What is the management approach for alpha-1 antitrypsin (A1AT) deficiency?

Management of Alpha-1 Antitrypsin Deficiency

All patients with confirmed severe A1AT deficiency (serum levels <11 μmol/L or <0.57 g/L) who have COPD with emphysema, FEV1 <80% predicted, and are non-smokers or former smokers (smoke-free ≥6 months) should receive augmentation therapy in addition to standard COPD management. 1, 2

Diagnostic Confirmation

Before initiating any treatment, establish the diagnosis through:

• Serum A1AT protein level measurement: Severe deficiency defined as <11 μmol/L (<0.57 g/L) 1, 2
• SERPINA1 gene sequencing: Required before starting augmentation therapy due to variability in protein levels and to identify dysfunctional variants with normal levels 1, 3
• Phenotyping: Most patients (95%) have PiZZ variant; Pi(null)(null) and PiSZ variants also exist 4, 5
• CT chest imaging: Document presence of emphysema, particularly basilar-predominant panacinar emphysema 1
• Pulmonary function testing: Establish baseline FEV1 and degree of obstruction 1

Augmentation Therapy Eligibility Criteria

Offer augmentation therapy when ALL of the following are met:

• Documented severe A1AT deficiency with serum levels <11 μmol/L (<0.57 g/L) 1, 2
• Confirmed SERPINA1 deficiency genotype (PiZZ, Pi(null)(null), or other severe variants) 1, 3
• FEV1 <80% predicted 1, 2
• CT-documented emphysema 1, 2
• Never-smoker OR former smoker who has been smoke-free for ≥6 months 1, 2
• Already receiving optimal COPD pharmacotherapy 1, 2

The Canadian Blood Services now provides augmentation therapy to all eligible Canadians meeting these criteria. 1

Standard COPD Management (Required for ALL Patients)

Regardless of augmentation therapy eligibility, implement comprehensive COPD management:

Pharmacological Interventions

• Bronchodilators: For symptomatic relief, even without objective bronchodilator responsiveness 1, 3
• Inhaled corticosteroids: For patients with bronchial hyperreactivity 1, 3
• Antibiotics: Early treatment for ALL purulent exacerbations due to increased elastolytic burden risk 1
• Systemic corticosteroids: Brief courses during acute exacerbations 1

Non-Pharmacological Interventions

• Smoking cessation: The single most critical intervention—smokers with A1AT deficiency have life expectancy <20 years after diagnosis 2, 3
• Pulmonary rehabilitation: For patients with functional impairment 1, 2
• Supplemental oxygen: When indicated by conventional criteria, including during air travel 1, 2
• Vaccinations: Annual influenza, pneumococcal, and hepatitis B vaccines 2, 3

Surgical Considerations

• Lung volume reduction surgery: May improve dyspnea and function, but benefits appear shorter-lived than in AAT-replete COPD; selection criteria remain unclear 1
• Lung transplantation: Consider for selected patients with severe functional impairment and airflow obstruction 1

Monitoring During Treatment

Annual Assessments

• Spirometry: Track FEV1 decline annually 2
• CT chest: Monitor emphysema progression using lung density measurements 1, 2
• Liver function tests: Simple liver enzymes and ultrasound for asymptomatic patients, as 30-40% of patients >50 years develop cirrhosis/carcinoma 1

Management of Heterozygotes

Patients with PiMZ or PiSZ phenotypes:

• Lower risk than PiZZ but still require aggressive management 2
• Focus on smoking cessation and standard COPD therapy 2
• PiSZ individuals with levels 9-23 μmol/L have moderately increased emphysema risk regardless of whether levels exceed 11 μmol/L 4
• Generally NOT candidates for augmentation therapy unless severely deficient 1

Liver Disease Management

For patients with A1AT deficiency-related liver disease:

• No specific therapy exists beyond liver transplantation for life-threatening liver failure 5, 6
• Monitor with periodic liver function tests and ultrasound 1
• Consider CT scans for patients with established cirrhosis 1
• Hepatitis C vaccination when available; evaluate interaction with chronic viral hepatitis 1

Critical Pitfalls to Avoid

• Do not start augmentation therapy in active smokers: Must be smoke-free ≥6 months 1, 2
• Do not rely on serum levels alone: Always confirm with SERPINA1 sequencing before augmentation therapy 1
• Do not withhold standard COPD therapy: Augmentation is adjunctive, not replacement therapy 1, 2
• Do not assume normal A1AT levels exclude deficiency: Some variants have normal levels but dysfunctional protein 3
• Do not overlook liver disease: Regular monitoring essential as liver complications cause significant mortality in non-smokers 1

Emerging Therapies

While not yet standard of care, research is advancing in:

• RNA editing to correct the E342K mutation 7
• Gene therapy approaches 1, 5
• Chemical chaperones to prevent protein polymerization 1
• Alternative delivery methods (inhaled, oral) for augmentation therapy 1

The evidence for augmentation therapy reducing lung density decline exists, but its effect on mortality and quality of life has not been conclusively demonstrated in adequately powered randomized controlled trials. 4 However, observational studies suggest potential survival benefits and disease progression reduction, justifying its use in appropriately selected patients. 1