Anomalous development of the hepatobiliary system in the Inv mouse

Extrahepatic biliary atresia (BA) is a devastating disease of the neonate i n which the hepatic and/or common bile duct is obliterated or interrupted. Infants and children with this diagnosis constitute 50% to 60% of the pedia tric population that undergoes orthotopic liver transplantation. However, t here is still very little known about the etiology and pathogenesis of BA, Several recent studies have demonstrated that anomalies of situs determinat ion are more commonly associated with BA than previously recognized. In thi s study, we examined the pathogenesis of jaundice in the inv mouse, a trans genic mouse in which a recessive deletion of the inversin gene results in s itus inversus and jaundice. The results show that these mice have cholestas is with conjugated hyperbilirubinemia, failure to excrete technetium-labele d mebrofenin from the liver into the small intestine, lack of continuity be tween the extrahepatic biliary tree and the small intestine as demonstrated by Trypan blue cholangiography, and a liver histological picture indicativ e of extrahepatic biliary obstruction with negligible inflammation/necrosis within the hepatic parenchyma. Lectin histochemical staining of biliary ep ithelial cells in serial sections suggests the presence of several differen t anomalies in the architecture of the extrahepatic biliary system. These r esults suggest that the inversin gene plays an essential role in the morpho genesis of the hepatobiliary system and raise the possibility that alterati ons in the human orthologue of inversin account for some of the cases of BA in which there are also anomalies of situs determination.