Clinical meaning
Alpha-1 antitrypsin (AAT) is a serine protease inhibitor (serpin) primarily produced by hepatocytes. Its main function is to inhibit neutrophil elastase in the lungs, protecting alveolar tissue from proteolytic destruction during inflammatory responses. The SERPINA1 gene has codominant alleles: M (normal), S (moderate deficiency), Z (severe deficiency — misfolded protein polymerizes in hepatocyte ER). ZZ homozygotes have AAT levels 10-15% of normal. Unopposed neutrophil elastase destroys alveolar walls, causing panlobular emphysema predominantly in the lung bases (unlike smoking-related centrilobular emphysema that favors upper lobes). The Z-variant AAT also polymerizes within hepatocyte ER, causing ER stress, hepatocyte injury, and cirrhosis — a gain-of-function toxic mechanism independent of the lung disease.
Diagnosis & workup
Diagnostics & workup: - Serum AAT level: <11 μmol/L (<57 mg/dL) in ZZ homozygotes (normal 20-53 μmol/L) - SERPINA1 genotyping: identifies M, S, Z, and rare alleles - AAT phenotyping by isoelectric focusing: confirms protein variant - PFTs: obstructive pattern (reduced FEV1/FVC) with hyperinflation, reduced DLCO - CT chest: panlobular emphysema predominantly in LOWER lobes (basilar predominant) - LFTs: elevated transaminases if hepatic involvement - Liver biopsy: PAS-positive, diastase-resistant globules in hepatocytes (accumulated Z-AAT) - Screen all patients with COPD diagnosed < 45 years, non-smokers with emphysema, or family history