Lysophosphatidic acid is a potential mediator of cholestatic pruritus.

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.

The molecular mechanism of cholestatic pruritus.

Pruritus is a frequent symptom in patients with cholestatic liver diseases. Pruritus can be excruciating and, in rare cases, become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. It was our hypothesis that compounds which accumulate in the circulation during cholestasis act as direct or indirect pruritogens by affecting signaling in itch fibers. To test this, we screened plasma samples of a large group of patients with various cholestatic conditions for their capacity to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and healthy controls. Purification revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signaling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that cholestatic patients with pruritus have highly elevated levels of serum autotaxin (ATX), the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding as ATX has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, causes itching in mice. On the basis of our results, we hypothesize that during cholestasis, expression of ATX is induced and gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibers. LPA then activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibers.