Congenital Hepatic Fibrosis and Caroli Disease

Autosomal Recessive Polycystic Kidney Disease (ARPKD), Congenital Hepatic Fibrosis (CHF) and Caroli’s Disease (CD), are genetic disorders of the kidney and liver caused by defective function of fibrocystin (FPC) or polyductin, the protein encoded by the PKHD1 gene. Despite sharing some common pathological traits, these diseases differ for several aspects, including age of onset.

FPC is localized in the primary cilia, basal bodies, and centromeres of several epithelial ductal structures, such as pancreatic and renal ducts, salivary glands, and biliary cells. FPC is expressed by cholangiocytes, and it is implicated in maintaining the tubular structure of the bile ducts. In mice, inactivation of the Pkhd1 gene causes biliary dysgenesis accompanied by periportal fibrosis and portal hypertension. The precise function of FPC is still largely unknown but is thought to be involved in a variety of cellular functions, including regulation of proliferation, secretion, differentiation, tubulogenesis, planar cell polarity and cell-matrix interaction.

Fibropolycystic diseases are characterized by ductal dysgenesia with generation of biliary microhamartomas and segmental dilations displaying a fetal-like phenotype (ductal plate remnants, that remain in connection with the biliary system), that progressively enlarge in association with a dense and worsening fibrosis and a smoldering portal inflammatory infiltrate, leading to portal hypertension and hepatic failure.

Our lab is currently studying the mechanistic relationship between the genetic defect and development of portal fibrosis using a mouse model harboring a deleting mutation in Pkhd1, that we have shown to have a phenotype orthologous to CHF/CD. These studies will increase our understanding of the mechanism linking cholangiocyte dysfunction to peribiliary fibrosis and will generate therapeutic strategies for patients with CHF/CD and also for other fibrosis cholangiopathies.