Mediators of pruritus during cholestasis.

PURPOSE OF REVIEW: Pruritus is a frequent symptom in patients with cholestatic liver diseases. Itching may be excruciating, may seriously impair quality of life and even induce suicidal ideation in the most severe cases.

RECENT FINDINGS: The molecular mechanism of itch signal transduction in cholestasis is largely unclear. It may be caused or potentiated by compounds that accumulate in the circulation during cholestasis, which either directly or indirectly affect signalling in itch fibres. In the past, bile salts and endogenous opioids have been proposed but never been proven to be key factors in itch perception during cholestasis. We have performed a screen for compounds in plasma from patients with various cholestatic conditions for their capacity to activate neuronal cell lines. In these sera, we could identify a potent neuronal activator as lysophosphatidic acid (LPA). LPA is a very potent signalling phospholipid that can activate cells through various LPA receptors. Quite strikingly, samples from itchy cholestatic patients contained higher amounts of LPA. These increased levels of LPA turned out to be caused by elevated levels of serum autotaxin, the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding, as autotaxin has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, caused scratching behaviour in mice.

SUMMARY: On the basis of our results, we hypothesize that during cholestasis expression of autotaxin is induced, which gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibres. LPA activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibres leading to the perception of pruritus.