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Anomalous development of the hepatobiliary system in the Inv mouse
M V Mazziotti1, L K Willis, R O Heuckeroth
1Department of Surgery, Washington University School of Medicine, Washington School of Medicine, St. Louis, MO, USA.
Insights
Biliary atresia (BA) in infants involves bile duct obstruction. This study suggests the inversin gene is crucial for hepatobiliary system development, potentially explaining some BA cases linked to situs anomalies.
Area of Science:
- Hepatology
- Developmental Biology
- Genetics
Background:
- Biliary atresia (BA) is a severe neonatal liver disease affecting bile duct integrity.
- BA necessitates liver transplantation in 50-60% of affected children.
- The etiology and pathogenesis of BA remain poorly understood, with emerging links to situs determination anomalies.
Purpose of the Study:
- To investigate the role of the inversin gene in the pathogenesis of jaundice and biliary abnormalities.
- To examine the utility of the inv mouse model for studying biliary atresia.
Main Methods:
- Utilized the inv mouse model with a deletion in the inversin gene, exhibiting situs inversus and jaundice.
- Assessed cholestasis, hyperbilirubinemia, hepatobiliary excretion using technetium-labeled mebrofenin, and biliary tract-intestinal continuity via Trypan blue cholangiography.
- Performed lectin histochemical staining on biliary epithelial cells to analyze biliary system architecture.
Main Results:
- Inv mice displayed cholestasis, conjugated hyperbilirubinemia, and impaired excretion of technetium-labeled mebrofenin.
- Cholangiography revealed a lack of continuity between the extrahepatic biliary tree and the small intestine.
- Histological examination indicated extrahepatic biliary obstruction without significant hepatic inflammation or necrosis.
- Lectin staining identified anomalies in the extrahepatic biliary system architecture.
Conclusions:
- The inversin gene plays a critical role in the morphogenesis of the hepatobiliary system.
- Alterations in the human orthologue of inversin may contribute to biliary atresia cases associated with situs determination anomalies.
Abstract:
Extrahepatic biliary atresia (BA) is a devastating disease of the neonate in which the hepatic and/or common bile duct is obliterated or interrupted. Infants and children with this diagnosis constitute 50% to 60% of the pediatric population that undergoes orthotopic liver transplantation. However, there is still very little known about the etiology and pathogenesis of BA. Several recent studies have demonstrated that anomalies of situs determination are more commonly associated with BA than previously recognized. In this study, we examined the pathogenesis of jaundice in the inv mouse, a transgenic mouse in which a recessive deletion of the inversin gene results in situs inversus and jaundice. The results show that these mice have cholestasis with conjugated hyperbilirubinemia, failure to excrete technetium-labeled mebrofenin from the liver into the small intestine, lack of continuity between the extrahepatic biliary tree and the small intestine as demonstrated by Trypan blue cholangiography, and a liver histological picture indicative of extrahepatic biliary obstruction with negligible inflammation/necrosis within the hepatic parenchyma. Lectin histochemical staining of biliary epithelial cells in serial sections suggests the presence of several different anomalies in the architecture of the extrahepatic biliary system. These results suggest that the inversin gene plays an essential role in the morphogenesis of the hepatobiliary system and raise the possibility that alterations in the human orthologue of inversin account for some of the cases of BA in which there are also anomalies of situs determination.