Title: Pediatric and adult liver disease in alpha1-antitrypsin deficiency
Source: Seminars in Liver Disease 2023, July 4. [E-publication]
Date of publication: July 2023
Publication type: Review
Abstract: Alpha1-antitrypsin (AAT) deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impair the production or secretion of this hepatocellular protein and lead to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2-10% of carriers as neonatal cholestasis and 20-35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.