Background & Aims

Chronic pruritus is a common and difficult-to-treat symptom in various chronic liver diseases, especially if cholestasis ist present. Past research on the underlying pathophysiology of itch in hepatobiliary disorders has mainly focused on potential biochemical mediators such as bile components, endogenous opioids and lysophosphatidic acid using cell- and animal-based models (1,2). However, there is scarce data on the involvment and possible pathologies of human afferent C-fibers, which act as pruritoceptors in the peripheral nervous system (3,4). In this study, we therefore aim at evaluating C-fiber function in patients with hepatobiliary disorders with and without chronic pruritus using neurophysiological tests including psychophysical assessment and microneurography.

Methods

We included 59 clinically well-characterized patients with chronic liver diseases. Pruritus was evaluated using validated questionnaires including a numeric rating scale (NRS). Patients were divided into those with clinical significant pruritus as defined of a mean itch rating of NRS ? 3 (pruritus high) and those below this cut-off (NRS <3; pruritus low)Patients underwent testing of skin nerve fiber function according to the quantitative sensory testing (QST) protocol and an electrical stimulation protocol using half-sine and sine-wave stimuli on the forearm and dorsum of the foot to selectively activate C-fibers in the skin. We additionally obtained skin punch biopsies at the forearm to analyze histology, especially intraepidermal nerve fiber density (IENFD). In a subset of patients, microneurography recordings of single C-fibers were performed for further C-fiber characterization.

Results

Both patient groups were comparable regarding age, laboratory values, disease entity and stage of liver disease. Singular sine-wave stimulation (0.025–0.4 mA) caused a dose-dependent pain sensation in both groups. In addition to pain, solely the high pruritus group experienced a dose-dependent itch sensation.
Similarly, a prolonged electrical sine-wave stimulation of 60s resulted in a significant itch sensation only in the high pruritus group. Adaptation was observed to pain but not itch intensity. The mean IENFD was strongly reduced in patients with cholestatic liver diseases (compared to age- and sexed-matched controls), with a trend towards lower IENFD in in the high pruritus group. In microneurography recordings, we detected a higher percentage of pathological properties in C-fibers of the pruritus high group.

Conclusions

Patients with chronic hepatic pruritus show altered C-fiber profiles in non-invasive and invasive assessments, demonstrating a functional change of C-fiber function in a systemic condition associated with chronic pruritus.

References

1) Kremer AE, Martens JJ, Kulik W, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010 Sep;139(3):1008-18, 1018.e1.
2) Meixiong J, Vasavda C, Snyder SH, et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. Proc Natl Acad Sci U S A. 2019 May 21;116(21):10525-10530.
3) Düll MM, Stengel M, Ries V, et al. Lysophosphatidic acid activates nociceptors and causes pain or itch depending on the application mode in human skin. Pain. 2022 Mar 1;163(3):445-460.
4) Fiebig A, Leibl V, Oostendorf D, et al. Peripheral signaling pathways contributing to non-histaminergic itch in humans. J Transl Med. 2023 Dec 12;21(1):908.

Presenting Author

Miriam M. Düll

Poster Authors

Miriam Düll

MD, MHBA

Department of Medicine 1, University Hospital Erlangen, Germany

Lead Author

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Hannah Kleinlein

Lead Author

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Fabienne Falter

Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg

Lead Author

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Andy Fiebig

Institute of Neurophysiology, Uniklinik RWTH Aachen, Aachen, Germany

Lead Author

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Andreas Kremer

Lead Author

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Barbara Namer

Institute of Neurophysiology/ IZKF research group neuroscience, Uniklinik RWTH Aachen, Germany

Lead Author

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Topics

  • Specific Pain Conditions/Pain in Specific Populations: Itch