Laboratory Testing for Alpha-1 Antitrypsin Deficiency

Risk Stratification and Testing Pathway

The Canadian Thoracic Society recommends beginning with serum A1AT level measurement, and if the level is <23 mmol/L (<1.2 g/L), proceeding immediately to DNA sequencing of the SERPINA1 gene coding regions (exons 2-5) for adults with suspected alpha-1 antitrypsin (A1AT) deficiency presenting with COPD or liver disease 1, 2
For patients with moderate clinical suspicion, such as those with COPD (without high-risk features), unexplained bronchiectasis, adult-onset asthma with persistent airflow obstruction, liver cirrhosis, or Granulomatosis with polyangiitis (GPA) vasculitis or panniculitis, start with serum A1AT level measurement, then proceed to DNA sequencing only if level is <23 mmol/L (<1.2 g/L) 1, 2

The American Thoracic Society recommends an interpretation threshold of ≥23 mmol/L (≥1.2 g/L) to rule out severe A1AT deficiency in moderate-risk patients, with a severe deficiency defined as <11 mmol/L (<0.57 g/L) 1, 2, 3
DNA sequencing of the SERPINA1 gene is the gold standard test, detecting all >300 genetic variants in a single assay, including rare and dysfunctional variants (like Pi*F) that may show normal serum levels 4, 3

The Canadian Thoracic Society advises against testing during acute illness, recent surgery, or active inflammation, as these conditions artificially elevate A1AT levels and can mask deficiency 3
The society also recommends not relying solely on serum levels in high-risk patients, even with levels >23 mmol/L (>1.2 g/L), and proceeding to DNA sequencing if the patient has early-onset COPD, minimal smoking exposure, panlobular emphysema, or family history 3

The use of a single tube collection for measuring A1AT levels in plasma and sequencing the gene from the buffy coat is possible 4
Unit reporting variability is a concern, with 12 different units of measurement used across laboratories, and 87.9% reporting in mass units (g/L or mg/dL) while 7.8% use molar units (mmol/L) 4
Confirmatory testing with DNA sequencing provides definitive genotype classification (PiZZ, PiMZ, Pi*SZ, etc.) which is essential for accurate risk assessment and cannot be achieved by protein levels alone 3

Early diagnosis of A1AT deficiency is critical due to the irreversible nature of lung damage, with delayed diagnosis associated with worse overall survival, transplant-free survival, reduced functional status, and diminished quality of life 4

For patients with a family history of alpha-1 antitrypsin deficiency suspected of having lung or liver disease, the American Thoracic Society recommends measuring serum alpha-1 antitrypsin levels immediately, followed by DNA sequencing of the SERPINA1 gene if the level is <23 mmol/L (<1.2 g/L) 5
Patients with high-risk features such as early-onset COPD, minimal smoking history, basal panlobular emphysema, family history of COPD or A1AT deficiency, or history of perinatal jaundice should undergo simultaneous serum A1AT measurement and genetic testing 5, 6
The American Thoracic Society suggests that if a patient has moderate-risk features, such as COPD, unexplained bronchiectasis, adult-onset asthma with persistent airflow obstruction, or liver cirrhosis, they should start with serum A1AT level measurement, and if the level is <23 mmol/L (<1.2 g/L), proceed to DNA sequencing of the SERPINA1 gene 5, 6

DNA sequencing of the SERPINA1 gene is the gold standard for diagnosis, surpassing traditional phenotyping methods, as it detects rare variants and dysfunctional genotypes that may be missed by serum levels 5, 7
Genetic testing is recommended for family members of patients with A1AT deficiency, as siblings and offspring of a heterozygous individual have a 25% chance of being heterozygous 8, 9, 10

The American Thoracic Society advises against relying solely on serum A1AT levels for diagnosis in patients with active liver disease or vasculitis, as levels may be normal in heterozygotes with these conditions 8
Liver biopsy is not recommended for diagnosis of A1AT deficiency, but may be used for staging liver disease severity in patients with clinically overt liver disease 8, 11

For suspected liver involvement, the Canadian Thoracic Society recommends combining phenotyping/genetic testing with abdominal ultrasound, and simple liver function tests and regular ultrasound for follow-up of asymptomatic A1AT-deficient individuals 7
Testing should be avoided during acute illness, recent surgery, or active thrombosis, as these can artificially lower A1AT levels 12