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Primary biliary cholangitis: pathogenesis and therapeutic opportunities

Abstract

Primary biliary cholangitis is a chronic, seropositive and female-predominant inflammatory and cholestatic liver disease, which has a variable rate of progression towards biliary cirrhosis. Substantial progress has been made in patient risk stratification with the goal of personalized care, including early adoption of next-generation therapy with licensed use of obeticholic acid or off-label fibrate derivatives for those with insufficient benefit from ursodeoxycholic acid, the current first-line drug. The disease biology spans genetic risk, epigenetic changes, dysregulated mucosal immunity and altered biliary epithelial cell function, all of which interact and arise in the context of ill-defined environmental triggers. A current focus of research on nuclear receptor pathway modulation that specifically and potently improves biliary excretion, reduces inflammation and attenuates fibrosis is redefining therapy. Patients are benefiting from pharmacological agonists of farnesoid X receptor and peroxisome proliferator-activated receptors. Immunotherapy remains a challenge, with a lack of target definition, pleiotropic immune pathways and an interplay between hepatic immune responses and cholestasis, wherein bile acid-induced inflammation and fibrosis are dominant clinically. The management of patient symptoms, particularly pruritus, is a notable goal reflected in the development of rational therapy with apical sodium-dependent bile acid transporter inhibitors.

Key points

  • Primary biliary cholangitis is a disease characterized by chronic injury to biliary epithelial cells, with dysregulated and interacting immune and cholestatic pathobiology.

  • In addition to presumed essential environmental triggers, primary biliary cholangitis encompasses immunogenetic risk, epigenetic regulation of biliary epithelia, adaptive and innate immunity, and bile acid physiology across the gut–liver axis.

  • A core autoimmune theme has arisen for HLA-restricted, IL-12–IFNγ-driven, immune-mediated lymphocytic cholangitis, with recognition that the injured biliary epithelium response is equally relevant to disease progression.

  • The role of anion exchanger 2, a Cl/HCO3 exchanger, its epigenetic regulation and how a deleterious change to the protective biliary bicarbonate umbrella can also contribute to immune injury are increasingly highlighted.

  • Therapeutic modulation of bile acid synthetic pathways both intrahepatically and via manipulation of the gut–liver axis has led to advances in drug therapies, with an emphasis on modulating the farnesoid X receptor and peroxisome proliferator-activated receptor pathways.

  • Future intervention paradigms need to focus on a shift from a ‘wait-to-fail’ concept of primary biliary cholangitis therapy to early individualized and highly effective targeted therapy.

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Fig. 1: Immune dysregulation in primary biliary cholangitis.
Fig. 2: Disruption of the protective biliary bicarbonate umbrella via defective AE2.
Fig. 3: Enterohepatic circulation of bile acids and their regulation of FXR.
Fig. 4: Interaction of PPAR and FXR pathways.

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A.F.G. has received consulting and/or speaker fees in the last 3 years from Abbvie and Intercept. G.M.H. has received consulting and/or speaker fees in the last 3 years from Blade, Cymabay, Falk, Genfit, Gilead, GSK, Intercept and Pliant. G.M.H. is supported by the Lily and Terry Horner Chair in Autoimmune Liver Disease Research.

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Gulamhusein, A.F., Hirschfield, G.M. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol 17, 93–110 (2020). https://doi.org/10.1038/s41575-019-0226-7

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