Unravelling the risk of (intermediate) antitrypsin deficiency

The seminal observation of severe deficiency of alpha-1-antitrypsin (AAT) with premature emphysema over 50 years ago led to the elastase–antielastase hypothesis of lung disease. Subsequent research identified alpha-1-antitrypsin deficiency (AATD) as an inherited metabolic genetic condition caused by mutations on the SERPINA1 gene, resulting in a reduction in the serum concentration of AAT.1 The role of AAT is to act as an inhibitor to the enzyme neutrophil elastase, and it is crucial in the homeostasis of elastase–antielastase activity, with an imbalance in this activity causing lung disease via a cycle of inflammation and proteolytic damage leading to premature emphysema, disability and death. There are over 100 mutations of SERPINA1 described in the literature, some of which are associated with AATD. The normal genotype is designated PiMM; the most common genotype resulting in severe deficiency is designated PiZZ. AATD is an autosomal codominant condition so heterozygosity can also create in genotypes resulting in mild and intermediate deficiency, such as PiMZ and PiSZ. The prevalence of AATD worldwide is estimated between 0.02% and 0.05%. Normal AAT serum concentration would be in the range 20–53 µmol/L, while deficient genotypes express varying levels, from 55% for PiMZ to 40% for PiSZ and <15% for PiZZ. While the risk of developing premature emphysema in PiZZ is beyond doubt, there has been considerable debate regarding the risk of SZ genotype (intermediate deficiency) and emphysema severity.2 The study carried out by Franciosi et al 3 in this journal is a welcome addition to the area aiming to further understand the PiSZ genotype and its effect on lung disease. Their results imply that …