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.

Keywords: Alagille syndrome (ALGS); JAG1; NOTCH2; Notch signaling; bile duct paucity; cholestasis; liver disease.

Figure 1

Liver biopsy from a 5-month old cholestatic infant with ALGS. (A) Hematoxylin and eosin stain of liver biopsy shows a portal tract (arrow) with branches of hepatic artery and portal vein but no bile duct present. (B) Cytokeratin 19 staining highlights minimal ductular reaction around portal tracts (arrow) throughout the biopsy. Scale bar =200 µM. ALGS, Alagille syndrome.