Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts.

Abstract

The observation of bile duct paucity is an important diagnostic finding in children, occurring in roughly 11% of pediatric liver biopsies. Alagille syndrome (ALGS) is a well-defined syndromic form of intrahepatic bile duct paucity that is accompanied by a number of other key features, including cardiac, facial, ocular, and vertebral abnormalities. In the absence of these additional clinical characteristics, intrahepatic bile duct paucity results in a broad differential diagnosis that requires supplementary testing and characterization. Nearly 30 years after ALGS was first described, genetic studies identified a causative gene, JAGGED1, which spearheaded over two decades of research aimed to meticulously delineate the molecular underpinnings of ALGS. These advancements have characterized ALGS as a genetic disease and led to testing strategies that offer the ability to detect a pathogenic genetic variant in almost 97% of individuals with ALGS. Having a molecular understanding of ALGS has allowed for the development of numerous in vitro and in vivo disease models, which have provided hope and promise for the future generation of gene-based and protein-based therapies. Generation of these disease models has offered scientists a mechanism to study the dynamics of bile duct development and regeneration, and in doing so, produced tools that are applicable to the understanding of other congenital and acquired liver diseases.