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  • Review Article
  • Published:

Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes

Nature Reviews Gastroenterology & Hepatology volume 12, pages 342–352 (2015)Cite this article

Subjects

Key Points

  • Biliary atresia is an inflammatory and fibrosing cholangiopathy of infancy caused by viruses, environmental toxins and targeted epithelial injury that obstructs extrahepatic bile ducts and rapidly progresses to end-stage cirrhosis

  • Precise clinical phenotyping classifies patients into nonsyndromic and embryonic forms, and into cyst-associated and cytomegalovirus-associated variants, which might have different disease pathologies

  • Liver tissue scoring for inflammation and fibrosis by histological features and gene expression profiles identifies different stages of disease at diagnosis

  • Analyses of human livers and models of experimental biliary atresia suggest that a type 1 immune response has a key role in the pathogenesis of bile duct injury and obstruction

  • The expression of type 2 cytokines promote cholangiocyte proliferation in extrahepatic bile ducts and hepatic fibrosis

  • Clinical, histological and molecular variability of disease at presentation form a strong rationale for future trials that take into consideration the predominant biological features of affected infants

Abstract

Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.

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Figure 1: Cellular targets and molecular events after RRV infection.
Figure 2: Biological processes and effectors of injury in biliary atresia.
Figure 3: Epithelial and fibrogenic response induced by IL-33.
Figure 4: Designing clinical trials based on biological stages of liver disease.

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Acknowledgements

The authors are supported by the NIH grants DK64008 and DK83781 to J.A.B. and DK95001 to A.M. J.A.B. is the Cincinnati Principal Investigator of the NIDDK-funded Childhood Liver Disease and Research Network (NIH grant DK62497).

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  1. Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, 45229-3039, OH, USA

    Akihiro Asai, Alexander Miethke & Jorge A. Bezerra

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  1. Akihiro Asai
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J.A.B. and A.A. contributed equally to researching data for the manuscript. All authors contributed equally to the discussion of content, writing and reviewing and editing the manuscript before submission.

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Correspondence to Jorge A. Bezerra.

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Asai, A., Miethke, A. & Bezerra, J. Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat Rev Gastroenterol Hepatol 12, 342–352 (2015). https://doi.org/10.1038/nrgastro.2015.74

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