Elevated Alpha-1 Antitrypsin Levels: Clinical Significance
An elevated alpha-1 antitrypsin (A1AT) level indicates an acute phase response to inflammation, infection, tissue injury, recent surgery, or pregnancy—not alpha-1 antitrypsin deficiency. 1, 2
Understanding A1AT as an Acute Phase Reactant
A1AT is an acute phase protein that rises 3- to 6-fold during inflammatory conditions, making elevated levels a marker of systemic inflammation rather than a pathologic state. 2, 3, 4, 5
Common Causes of Elevated A1AT Levels
- Active infections (bacterial, viral, or fungal) trigger A1AT elevation as part of the host inflammatory response. 2
- Acute exacerbations of chronic diseases (COPD flares, inflammatory bowel disease, rheumatologic conditions) cause A1AT to rise. 2
- Recent surgery or tissue injury stimulates A1AT production as part of wound healing. 1, 2
- Pregnancy causes A1AT levels to increase 4- to 6-fold above baseline, representing a normal physiologic response. 6, 4
- Malignancy and chronic inflammatory states can produce sustained A1AT elevation. 7
Critical Diagnostic Pitfall
The most important clinical implication of elevated A1AT is that it can mask underlying A1AT deficiency. Patients with true genetic A1AT deficiency may show falsely normal or even elevated levels during acute illness, with levels reaching as high as 1.4 g/L (140 mg/dL) during inflammatory episodes. 1, 2, 3
When to Suspect Masked Deficiency
- Never test for A1AT deficiency during acute illness, recent surgery, or active inflammation, as these conditions artificially elevate A1AT levels and obscure the diagnosis. 1, 8, 2
- If clinical suspicion for A1AT deficiency remains high despite normal or elevated A1AT levels, proceed directly to DNA sequencing of the SERPINA1 gene rather than relying on repeat protein measurements. 1, 8, 2
- High-risk features mandating genetic testing regardless of A1AT level include early-onset COPD (before age 40), minimal smoking exposure (<10 pack-years), panlobular emphysema, or family history of A1AT deficiency. 1, 8
Genotype-Specific Inflammatory Response
Different A1AT genotypes respond differently to inflammation, with important implications for interpretation:
- PI*MM (normal) genotype shows a strong acute phase response, with median levels rising from 142 mg/dL to 162 mg/dL during inflammation. 3
- PI*MZ (heterozygote) genotype shows median levels rising from 85 mg/dL to 104 mg/dL, and approximately 25% of PI*MZ individuals have signs of inflammation that mask their reduced baseline levels. 3
- PI*ZZ (severe deficiency) genotype shows a reduced acute phase response compared to normal individuals, but levels can still rise enough to appear falsely reassuring. 1, 2, 3
Practical Testing Recommendations
When evaluating an elevated A1AT level, measure C-reactive protein (CRP) simultaneously to determine whether inflammation is present and affecting the A1AT measurement. 3
- If CRP ≥5 mg/L, the elevated A1AT is likely due to acute phase response and the test should be repeated after resolution of the inflammatory condition. 3
- If CRP is normal and A1AT is elevated, this represents true elevation and A1AT deficiency is effectively ruled out in moderate-risk patients. 8
- For high-risk patients with suggestive clinical features, proceed to SERPINA1 gene sequencing regardless of A1AT or CRP levels, as rare dysfunctional variants can produce normal circulating levels with non-functional protein. 1, 8
When Elevated A1AT Has No Clinical Significance
In the absence of specific clinical concerns for A1AT deficiency, an isolated elevated A1AT level requires no further workup beyond identifying and addressing the underlying inflammatory condition. The elevation itself does not cause disease and resolves when the inflammatory stimulus resolves. 2, 4, 7