How to work up alpha-1-antitrypsin deficiency as an outpatient Gastroenterologist (GI)?

Alpha-1 Antitrypsin Deficiency Workup for Outpatient Gastroenterologists

The optimal workup for alpha-1 antitrypsin deficiency (AATD) in the outpatient GI setting should follow a two-step approach: first measuring serum alpha-1 antitrypsin level, followed by DNA sequencing of the SERPINA1 gene for definitive diagnosis. 1, 2

Initial Testing

1. Serum Alpha-1 Antitrypsin Level

   • Collect blood in a red cap tube
   • Measure serum AAT protein level
   • Interpret results:
     • Normal: >23 μmol/L (>1.2 g/L)
     • Suspicious for deficiency: <23 μmol/L (<1.2 g/L)

2. Genetic Testing

   • Collect blood in a lavender cap tube for DNA analysis
   • For all patients with AAT levels <23 μmol/L (<1.2 g/L), proceed to DNA sequencing
   • DNA sequencing of all coding exons of SERPINA1 gene (not just targeted genotyping)

When to Test

Test for AATD in patients with:

• Unexplained liver disease at any age
• Elevated liver enzymes without clear cause
• Family history of AATD or unexplained liver disease
• Early-onset emphysema (especially with minimal smoking history)
• Panniculitis or vasculitis with no identified cause

Pitfalls to Avoid

• Don't rely solely on serum protein electrophoresis (SPEP) - This method misses approximately 16% of ZZ phenotypes and 71% of MZ phenotypes 3
• Don't rely only on serum levels without genetic confirmation - Some variants have normal circulating levels but dysfunctional protein 2
• Be aware of false normal AAT levels - AAT is an acute phase reactant that increases during inflammation, potentially masking deficiency 1, 2
• Don't use targeted genotyping alone - While it can identify common variants (Z, S), it will miss rare mutations that may be clinically significant 1, 4

Interpretation of Results

• Severe deficiency: AAT levels <11 μmol/L (<0.57 g/L), typically associated with PiZZ, Pi(null)(null) genotypes 5
• Moderate deficiency: AAT levels 9-23 μmol/L (PiSZ and other heterozygotes) 5
• Carriers: Often have intermediate levels but may still have increased risk with environmental exposures

Clinical Implications for GI Practice

• Liver manifestations can occur at any age, from neonatal cholestasis to adult-onset cirrhosis
• Liver disease risk is highest in PiZZ and Pi(null)(null) individuals
• Liver disease can occur independently of lung disease
• Early diagnosis allows for:
  • Family screening
  • Monitoring for disease progression
  • Lifestyle modifications (avoiding alcohol, hepatotoxic medications)
  • Consideration for liver transplant evaluation in advanced disease

Next Steps After Diagnosis

1. Refer to pulmonology for lung function assessment if not already done
2. Monitor liver function with regular liver enzyme tests and imaging
3. Screen first-degree relatives with both serum AAT levels and genetic testing 1
4. Consider referral to specialized centers for patients with novel mutations or severe disease

Nomenclature Considerations

The Canadian Thoracic Society recommends transitioning from the traditional Pi protein phenotyping nomenclature (PiMM, PiZZ, etc.) to the standardized Human Genome Variation Society (HGVS) nomenclature for genetic variants 1. This provides more precise classification and facilitates better understanding of disease risk.

By following this systematic approach to AATD testing, gastroenterologists can ensure accurate diagnosis, appropriate management, and improved outcomes for patients with this underdiagnosed condition.