Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases


Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

Key points

  • Reactivation of morphogen signalling (such as Notch, Wnt–β-catenin and Hedgehog) takes place during biliary repair and orchestrates the balance between biliary remodelling and fibrogenesis and transdifferentiation and carcinogenesis.

  • Polycystins control fundamental Ca2+–cAMP-dependent cell signalling processes in cholangiocytes and, when defective, these proteins enhance cell proliferation and activate angiogenic signalling that leads to cystogenesis.

  • Polycystin-2 can be modulated in response to biliary inflammation and mediates vascular endothelial growth factor secretion and cholangiocyte proliferation in acquired cholangiopathies.

  • Genetic defects in fibrocystin are associated with altered β-catenin signalling, which generates an auto-inflammatory response with secretion of chemokines that are able to attract macrophages, resulting in biliary fibrogenesis.

  • Cystic fibrosis transmembrane conductance regulator (CFTR) regulates cholangiocyte innate immunity and maintains Toll-like receptor tolerance; loss of CFTR predisposes the biliary epithelium to inflammation and damage in response to gut-derived microbial components.

  • Pathological mechanisms identified in genetic cholangiopathies can be applied to acquired cholangiopathies and might represent potential targets for the next generation of treatments.

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Fig. 1: Notch signalling in biliary development and disease.
Fig. 2: Signalling mechanisms involved in cyst growth in ADPKD.
Fig. 3: Novel mechanisms of biliary fibrosis in ARPKD.
Fig. 4: CFTR function in cholangiocytes.


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This work was supported by the National Institutes of Health (RO1DK096096 (M.S.), RO1DK-079005-07 (M.S.) and RO1DK101528 (C.S.)); by DK034989 Silvio O. Conte Digestive Diseases Research Core Center (M.S., C.S. and R.F.); by PSC Partners Seeking a Cure (M.S.); by a grant from Connecticut Innovations (16-RMA-YALE-26) (M.S.); by a grant from Cystic Fibrosis Foundation (FIOROT18GO) (R.F.); by the University of Padua, Progetti di Ricerca di Dipartimento (PRID) 2017 (L.F.); by the Spanish Ministry of Economy and Competitiveness and “Instituto de Salud Carlos III” grants PI14/00399, PI17/00022 and Ramon y Cajal Programme RYC-2015-17755 (M.J.P.) and by PI15/01132, PI18/01075 and Miguel Servet Programme CON14/00129 co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER) (J.M.B.); by CIBERehd, Spain (M.J.P. and J.M.B.); by IKERBASQUE, Basque foundation for Science, Spain (M.J.P. and J.M.B.); by “Diputación Foral de Gipuzkoa” DFG18/114 (M.J.P.), DFG15/010 and DFG16/004 (J.M.B.); by BIOEF (Basque Foundation for Innovation and Health Research): EiTB Maratoia BIO15/CA/016/BD (J.M.B.); by the Department of Health of the Basque Country (2015111100 (M.J.P.) and 2017111010 (J.M.B.)); and by AECC Scientific Foundation (J.M.B.).

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Nature Reviews Gastroenterology & Hepatology thanks S. Karpen and the other anonymous reviewers for their contribution to the peer review of this work.

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Correspondence to Mario Strazzabosco.

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Fabris, L., Fiorotto, R., Spirli, C. et al. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat Rev Gastroenterol Hepatol 16, 497–511 (2019) doi:10.1038/s41575-019-0156-4

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