Caroli's Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model

Abstract

Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD). It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF). The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK) rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats.

Figure 1

The liver of a Caroli's disease patient with CHF. Multiple cystic dilatations of the intrahepatic bile ducts are grossly (a) and histologically (b) visible. Hematoxylin-eosin staining (b).

Figure 2

Dynamic CT reveals multiple cystic dilatations of the intrahepatic bile ducts in a patient with Caroli's disease with CHF. The arrows indicate the central dot sign.

Figure 3

The liver of a PCK rat. The gross (a) and histological (b) appearance of the adult rat liver closely resembles those of patients with Caroli's disease with CHF (Figure 1). Hematoxylin-eosin staining (b).

Figure 4

Ductal plate malformation in the fetal liver of a PCK rat. Compared with a normal fetal rat (a), dilatation of the ductal plate is evident in the PCK liver (b, asterisks). Hematoxylin-eosin staining (a, b).