What is the Alpha-1 Antitrypsin (A1A) test?

What is the A1A (Alpha-1 Antitrypsin) Test?

The A1A test refers to diagnostic testing for alpha-1 antitrypsin (AAT) deficiency, which involves measuring serum or plasma AAT levels and/or performing genetic testing of the SERPINA1 gene to identify this hereditary condition that predisposes individuals to early-onset emphysema and liver disease. 1

Purpose of Testing

The A1A test identifies individuals with AAT deficiency, a genetic disorder affecting approximately 1 in 2,000-5,000 Caucasians, which causes:

• Premature emphysema and COPD (typically presenting between ages 32-41 in smokers) 2, 3
• Liver cirrhosis in both children and adults 3
• Less commonly: panniculitis, systemic vasculitis, and other inflammatory conditions 3

Early diagnosis is critical because late detection has been associated with reduced functional status, quality of life, and worse overall survival. 1, 2

Testing Methodology

Two-Step Approach (Recommended)

The Canadian Thoracic Society (2025) recommends a risk-stratified testing algorithm: 1

For Moderate Clinical Suspicion:

• Step 1: Measure serum or plasma AAT level
  • If AAT ≥ 23 mmol/L (≥ 1.2 g/L): Rules out severe deficiency 1
  • If AAT < 23 mmol/L (< 1.2 g/L): Proceed to genetic testing 1
• Step 2: DNA sequencing of SERPINA1 gene coding regions (exons 2-5) 1

For High Clinical Suspicion:

• Proceed directly to DNA sequencing as the initial test 1

Gold Standard

DNA sequencing of the SERPINA1 gene is the gold standard because: 1

• Genetic mutations are invariable (unlike AAT levels which fluctuate) 1
• Detects all variants, including rare dysfunctional variants with normal AAT levels (e.g., Pi*F) 1
• Targeted genotyping with PCR only detects limited common variants and can miss rare mutations 1

Practical Collection

A single lavender-top tube (EDTA) can be used to measure AAT levels in plasma and perform DNA sequencing from the buffy coat, though serum and plasma are considered equivalent for AAT measurement. 1

Who Should Be Tested

Mandatory Testing Populations

The American Thoracic Society/European Respiratory Society provides Type A recommendations (strongest level) for: 2, 4

• All adults with COPD 1, 2
• Early-onset emphysema (age < 40 years, regardless of smoking history) 1, 2
• COPD with low smoking exposure (< 10 pack-years) 1
• Adult-onset asthma with persistent airflow obstruction 1
• Unexplained bronchiectasis 1
• All first-degree relatives of individuals with confirmed AAT deficiency 5, 2

Additional Testing Indications

• Basal panlobular emphysema on imaging 1
• Liver cirrhosis of unknown cause 1, 2
• Granulomatosis with polyangiitis (GPA) vasculitis or panniculitis 1
• History of perinatal jaundice 1
• Family history of COPD or AAT deficiency 1

Interpretation of Results

Severe Deficiency Threshold

• Functional AAT level < 11 mmol/L (< 0.57 g/L) indicates severe deficiency requiring augmentation therapy consideration 1, 6
• AAT level ≥ 23 mmol/L (≥ 1.2 g/L) excludes severe deficiency in most cases 1

Common Genotypes

The most frequent severe deficiency allele is Pi*Z (p.E342K), accounting for approximately 95% of severe cases. 5 This mutation causes:

• Protein misfolding and hepatocyte retention 1
• Markedly reduced circulating AAT levels 1
• Increased susceptibility to both emphysema and liver disease 1

Pi*S (p.E264V) represents an intermediate deficiency state. 1

Heterozygote Considerations (MZ Phenotype)

Individuals with Pi*MZ genotype have AAT levels around 60% of normal and: 7

• 2.2-fold increased risk of COPD hospitalization 7
• 2.8 odds ratio for rapid FEV1 decline if smoking 7
• 1.8-3.1 odds ratio for chronic liver disease 7
• Do not require routine specialized monitoring unless risk factors present 7

Clinical Implications of Testing

Benefits of Early Detection

• Enables smoking cessation counseling (the single most important intervention) 1, 2
• Allows avoidance of high-risk occupational exposures (dust, fumes, respiratory irritants) 1, 2
• Permits early initiation of augmentation therapy while lung function preserved 1, 4
• Triggers family screening to identify at-risk relatives 1, 2
• Establishes surveillance for lung and liver disease 1, 2

Augmentation Therapy Eligibility

The Canadian Thoracic Society (2025) conditionally recommends augmentation therapy for patients meeting ALL criteria: 1

• Never or previously smoked
• FEV1 < 80% predicted
• Documented emphysema
• Documented SERPINA1 genotypes associated with deficiency
• Severely reduced functional AAT level (< 11 mmol/L or < 0.57 g/L)
• Receiving optimal COPD therapies

Augmentation therapy preserves CT lung density (high quality evidence) and may reduce mortality (very low quality evidence). 1

Important Caveats

Limitations of Serum Testing Alone

• AAT is an acute phase reactant; levels increase during inflammation, infection, pregnancy, or estrogen therapy 1
• May miss dysfunctional variants with normal quantitative levels (e.g., Pi*F) 1
• Cannot reliably detect heterozygote carriers in family screening 1

Nomenclature Transition

Modern testing should report results using Human Genome Variation Society (HGVS) nomenclature for DNA-based methods, though dual reporting with traditional Pi typing is recommended during the transition period. 1, 5

Underdiagnosis Problem

AAT deficiency remains greatly underrecognized despite being one of the most common inherited conditions, with average diagnostic delays of 5.3 years after first symptoms. 1, 8 The clinical picture alone is inadequately sensitive to alert clinicians. 1