https://pubmed.ncbi.nlm.nih.gov/37611641/ BILIARY ATRESIA

J Hepatol. 2023 Aug 21;S0168-8278(23)05060-2.
doi: 10.1016/j.jhep.2023.08.010.Online ahead of print.

A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia

Iris E M de Jong 1, Mallory L Hunt 2, Dongning Chen 3, Yu Du 4, Jessica Llewellyn 5, Kapish Gupta 5, David Li 5, Dorothea Erxleben 6, Felipe Rivas 6, Adam R Hall 7, Emma E Furth 8, Ali Naji 9, Chengyang Liu 9, Abhishek Dhand 10, Jason A Burdick 11, Marcus G Davey 12, Alan W Flake 12, Robert J Porte 13, Pierre A Russo 14, J William Gaynor 2, Rebecca G Wells 15

Abstract

Introduction: Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury.

Methods: Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes.

Results: A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device.

Conclusion: The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD.