When is alpha-1 antitrypsin (A1AT) replacement therapy indicated for patients with alpha-1 antitrypsin deficiency, particularly those with chronic obstructive pulmonary disease (COPD) or liver disease?

Alpha-1 Antitrypsin Replacement Therapy Indications

Alpha-1 antitrypsin (A1AT) augmentation therapy is indicated for patients with COPD and severe A1AT deficiency (<11 mmol/L or <0.57 g/L) who have documented emphysema on CT scan, FEV1 <80% predicted, confirmed SERPINA1 deficiency genotypes, are never-smokers or former smokers (smoke-free ≥6 months), and are receiving optimal COPD therapy. 1, 2

Core Eligibility Criteria (All Must Be Met)

The 2025 Canadian Thoracic Society guidelines establish a strict algorithmic approach requiring simultaneous fulfillment of six conditions 1:

• Severe A1AT deficiency: Serum A1AT level <11 mmol/L (<0.57 g/L) 1
• Genetic confirmation: Documented SERPINA1 deficiency genotypes (typically Pi*ZZ, but requires DNA sequencing confirmation) 1, 2
• Documented emphysema: High-resolution CT chest showing emphysema (not just airflow obstruction) 2, 3
• Impaired lung function: Post-bronchodilator FEV1 <80% predicted 1
• Smoking status: Never-smoker OR former smoker who has been smoke-free for at least 6 months 1, 2, 3
• Optimal baseline therapy: Already receiving appropriate pharmacological and non-pharmacological COPD management including bronchodilators, inhaled corticosteroids, vaccinations, pulmonary rehabilitation, supplemental oxygen (if indicated), and comprehensive case management 1

Critical Exclusions (Absolute Contraindications)

Do not initiate augmentation therapy if any of the following are present 2:

• Active smoking (current smoker or quit <6 months ago) 2, 3
• IgA deficiency with anti-IgA antibodies 2
• Absence of documented emphysema on CT imaging 2, 3
• Severe A1AT deficiency not established (level ≥11 mmol/L) 3

Evidence Quality and Strength of Recommendation

The recommendation is conditional based on high-quality evidence for CT lung density preservation but very low-quality evidence for mortality benefit 1. The FDA label explicitly states that "the effect of augmentation therapy with GLASSIA or any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency has not been conclusively demonstrated in randomized, controlled clinical trials" 3.

The strongest observational evidence comes from patients with moderate emphysema (FEV1 31-65% predicted), showing yearly FEV1 decline of -53 mL in treated versus -75 mL in untreated groups (p<0.02), and mortality benefit specifically in the subgroup with FEV1 35-49% predicted 2.

Diagnostic Workup Required Before Therapy

Mandatory Laboratory Testing

• Serum A1AT level: Must be <11 mmol/L (<0.57 g/L) to meet severe deficiency threshold 1, 2
• SERPINA1 gene sequencing: Gold standard test required before initiating therapy, as over 300 genetic variants exist and some produce normal circulating levels but dysfunctional protein 2, 4
• Post-bronchodilator spirometry: Document FEV1 <80% predicted 2
• Smoking cessation verification: Confirm smoke-free status for ≥6 months 2, 3
• Hepatitis A and B vaccination status: Document and administer if not current 2
• Baseline liver function tests (AST, ALT, bilirubin, alkaline phosphatase), particularly in elderly patients 2, 5
• C-reactive protein: Baseline inflammatory marker 2

Mandatory Imaging

• High-resolution CT chest: Must document presence of emphysema 2, 3

Common Pitfalls to Avoid

Do not assume A1AT deficiency diagnosis alone justifies augmentation therapy 2. The rationale for augmentation is specifically to prevent further lung destruction by restoring anti-elastase protection in patients with established emphysema, not to prevent initial lung disease development 2.

Do not rely solely on serum A1AT levels for diagnosis 1, 4. As an acute phase protein, A1AT levels fluctuate during acute inflammation, infection, recent surgery, or active thrombosis, potentially masking deficiency 1, 4. DNA sequencing is mandatory because some genetic variants (like Pi*F) produce normal serum levels but dysfunctional protein 4.

Do not test during acute illness 4. Avoid testing during acute exacerbations, recent surgery, or active inflammation, as these artificially elevate A1AT levels 4.

Do not initiate therapy in active smokers 2, 3. Continued smoking accelerates emphysema progression and negates the protective benefits of augmentation therapy, making treatment futile 2. Smokers with A1AT deficiency have a life expectancy <20 years after diagnosis 5.

Conditions NOT Indicated for Augmentation Therapy

The 2025 Canadian Thoracic Society guideline explicitly states augmentation therapy does not address 1:

• A1AT deficiency-related liver disease 1
• Necrotizing panniculitis 1
• Anti-neutrophil-cytoplasmic antibody-positive vasculitis 1
• Asthma with persistent airflow obstruction without CT-documented emphysema 2
• Unexplained bronchiectasis without CT-documented emphysema 2
• Patients with FEV1 ≥80% predicted (benefit unknown in this population) 2

Dosing and Administration

Standard FDA-approved dosing: 60 mg/kg body weight administered intravenously once weekly 2, 3. The infusion rate should not exceed 0.2 mL/kg body weight per minute 3. Administer within three hours of entering the vials using a 5 micron in-line filter 3.

Monitoring During Therapy

• Annual spirometry: Assess FEV1 decline 5
• CT imaging: Monitor emphysema progression 5
• Liver function monitoring: Particularly important as 30-40% of patients over age 50 develop cirrhosis or hepatocellular carcinoma 5

Special Populations

Heterozygous carriers (PiMZ, PiSZ) are at lower risk than Pi*ZZ individuals and augmentation therapy is not indicated; management focuses on smoking cessation and standard COPD therapy 5.

Family screening is recommended for first-degree relatives (parents, siblings, offspring) of individuals identified with abnormal A1AT genes, as siblings and offspring of a heterozygous individual have a 25% chance of being heterozygous 2, 4.