Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands.
Gastroenterology (Impact Factor: 16.72). 09/2010; 139(3):1008-18, 1018.e1. DOI: 10.1053/j.gastro.2010.05.009
Source: PubMed


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.
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.
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.
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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    • "The parents of the patients noted an improvement in sleep disturbance during the night and in their child’s skin condition. In contrast to the relief of the itching, the serum levels of bile acids and ATX and of ATX activity, all of which have been proposed as potential pruritogens in cholestasis [24], were not decreased by 4PB therapy in any of the patients (Figures  2B, 3A, B). The itch remained unchanged for 6, 4, and 6 weeks after cessation of 4PB therapy in patients 1, 2, and 3, respectively, but then gradually exacerbated, resulting in regeneration of erosion and hemorrhage again because of intense scratching. "
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    • "Similarly, symptoms of nerve injury-induced neuropathic pains are attenuated in mice with heterozygous ATX/ENPP2 gene mutations, suggesting an involvement of ATX/ENPP2 in pain generation [20]. Serum ATX/ENPP2 levels are increased in patients with follicular lymphoma [21] and in patients with intrahepatic cholestasis of pregnancy (ICP) [22], suggesting that the LPA produced by ATX/ENPP2 may affect the pathology of these diseases. Moreover, plasma LPA levels were increased in patients with acute coronary syndrome (ACS), suggesting a possible involvement of ATX/ENPP2 in this disease [17]. "
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    • "Besides bile acids, which apparently seem to play a major role as pruritogens, elevated levels of endogenous opioids and amphiphilic lysophosphatidic acid (LPA) were also found in patients with cholestatic pruritus [16]. In contrast to bile acids, LPA and autotaxin (the enzyme responsible for the transformation of lysophosphatidylcholine into LPA) plasma levels were demonstrated to correlate significantly with the severity of patients’ pruritus [19]. This indicates a crucial role of LPA and autotaxin in the pathophysiology of pruritus. "
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