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Mechanisms of pruritus in cholestasis: understanding and treating the itch

Abstract

Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.

Key points

  • Pruritus can be a burdensome symptom, dramatically impairing the quality of life of people affected with a cholestatic liver disease.

  • Potential pruritogens in cholestasis activate a complex neural network leading to the sensation of itch.

  • Candidate pruritogens include certain lysophospholipids and sulfated progesterone metabolites, among others.

  • First-line effective treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin.

  • First-line treatment in intrahepatic cholestasis of pregnancy remains ursodeoxycholic acid, supported in the third trimester by rifampicin, if needed.

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Fig. 1: Potential pruritogens in cholestasis-associated pruritus and antipruritic interventions.
Fig. 2: The sensation of pruritus.
Fig. 3: Model of feedback regulation of autotaxin formation by LPA and its receptor.

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Acknowledgements

The authors are grateful for stimulating discussions with Hanns-Ulrich Marschall, University of Gothenburg, Sweden, and Catherine Williamson, King’s College London, UK.

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Beuers, U., Wolters, F. & Oude Elferink, R.P.J. Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol 20, 26–36 (2023). https://doi.org/10.1038/s41575-022-00687-7

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