Why are alpha 1 antitrypsin (A1AT) levels checked?

Alpha-1 Antitrypsin Testing: Indications and Clinical Importance

Alpha-1 antitrypsin (A1AT) levels should be checked in all individuals with COPD at diagnosis, adult-onset asthma with persistent airflow obstruction, and unexplained bronchiectasis to identify potentially treatable genetic deficiency that impacts mortality and morbidity. 1

Primary Indications for A1AT Testing

A1AT testing is indicated in the following clinical scenarios:

High Clinical Suspicion

• Early-onset COPD (before age 40)
• COPD with minimal smoking history (<10 pack-years)
• Basal panlobular emphysema
• Family history of COPD or A1AT deficiency
• History of perinatal jaundice
• Unexplained liver disease or elevated liver enzymes

Moderate Clinical Suspicion

• All patients with COPD at diagnosis
• Adult-onset asthma with persistent airflow obstruction
• Unexplained bronchiectasis
• Liver cirrhosis without known etiology
• Granulomatosis with polyangiitis (Wegener's) or panniculitis

Clinical Rationale for Testing

Testing for A1AT deficiency is crucial because:

1. Early detection prevents irreversible damage: Lung damage in A1AT deficiency is irreversible, making early diagnosis critical for initiating appropriate interventions 1

2. Delayed diagnosis worsens outcomes: Studies show that delayed diagnosis is associated with worse overall survival and transplant-free survival 1

3. Clinical presentation alone is insufficient: The clinical picture is not adequately sensitive to alert clinicians to the presence of the disease 1

4. Targeted interventions can be initiated: Early identification allows for:

   • Consideration of augmentation therapy
   • Avoidance of environmental exposures
   • Smoking cessation
   • Family screening
   • Monitoring for liver disease 2

Diagnostic Algorithm

Two-Step Testing Approach:

1. Initial Testing:

   • For moderate suspicion: Measure serum A1AT level
   • For high suspicion: Consider both serum A1AT level and genetic testing simultaneously

2. Follow-up Testing:

   • If A1AT level < 23 μmol/L (< 1.2 g/L): Proceed to DNA sequencing of SERPINA1 gene
   • If A1AT level ≥ 23 μmol/L (≥ 1.2 g/L) with moderate suspicion: No A1AT deficiency
   • If high clinical suspicion despite normal levels: Consider DNA sequencing to detect dysfunctional variants 1, 2

Important Testing Considerations:

• Acute phase reactant: Be aware that A1AT levels can be falsely elevated during inflammation, potentially masking deficiency 2
• Avoid targeted genotyping alone: It may miss rare mutations 2
• Use standardized nomenclature: The Human Genome Variation Society (HGVS) nomenclature provides more precise classification 2

Clinical Impact of Diagnosis

Identifying A1AT deficiency has significant implications:

1. Augmentation therapy consideration: For patients with severe deficiency (levels <11 μmol/L or <0.57 g/L) with documented emphysema and FEV1 <80% predicted 1, 3

2. Family screening: First-degree relatives should be tested with both serum levels and genetic testing 2

3. Liver monitoring: Regular liver function tests and imaging are recommended 2

4. Lifestyle modifications:

   • Smoking cessation is critical
   • Avoidance of environmental pollutants
   • Maintaining vaccination status
   • Avoiding hepatotoxic medications 1, 4

Common Pitfalls to Avoid

1. Underdiagnosis: Despite being one of the most common inherited conditions (affecting about 1 in 2000-5000 people), A1AT deficiency remains underrecognized 5

2. Relying solely on protein levels: Some genetic variants (like Pi*F) have normal circulating levels but dysfunctional protein 1

3. Missing heterozygotes: Heterozygous carriers may still have increased risk, especially with environmental exposures 6

4. Delayed testing: Testing should be performed at diagnosis of COPD, not after years of disease progression 1

5. Overlooking non-pulmonary manifestations: A1AT deficiency can also present with liver disease, panniculitis, or vasculitis 7

By implementing systematic testing for A1AT deficiency in appropriate populations, clinicians can identify affected individuals earlier, potentially improving outcomes through targeted interventions and family screening.