Progressive familial intrahepatic cholestasis. Genetic basis and treatment

Major advances in the understanding of the molecular mechanisms of bile formation and genetic studies of children with chronic cholestasis uncovered the molecular basis of PFIC. Specific defects in the FIC1, BSEP, and MDR3 genes are responsible for distinct PFIC phenotypes. These findings have confirmed the autosomal recessive inheritance of the disease and now provide specific diagnostic tools for the investigation of children with PFIC. This understanding should also allow prenatal diagnosis in the future. Identification of mutations in these genes will allow genotype-phenotype correlations to be defined within the spectrum of PFIC. These correlations performed in patients previously treated by UDCA or biliary diversion should identify those PFIC patients who could benefit from these therapies. In the future, other therapies, such as cell and gene therapies, might represent an alternative to liver transplantation. It remains to be determined if defects in the FIC1, BSEP, and MDR3 genes are responsible for all types of PFIC, or if other yet undiscovered genes, possibly involved in bile formation or its regulation, may be involved in the pathogenesis of PFIC.