What is the recommended diagnostic test for a patient with a family history of alpha 1 antitrypsin deficiency, suspected of having lung disease or liver disease?

Blood Test for Alpha-1 Antitrypsin Deficiency

For a patient with a family history of alpha-1 antitrypsin deficiency suspected of having lung or liver disease, measure serum alpha-1 antitrypsin (A1AT) levels immediately, followed by DNA sequencing of the SERPINA1 gene if the A1AT level is <23 mmol/L (<1.2 g/L). 1

Diagnostic Testing Algorithm

High Clinical Suspicion Scenario

If your patient has any of the following high-risk features, proceed directly to both serum A1AT measurement AND genetic testing simultaneously 1:

• Early-onset COPD (age <40 years) 1
• COPD with minimal smoking history (<10 pack-years) 1
• Basal panlobular emphysema on imaging 1
• Family history of COPD or A1AT deficiency 1
• History of perinatal jaundice 1

Moderate Clinical Suspicion Scenario

If your patient has moderate-risk features (COPD, unexplained bronchiectasis, adult-onset asthma with persistent airflow obstruction, or liver cirrhosis), start with serum A1AT level measurement 1:

• If A1AT level is <23 mmol/L (<1.2 g/L), proceed to DNA sequencing of SERPINA1 gene 1
• If A1AT level is borderline normal (12-35 μmol/L or 90-140 mg/dl), still perform genetic testing as these levels may indicate intermediate phenotypes (SZ, SS, MZ) 1

Why DNA Sequencing Over Phenotyping

DNA sequencing of the SERPINA1 gene is now the gold standard, surpassing the older isoelectric focusing (IEF) phenotyping method. 2 This is critical because:

• DNA sequencing detects rare variants that phenotyping misses 2
• Serum levels fail to detect dysfunctional genotypes like Pi*F 1
• Serum levels unreliably detect carriers in family screening 1
• Results are invariant and more definitive 2

Family Screening Recommendations

Testing should be discussed with all first-degree relatives (siblings, offspring, parents) of your patient, acknowledging it can reasonably be accepted or declined. 1 The rationale:

• Siblings of a heterozygous individual have a 25% chance of being heterozygous 1
• Offspring of a heterozygous parent have a 25% chance of being heterozygous 1
• Even heterozygotes may be at risk for adverse health effects, particularly with concurrent liver disease from alcohol or hepatitis C 1

Critical Pitfalls to Avoid

Do not rely solely on serum A1AT levels for diagnosis in patients with active liver disease or vasculitis. 1 In heterozygotes with active liver or vasculitic disease, plasma A1AT levels are frequently normal, requiring genetic testing for accurate diagnosis 1.

Do not perform liver biopsy to diagnose A1AT deficiency. 1 Serum phenotyping or genetic testing is the diagnostic standard; liver biopsy is only for staging liver disease severity in those with clinically overt liver disease 1. However, if periodic acid-Schiff-positive globules are incidentally found on liver biopsy, this should prompt immediate A1AT testing 1.

Liver Disease Evaluation

For suspected liver involvement, combine phenotyping/genetic testing with abdominal ultrasound—liver biopsy is unnecessary for diagnosis 2. Simple liver function tests and regular ultrasound are sufficient for follow-up of asymptomatic A1AT-deficient individuals 2.

Testing Timing Considerations

Avoid testing during acute illness, recent surgery, or active thrombosis, as these can artificially lower A1AT levels. While the guidelines focus on lung and liver disease, acquired causes of low A1AT levels must be excluded before diagnosing hereditary deficiency, similar to principles used in other protease inhibitor deficiencies 3.

The 2025 Canadian Thoracic Society guideline represents the most current evidence-based approach, superseding the 2003 ATS/ERS recommendations regarding testing methodology by prioritizing DNA sequencing over traditional phenotyping 1.