Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus
Abstract
Background & aims Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.Methods Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device.Results Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal.Conclusions We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.
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Autotaxin is the only variable that has so far been identified to correlate with the severity of cholestatic pruritus.
“Autotaxin is the only variable that has so far been identified to correlate with the severity of cholestatic pruritus. 25”
From A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis (2016) · cites this paper as [25]
Serum autotaxin activity correlates with itch intensity in cholestatic patients and falls with antipruritic therapies in parallel with itch improvement.
“Serum ATX activity was the first biomarker ever to correlate with itch intensity in cholestatic patients 11 and markedly decreased under antipruritic therapeutic strategies, such as rifampicin, nasobiliary drainage, or molecular adsorbent recirculating system therapy, again correlating with the degree of improved itch intensity.12”
From Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial (2021) · cites this paper as [11]
Lysophosphatidic acid is a potential copruritogen in cholestasis.
“We recently identified the potent neuronal activator lysophosphatidic acid (LPA) as potential copruritogen in cholestasis.11”
From Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial (2021) · cites this paper as [11]
ATX and its product LPA are components that may contribute to cholestasis-associated itch.
“In line with our pathophysiological concept of cholestasis-associated pruritus, we recently identified ATX and its product, the pruritogen LPA, as components possibly contributing to cholestasis-associated itch.11”
From Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial (2021) · cites this paper as [11]
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- Authors
- Kremer, A. E., Martens, J. J. W. W., Kulik, W., Ruëff, F., Kuiper, E. M. M., van Buuren, H. R., van Erpecum, K. J., Kondrackiene, J., Prieto, J., Rust, C., Geenes, V. L., Williamson, C., Moolenaar, W. H., Beuers, U., & Oude Elferink, R. P. J.
- Affiliations
- University of Amsterdam (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Ludwig-Maximilians-Universität München (DE)
- Erasmus MC (NL)
- Imperial College London (GB)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Kremer, Andreas E.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 139
- Issue
- 3
- Pages
- 1008-1018.e1
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2108087274
- Cited by
- 410
- References
- 1
- Citations by year
- 2026: 22 · 2025: 13 · 2024: 24 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 32 · 2019: 38 · 2018: 33 · 2017: 28 · 2016: 24 · 2015: 28 · 2014: 35 · 2013: 25 · 2012: 24
- FWCI
- 25.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- lysophosphatidic acid, cholestatic pruritus, autotaxin, intrahepatic cholestasis of pregnancy, primary biliary cirrhosis, intracellular calcium, sensory neurons, scratching behavior, bile salts, nasobiliary drainage, pruritogens
- MeSH terms
- Lysophospholipase D, Adult, Aged, Animals, Calcium, Cholestasis, Intrahepatic, Chromatography, High Pressure Liquid, Disease Models, Animal, Drainage, Female, Fluorometry, Humans, Injections, Intradermal, Liver Cirrhosis, Biliary, Lysophospholipids, Male, Mice, Inbred C57BL, Middle Aged, Multienzyme Complexes, Neurons, Phosphoric Diester Hydrolases, Pregnancy, Pregnancy Complications, Pruritus, Pyrophosphatases, Severity of Illness Index, Mass Spectrometry, Time Factors, Up-Regulation, Phosphodiesterase I, Cell Line, Tumor, Mice
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