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Primary sclerosing cholangitis

Nature Reviews Disease Primers volume 11, Article number: 17 (2025) Cite this article

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Abstract

Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.

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Fig. 1: Global prevalence of PSC alone and in coexistence with IBD.
Fig. 2: Disease phenotypes of inflammatory bowel disease in patients with PSC.
Fig. 3: Principle aspects of bile duct lesions in PSC.
Fig. 4: International Primary Sclerosing Cholangitis Study Group Diagnostic Criteria for PSC.
Fig. 5: Diagnosis and risk stratification in PSC.
Fig. 6: Effects of PSC on PROs.

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Acknowledgements

The authors thank J. Debarry and S. Riese for providing editorial assistance. They thank X. Jiang for help in developing Fig. 3.

Author information

Authors and Affiliations

  1. Hannover Medical School (MHH) and Centre for Individualised Infection Medicine (CiiM), Hannover, Germany

    Michael P. Manns

  2. Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

    Annika Bergquist

  3. Norwegian PSC Research Center, Department of Transplantation Medicine, Clinic of Surgery and Specialized medicine, Oslo University Hospital, Oslo, Norway

    Tom H. Karlsen

  4. Research Institute of Internal Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Tom H. Karlsen

  5. Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA

    Cynthia Levy

  6. Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA

    Andrew J. Muir

  7. Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands

    Cyriel Ponsioen

  8. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Michael Trauner

  9. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Union Hospital, Hong Kong SAR, China

    Grace Wong

  10. Center for Outcome Research in Liver Diseases, Washington, DC, USA

    Zobair M. Younossi

Authors
  1. Michael P. Manns
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  2. Annika Bergquist
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  3. Tom H. Karlsen
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  4. Cynthia Levy
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  5. Andrew J. Muir
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  6. Cyriel Ponsioen
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  7. Michael Trauner
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  8. Grace Wong
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  9. Zobair M. Younossi
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Contributions

Introduction (M.P.M.); Epidemiology (A.B.); Mechanisms/pathophysiology (T.H.K.); Diagnosis, screening and prevention (A.J.M.); Management (C.L., C.P. and M.T.); Quality of life (Z.M.Y.); Outlook (G.W. and M.P.M.); overview of the Primer (M.P.M.). All authors have reviewed and provided input on all sections.

Corresponding author

Correspondence to Michael P. Manns.

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M.P.M. received grants and or consulting fees from Falk Pharma GmbH (Freiburg, Germany), Gilead Sciences, Intercept and Novartis. A.B. received research grants from Gilead Sciences and is part of the Advisory Board Ipsen. T.H.K. received consulting fees from MSD, Albireo and Falk Pharma, and is Board Member and President Elect at Biomed Alliance. C.L. has received research grants and consulting fees from Gilead Science, Ipsen, High Tide, Mirum, Escient, Chemomab and Intercept. A.J.M. received research grants from Gilead Science and Pilant Therapeutics. C.P. received grants from Gilead Sciences, NGM and Perspectum, consultancy fees from Pliant and Chemomab, and speaker’s fees from Tillotts. M.T. has received research grants from Albireo, Alnylam, Cymabay, Falk, Genentech, Gilead, Intercept, MSD, Takeda and Ultragenyx, and travel grants from Abbvie, Falk, Gilead, Intercept and Jannsen. He has advised for Abbvie, Albireo, Agomab, BiomX, Boehringer Ingelheim, Chemomab, Falk Pharma GmbH, Genfit, Gilead, Hightide, Ipsen, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, and has served as speaker for Albireo, BMS, Boehringer Ingelheim, Falk, Gilead, Intercept, Ipsen, Madrigal and MSD. He is a co-inventor (service inventions) of patents for the medical use of norUDCA (nor-ursodeoxycholic acid/norucholic acid)/NCA filed by the Medical Universities of Graz and Vienna. G.W. has served as an advisory committee member for AstraZeneca, Gilead Sciences, GlaxoSmithKline and Janssen, and as a speaker for Abbott, AbbVie, Ascletis, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen and Roche. She has also received a research grant from Gilead Science. Z.M.Y. received research funding and/or serves as a consultant to Intercept, Cymabay, Boehringer Ingelheim, BMS, GSK, NovoNordisk, AstraZeneca, Ipsen, Siemens, Madrigal, Merck and Abbott.

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Nature Reviews Disease Primers thanks N. Cazzagon, A. M. Loza, A. Tanaka and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Manns, M.P., Bergquist, A., Karlsen, T.H. et al. Primary sclerosing cholangitis. Nat Rev Dis Primers 11, 17 (2025). https://doi.org/10.1038/s41572-025-00600-x

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