Blood Testing for Non-Smoking COPD with Family History
For a non-smoking patient with a family history of COPD and early onset symptoms, measure serum alpha-1 antitrypsin (AAT) level immediately, followed by DNA sequencing of the SERPINA1 gene to definitively diagnose alpha-1 antitrypsin deficiency. 1
Why This Patient Needs Testing
Your clinical scenario represents high clinical suspicion for alpha-1 antitrypsin deficiency based on three critical features: 1
- Family history of COPD - First-degree relatives of AAT-deficient individuals have significantly increased risk of carrying deficiency alleles 1, 2
- Early onset symptoms - Symptoms before age 40 are a hallmark of AAT deficiency 1
- Non-smoking status - COPD in a non-smoker should immediately trigger consideration of AAT deficiency 1, 2
The Canadian Thoracic Society explicitly recommends testing all first-degree relatives of individuals with documented AAT deficiency, even without symptoms. 2 Your patient meets even stricter criteria by having symptoms. 1
The Two-Step Testing Algorithm
Step 1: Serum AAT Level
- Draw blood to measure serum alpha-1 antitrypsin concentration 1
- Critical threshold: 23 mmol/L (1.2 g/L) 1, 3
- Levels below this threshold indicate possible deficiency and mandate genetic testing 1
- Severe deficiency defined as: <11 mmol/L (<0.57 g/L) 3
Step 2: DNA Sequencing (SERPINA1 Gene)
Given this patient's high clinical suspicion, proceed directly to DNA sequencing simultaneously with the serum level, rather than waiting for results. 1, 3 This is because:
- DNA sequencing is the gold standard for diagnosis 1, 3
- It detects all >300 genetic variants in a single test 3
- Serum levels can be falsely normal during acute inflammation 1, 3
- Some dysfunctional variants (like Pi*F) show normal serum levels but still cause disease 1, 3
Critical Testing Pitfalls to Avoid
Do NOT test during: 3
- Acute illness or infection
- Recent surgery
- Active inflammation
These conditions artificially elevate AAT levels (it's an acute phase reactant), potentially masking deficiency and causing false-negative results. 1, 3
Do NOT rely solely on serum levels in high-risk patients like yours - even if the level comes back >23 mmol/L, still proceed with genetic testing given the family history and early symptoms. 1
What the Genetic Test Reveals
DNA sequencing identifies the specific genotype: 1, 3
- Pi*ZZ - Severe deficiency (most common severe form, 1.2% of COPD patients) 4
- Pi*SZ - Severe deficiency (0.3% of COPD patients) 4
- Pi*MZ - Intermediate deficiency (2.89% of COPD patients, increased risk especially with smoking or occupational exposures) 4, 5
- Pi*MS - Mild deficiency (2.5% of COPD patients) 4
This precise genotype classification cannot be achieved by protein levels alone and is essential for accurate risk assessment and family counseling. 1, 3
Why Early Diagnosis Matters for This Patient
Life expectancy in AAT-deficient non-smokers can be nearly normal (69 years) versus only 49 years in smokers. 2 Early diagnosis enables:
- Absolute avoidance of smoking (the single most important intervention) 2, 5
- Avoidance of risky occupational exposures (dust, fumes, respiratory irritants) 2
- Testing of other family members who may be at risk 2, 3
- Consideration for augmentation therapy if severe deficiency is confirmed with documented emphysema 1
Late diagnosis is associated with reduced functional status, worse quality of life, and decreased overall survival. 3 The average diagnostic delay typically exceeds 5 years, with diagnosis occurring around age 45 - far too late for optimal intervention. 6
Practical Collection Method
A simple dried blood spot on filter paper (finger stick) can be used for both AAT level measurement and DNA extraction from the buffy coat, making testing accessible and easy to perform. 3, 4, 7 This method correlates well with standard venipuncture techniques and allows samples to be sent by surface mail to specialized laboratories. 7