The mechanisms of cholestasis-associated itch

Itch is, next to fatigue, the most frequent symptom in patients with chronic cholestatic disorders and has serious impact on their lives. Cholestasis is the term for diminished or impaired bile flow. The molecular mechanisms leading to cholestasis-associated itch (pruritus) are still unresolved and the involved pruritogens are indecisive.
Lysophosphatidic acid (LPA) is a possible pruritogen in patients with cholestasis. LPA is produced out of lysophosphatidylcholine (LPC) by the enzyme autotaxin (ATX). A significant correlation is present between ATX activity and itch intensity. During cholestasis, not only serum ATX levels are increased, but also serum bile salts and bile salt-like (cholephilic) compounds. The ATX protein contains a hydrophobic tunnel structure, which can bind different hormone-like structures and specific bile salts, leading to (partial) inhibition of the protein. The negative feedback regulation in the expression of the Atx gene is relieved by this inhibition, which can contribute to increased serum ATX activity in patients with cholestasis.
In order to study cholestasis-associated itch, we measured scratch activity in different cholestatic mouse models. After induction of cholestasis and increasing serum ATX activity, no increase in scratch activity was observed.
We screened diverted bile of patients with cholestasis-associated itch for specific compounds that are able to activate the (itch-) sensor TRPA1. HPODE, a metabolite of linoleic acid, is a TRPA1-specific pruritogen, but did not show a significant correlation with the itch score in cholestatic patients, indicating that a combination of pruritogens is needed to induce cholestasis-associated itch.