Pathophysiology
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 โ 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 โ a gain-of-function toxic mechanism independent of the lung disease.