required for all patients on augmentation therapy: 4

• Spirometry to track FEV1 decline 2, 4
• CT chest to monitor emphysema progression using lung density measurements 4
• Liver function tests (AST, ALT, bilirubin, alkaline phosphatase) to monitor for liver disease 3, 4

Liver Disease Management

A1AT deficiency causes liver disease in 10% of children and can progress to cirrhosis in adults. 7 The Pi*ZZ genotype causes trapping of abnormally folded protein polymers in hepatocytes. 6

• Baseline liver function tests required for all patients 3, 4
• Periodic monitoring with liver function tests and ultrasound 4
• CT scans for patients with established cirrhosis 4
• Liver transplantation is the only curative treatment for A1AT deficiency-related liver disease 7

Heterozygous States (PiMZ, PiSZ)

Heterozygous patients are at lower risk than Pi*ZZ but still require aggressive smoking cessation and standard COPD management. 2 Augmentation therapy is not indicated for heterozygous states. 1

Critical Pitfalls to Avoid

• Never initiate augmentation therapy in active smokers—it is futile and wastes resources 3, 4
• Never rely on serum A1AT levels alone—genetic confirmation with SERPINA1 sequencing is mandatory 1, 3
• Never withhold standard COPD therapy—augmentation is adjunctive, not replacement 3, 4
• Never assume A1AT deficiency diagnosis alone justifies augmentation—emphysema must be documented on CT 3
• Never overlook liver disease screening—baseline and periodic monitoring required 3, 4
• Never forget IgA deficiency screening—IgA deficiency with anti-IgA antibodies is an absolute contraindication to augmentation therapy 3

Special Considerations for Anesthesia and Pregnancy

• Anesthesia can be tolerated even with FEV1 <1.0 L if ventilation uses prolonged expiration time 1
• Pregnancy carries increased risk of miscarriage (29% in case series) and pneumothorax in patients with preexisting bullae 1
• Air travel requires oxygen supplementation if predicted cabin pressure oxygen tension <55 mmHg 1