Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

• Published in: Seminars in liver disease Vol. 43; no. 3; p. 258
• Main Authors: Ruiz, Mathias, Lacaille, Florence, Schrader, Christina, Pons, Monica, Socha, Piotr, Krag, Aleksander, Sturm, Ekkehard, Bouchecareilh, Marion, Strnad, Pavel
• Format: Journal Article
• Language: English
• Published: United States 01.08.2023
• Subjects: Adult; alpha 1-Antitrypsin Deficiency - complications; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - therapy; Child; Cholestasis - complications; Genotype; Humans; Infant, Newborn; Liver Cirrhosis - complications; Liver Cirrhosis - genetics
• ISSN: 1098-8971
• DOI: 10.1055/a-2122-7674

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in , the AAT gene that impairs the production or secretion of this hepatocellular protein and leads 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 to 10% of carriers as neonatal cholestasis and 20 to 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.