Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder caused by pathogenic variants in the SERPINA1 gene. The Z allele is the most clinically important severe variant; the S allele generally causes a less severe reduction in circulating protein. The phenotype is shaped by the genotype, the serum alpha-1 antitrypsin concentration, smoking exposure, and other lung insults. Alpha-1 antitrypsin is produced mainly by hepatocytes and circulates to the lungs, where it inhibits neutrophil elastase. Neutrophil elastase is useful during infection, but without adequate inhibition it continues digesting structural proteins. The result is destruction of alveolar elastin, loss of elastic recoil, permanent air-space enlargement, and obstructive physiology. This is why AATD classically produces panacinar emphysema with lower-lobe predominance, often at a younger age than typical smoking-related COPD, which more often produces an upper-lobe centrilobular pattern. The liver problem follows a different route. A Z protein can misfold, polymerize, and remain trapped inside hepatocytes instead of being secreted into the bloodstream. That retained protein injures the liver and may progress through fibrosis to cirrhosis and hepatocellular carcinoma. A useful clinical distinction is...