Location: Children's Nutrition Research CenterTitle: Towards a model of biliary atresia - pilot feasibility study in newborn piglets
|WESENBERG HELT, THORA - Rigshospitalet - Copenhagen University Hospital|
|BUELUND, LENE - University Of Copenhagen|
|BORGEWARDT, LISE - Rigshospitalet - Copenhagen University Hospital|
|ERIKSEN, THOMAS - University Of Copenhagen|
|JOHANSEN, LARS - Rigshospitalet - Copenhagen University Hospital|
|DE NIJS, ROBIN - Rigshospitalet - Copenhagen University Hospital|
|HOLM, SOREN - Rigshospitalet - Copenhagen University Hospital|
|Burrin, Douglas - Doug|
|THYMANN, THOMAS - University Of Copenhagen|
|BRIX CHRISTENSEN, VIBEKE - University Of Copenhagen|
Submitted to: Biochemistry and Biophysics Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/17/2023
Publication Date: 5/23/2023
Citation: Wesenberg Helt, T., Buelund, L., Borgewardt, L., Eriksen, T., Johansen, L., De Nijs, R., Holm, S., Burrin, D.G., Thymann, T., Brix Christensen, V. 2023. Towards a model of biliary atresia - pilot feasibility study in newborn piglets. Biochemistry and Biophysics Reports. 34. Article 101487. https://doi.org/10.1016/j.bbrep.2023.101487.
Interpretive Summary: Biliary atresia (BA) is a rare liver disease in infants that leads to jaundice, liver injury and often requires a liver transplant. The liver injury in BA infants occurs because the ducts that drain bile from the liver into the intestine do not form correctly prior to birth due to unknown reasons. An adverse effect of jaundice in BA infants is liver tissue injury caused by accumulation of bile acids in the liver and blood. There is a lack of appropriate animal models of spontaneous development of biliary atresia. In this study, we used neonatal piglets to model biliary atresia by ligating the bile duct (BDL group) soon after birth. After two weeks of BDL, we performed imaging studies in BDL and control pigs to verify whether BDL prevented the flow of bile out of the liver into the gallbladder and intestine. Imaging studies confirmed that BDL did block bile flow into the intestine. Importantly, we found that BDL caused fat accumulation on stool samples due to lack of bile acid function in intestinal fat digestion. We also found that BDL pigs experienced clinical signs of cholestasis or jaundice marked by increased plasma bilirubin and GGT levels. Our results confirm that BDL in newborn piglets provides a new animal model to study the effects of severe jaundice and liver injury that often is observed in infants with biliary atresia.
Technical Abstract: Biliary atresia (BA) is a rare congenital liver disease with unknown etiology, and it is the most common indication for liver transplantation in children. As BA infants suffer from intestinal malabsorption and neurodevelopmental deficits, it is necessary to identify optimal medical and nutritional strategies using appropriate neonatal animal models. We aim to determine the feasibility of using newborn piglets with surgically induced cholestasis (bile duct ligation (BDL)) to mimic clinical features of BA. Six piglets were subjected to abdominal surgery on day 4 after birth. The bile ducts were ligated, and the piglet were followed for up to 12 days. On day 12 the piglets were subjected to a hepatobiliary scintigraphy using the tracer radiolabeled Technetium(99m-tc)-mebrofenin, and blood samples were collected for biochemical profiling. Of the six piglets, hepatobiliary scintigraphy verified that two piglets (BDL) had no excretion of bile into the duodenum, i.e. full cholestasis with a hepatic extraction fraction of 84–87% and clearance time of 230–318 min. One piglet (SHAM) had bile excretion to the duodenum. In accordance with this, the BDL piglets had steatorrhea, and increased levels of bilirubin and gammaglutamyl transferase (GGT). The last three piglets were euthanized due to bile leakage or poor growth. Surgically induced cholestasis in young piglets, may offer an animal model that displays clinical characteristics of biliary atresia, including malabsorption, hyperbilirubinaemia, increased GGT and reduced hepatic excretory function. Following refinement, this animal model may be used to optimize feeding strategies to secure optimal nutrition and neurodevelopment for neonatal cholestasis/BA patients.