Gastroenterology

Gastroenterology

Volume 139, Issue 3, September 2010, Pages 1008-1018.e1
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

https://doi.org/10.1053/j.gastro.2010.05.009Get rights and content

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 ([Ca2+]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 [Ca2+]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 [Ca2+]i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca2+]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 μ-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.

Section snippets

Human Subjects

Peripheral venous blood was obtained from healthy donors, pregnant women, and patients with cholestatic disorders after informed consent according to the Declaration of Helsinki. The study was approved by the local medical ethical committees. Blood samples were immediately centrifuged at 4°C, and serum was frozen in aliquots at −80°C. ICP was diagnosed, as previously described,18 in pregnant women with pruritus who had no rash in conjunction with increased serum liver transaminase and/or bile

Neuron-Activating Serum Factor Identified as LPA

To identify potential pruritogens in cholestasis, we screened sera from pruritic patients for activation in different neuronal cell lines. We chose [Ca2+]i as an indicator of neuronal activation because it is a key mediator of the neuronal secretory response toward diverse receptor-dependent and -independent stimuli. In the human neuroblastoma cell line SH-SY5Y, we observed a dose-dependent increase in intracellular calcium concentrations with the addition of serum (Figure 1A). Interestingly,

Discussion

Pruritus is a common and disabling symptom in cholestatic liver diseases and many other systemic disorders, including renal insufficiency; endocrine, hematologic, and metabolic diseases; various infections; and certain malignancies. The causal factors of pruritus are unknown in most of these diseases. Here we provide clinical and experimental evidence that LPA is a potential mediator of cholestatic itch.

The discovery of itch-specific sensory neurons in the skin by Schmelz et al revolutionized

Acknowledgments

The authors thank Dr H. Reesink (Academic Medical Center, Amsterdam, The Netherlands) for kindly providing blood samples from patients with hepatitis C virus, Dr J. Aoki (University of Tokyo, Tokyo, Japan) for 5E5-autotaxin antibody, Dr H. van Lenthe (Academic Medical Center, Amsterdam, The Netherlands) for performing high-performance liquid chromatography/mass spectroscopy, and Jenny Chambers (Imperial College London, London, England) for her elaborate contribution to collection and

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Deutsche Forschungsgemeinschaft (KR3618/1-1 to A.E.K.).

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