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  • Review Article
  • Published:

Novel therapeutic targets in primary biliary cirrhosis

Nature Reviews Gastroenterology & Hepatology volume 12, pages 147–158 (2015)Cite this article

Subjects

Key Points

  • Primary biliary cirrhosis (PBC) leads to progressive cholestasis, biliary fibrosis and cirrhosis and characteristic symptoms with a marked effect on life quality

  • Ursodeoxycholic acid (UDCA) nonresponse or under-response has a major effect on outcome, substantially increasing the likelihood that liver transplantation will be required, or that patients will die of the disease

  • Patients with high-risk, treatment-unresponsive or highly symptomatic disease need new treatment approaches; as yet, no agents demonstrating disease-modifying actions have been shown to improve systemic symptoms

  • Excellent opportunities are offered by targeting the immune response, biliary injury and fibrotic processes

  • Combination therapies with a stratified approach, in which specific treatments are targeted at the pathological processes at play, or single agents with multiple actions, are likely to be needed

Abstract

Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy—ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.

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Figure 1: Pathway for the current understanding of PBC pathogenesis and potential targets for therapeutic intervention.
Figure 2: Mechanisms of BEC injury in PBC.
Figure 3: The immune response in PBC is multifaceted and involves both adaptive and innate components.
Figure 4: Therapy for pruritus is largely empirical.

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Acknowledgements

The work of the authors is supported by grant L001489 from the UK Medical Research Council (D.E.J.J.). The authors thanks Dr E. Liaskou for her help in developing Figure 3.

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Authors and Affiliations

  1. Institute of Cellular Medicine, 3rd Floor William Leech Building, Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Jessica K. Dyson, Derek A. Mann & David E. J. Jones

  2. Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Wolfson Drive, Birmingham, B15 2TT, UK

    Gideon M. Hirschfield & David H. Adams

  3. Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, G4-216, University of Amsterdam, PO Box 22600, Amsterdam, NL-1100 DD, Netherlands

    Ulrich Beuers

  4. College of Health Solutions, Arizona State University, 550 North 3rd Street, Phoenix, 85004, AZ, USA

    Keith D. Lindor

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All authors contributed equally to this manuscript.

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Correspondence to Jessica K. Dyson.

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Competing interests

G.M.H. is an investigator and/or consultant for Biotie Therapies, Bristol–Myers Squibb, Falk Pharma, FF Pharma, Gilead, GlaxoSmithKline, Intercept, Johnson & Johnson, NGM Biopharmaceuticals; he is a co-investigator for UK PBC, supported by a stratified medicine award from the UK Medical Research Council. U.H.B has consultant agreements via the University of Amsterdam with Intercept and Novartis, and receives lectures fees from the Falk Foundation. D.A.M. is a consultant and collaborator with GlaxoSmithKline, Medimmune, Novartis, UCB. K.D.L. is an unpaid member of the advisory board for Intercept and Lumena and a paid consultant for Abbvie and Gilead. D.E.J.J. receives UK PBC research and trial funding from GlaxoSmithKline, Intercept and Lumena, and acts as a consultant via Newcastle University for Intercept, Johnson & Johnson and Novartis. The other authors declare no competing interests.

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Summary of previous therapeutic trials in PBC (PDF 94 kb)

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Dyson, J., Hirschfield, G., Adams, D. et al. Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol 12, 147–158 (2015). https://doi.org/10.1038/nrgastro.2015.12

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