My serum alpha‑1‑antitrypsin (A1AT) level is 254 mg/dL; what does this elevated result mean and what should be the next steps in management?

Elevated Alpha-1 Antitrypsin Level: Interpretation and Management

Your A1AT level of 254 mg/dL is well above the protective threshold and effectively rules out severe alpha-1 antitrypsin deficiency, but this elevated result likely represents an acute-phase reaction to inflammation, infection, or other physiologic stress rather than a normal baseline value. 1

Understanding Your Result

Normal Reference Ranges

• Normal (PI*MM) phenotype: 150-350 mg/dL 1
• Protective threshold: ≥80 mg/dL (by radial immunodiffusion) or ≥50 mg/dL (by nephelometry), equivalent to ≥11 μmol/L 1
• Severe deficiency threshold: <57 mg/dL (<11 μmol/L) 2
• Your level of 254 mg/dL: Falls within the normal range for PI*MM individuals 1

Critical Interpretation Caveat

Alpha-1 antitrypsin is an acute-phase reactant protein, meaning its levels increase 3-4 fold during inflammation, infection, tissue injury, pregnancy, or estrogen use. 1, 3, 4 Your elevated level may be masking an underlying deficiency state if you have active inflammation. 4

Immediate Next Steps

Step 1: Assess for Acute-Phase Response

Check C-reactive protein (CRP) level simultaneously with repeat A1AT measurement. 4 If CRP is ≥5 mg/L, your A1AT level is artificially elevated and cannot be reliably interpreted. 4

Avoid testing during:

• Acute illness or infection 2
• Recent surgery 2
• Active inflammation or thrombosis 2
• Pregnancy or estrogen therapy 1

Step 2: Risk Stratification for Further Testing

Proceed directly to DNA sequencing of SERPINA1 gene (exons 2-5) if you have ANY of these high-risk features, regardless of your A1AT level: 1, 2

• Early-onset COPD (before age 40) 1, 2
• Minimal smoking history (<10 pack-years) with COPD 1
• Panlobular/basilar emphysema pattern on imaging 1, 2
• Family history of COPD or A1AT deficiency 1, 2
• History of neonatal jaundice 2
• First-degree relative with confirmed A1AT deficiency 5, 6

If you have moderate-risk features only (COPD without high-risk features, unexplained bronchiectasis, adult-onset asthma with persistent airflow obstruction, liver cirrhosis), repeat A1AT level when inflammation resolves: 1, 2

• If repeat level remains ≥120 mg/dL (≥23 μmol/L or ≥1.2 g/L), severe deficiency is ruled out 1
• If repeat level drops to <120 mg/dL, proceed to DNA sequencing 1

Step 3: Definitive Testing When Indicated

DNA sequencing of SERPINA1 gene is the gold standard and detects all >300 genetic variants, including rare dysfunctional variants (like PI*F) that may show falsely normal serum levels. 1, 2 This single test provides definitive genotype classification (PIZZ, PIMZ, PI*SZ, etc.) that cannot be achieved by protein levels alone. 1, 2

Common Pitfalls to Avoid

Measurement Variability Issues

• Commercial assays may overestimate A1AT by 35-40%, particularly with radial immunodiffusion. 1
• Nephelometry can be falsely elevated by lipemia or hemolysis. 1
• Test-retest reproducibility of A1AT levels is weak due to acute-phase variability. 1

Genotype-Specific Inflammation Response

Different genotypes respond differently to inflammation: 4

• PI*MM individuals show strong acute-phase response (median increase from 142 to 162 mg/dL) 4
• PI*MZ heterozygotes show moderate response (median increase from 85 to 104 mg/dL), and approximately 25% of PI*MZ individuals have inflammation masking their true deficiency status 4
• PI*ZZ individuals show blunted response but can still reach falsely reassuring levels 4

When Serum Levels Are Unreliable

Do not rely solely on serum A1AT levels in these situations: 2

• Active liver disease (levels may be normal in heterozygotes despite deficiency) 2
• Active vasculitis (Granulomatosis with polyangiitis) 2
• Any acute inflammatory condition 2, 4

Clinical Context

Why This Matters

Early diagnosis is critical because lung damage from A1AT deficiency is irreversible, and delayed diagnosis is associated with worse overall survival, reduced transplant-free survival, diminished functional status, and lower quality of life. 2, 5

If Deficiency Is Eventually Confirmed

• Absolute smoking cessation is mandatory (life expectancy: 69 years for non-smokers vs. 49 years for smokers with PI*ZZ deficiency) 5
• Avoid occupational exposures to dust, fumes, and respiratory irritants 5
• Augmentation therapy with intravenous A1AT (60 mg/kg weekly) may be indicated if emphysema develops, targeting serum levels >11 μmol/L 7, 8
• Family screening of first-degree relatives is essential 5, 6

In summary: Your current level of 254 mg/dL is reassuring but requires correlation with inflammatory markers and clinical context before definitively excluding A1AT deficiency, particularly if you have high-risk clinical features. 1, 2, 4