A series of studies that directly addressed the molecular mechanisms that control liver development and hepatic excretory function served as the biologic basis for enhanced understanding of the molecular basis of hepatobiliary dysfunction manifest as intrahepatic Vismodegib chemical structure cholestasis.[27, 28, 75] The heterogeneity reflected inherited defects in mechanisms involved in the generation of bile flow, specifically canalicular transport proteins resulting in substrate retention manifest
as cholestasis. Patients with the most common types of PFIC were shown to harbor mutations in genes encoding proteins involved in bile acid transport: (1) ATP8B1 gene, encoding FIC1 (patients with PFIC Type 1); (2) ABCB11 gene, encoding the bile salt export
pump (BSEP, patients with PFIC Type 2); and (3) ABCB4 gene, encoding the multidrug Stem Cell Compound Library screening resistance protein-3 (MDR3, patients with PFIC Type 3). In addition, the complex phenotype, molecular genetics, and inheritance pattern of Alagille syndrome were defined, with linkage to mutations in human Jagged1 (JAG1), which encodes a ligand for the Notch receptor.[76-78] The Notch gene family encodes evolutionarily conserved transmembrane receptors involved in cell fate specification during embryonic development. This locus controls the ability of cells that are nonterminally differentiated to respond to differentiation and proliferation signals. In Alagille syndrome, mutations in JAG1 disrupt the gene product, altering cell-to-cell signaling during development. These investigations allowed classification of these disorders into distinct subsets[28] (Table 1). To translate this knowledge into practical applications in the clinic, Jorge Bezerra and co-workers[79] developed the “Jaundice Chip,”
which uses a “resequencing” platform that enables the detection of mutations of these genes. Studies also addressed the importance of heterozygosity Leukotriene-A4 hydrolase for these genes in creating genetic susceptibility to injury initiated by other agents such as drugs, toxins, or viruses. In addition, detailed understanding of the underlying pathophysiology of altered bile acid transport allowed for the development of specific targeted therapy. Based on initial studies, ursodeoxycholic acid became popular as a therapeutic agent in patients with intrahepatic cholestasis; this is now an accepted form of therapy worldwide.[80, 81] The body of knowledge related to hepatobiliary disease in children expanded in other needed areas. Enigmatic disorders presenting as acute liver failure, chronic hepatitis, or hepatocellular carcinoma yielded to biochemical analysis and molecular dissection and were proven to be caused by inborn errors of lipid, amino acid, or carbohydrate metabolism. The recognition of the metabolic basis for liver disease allowed for targeted nontransplant strategies for the management of affected patients.