The Molecular Mechanism of Cholestatic Pruritus

Abstract

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.

Recent advances in the management of pruritus in chronic liver diseases

“…Bile salts have been reported to induce degranulation of mast cells in vitro , which may contribute to pruritus in cholestatic patients. However the relationship between bile salts and pruritus has not been clarified[11], although some metabolites of bile salts may contribute to pruritus[12]. Second, endogenous opioid levels have been reported increased in cholestatic patients[12,13].…”

“…However the relationship between bile salts and pruritus has not been clarified[11], although some metabolites of bile salts may contribute to pruritus[12]. Second, endogenous opioid levels have been reported increased in cholestatic patients[12,13]. Activation of μ-opioid receptors may cause pruritus by reducing pain signaling, with μ-opioid receptor antagonists showing antipruritic effects in patients with chronic cholestasis[14,15].…”

“…Activation of μ-opioid receptors may cause pruritus by reducing pain signaling, with μ-opioid receptor antagonists showing antipruritic effects in patients with chronic cholestasis[14,15]. However the correlation between those increased opioid levels and pruritus remains unclear[12,13]. Thus, these mechanisms could not fully explain the pathogenesis of pruritus.…”

“…Lysophosphatidic acid (LPA) has been regarded as a specific target pruritogen/neurotransmitter in patients with cholestasis[11,12]. LPA is generated from lysophosphatidylcholine (LPC) by autotaxin (ATX)[40,41].…”

Extracorporeal devices for treatment of refractory pruritus in cholestatic liver disease

“…Levels of autotaxin (ATX) were also measured in a small series of MARS-treated patients in Amsterdam as part of a major research program into mechanisms underlying pruritus in PBC and other cholestatic conditions [6][7][8]. Autotaxin is the enzyme that converts lysophosphatidylcholine (LPC, lysoPC) into lysophosphatidic acid (LPA).…”