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Authors: Ronald Oude Elferink, Ruth Bolier, Andreas E. Kremer, Ulrich Beuers
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. We appreciate Dr. Bergasa's comment on our findings about the association between cholestatic itch and serum autotaxin (ATX) activity. ATX has phospholipase D activity and generates most of the lysophosphatidic acid (LPA) in blood. LPA is a potent lipid‐signaling molecule for which at least six LPA receptors exist, some of which are on neurons. We agree with Dr. Bergasa that the hypothesis of LPA contributing to cholestatic pruritus still needs to be proven. Therefore, we described LPA as a potential pruritogen in cholestatic itch in our review cited above. Although intradermally injected LPA causes scratching,1 this does not yet prove that LPA produced by ATX is the pruritogen in cholestasis. We are currently testing the hypothesis that ATX and its product, LPA, really do play a role in cholestatic pruritus. Nevertheless, our understanding of the role of ATX in cholestatic pruritus appears more advanced than that of endogenous opioids. In 1992, the group of Dr. Jones has first shown that endogenous opioids are elevated in cholestatic rats.2 They hypothesized that an increased opioidergic tone in cholestatic patients causes itch. However, a relation between increased opioidergic tone and the extent of pruritus has never been reproducibly demonstrated in cholestatic humans. Dr. Bergasa acknowledges this lack of evidence, but argues that the postulated increased opioidergic tone must be the responsible mechanism because cholestatic patients treated with opioid antagonist often develop an opiate withdrawal‐like reaction. However, this does not prove that opioids are the key factor in cholestatic pruritus. Such proof is also not provided by the fact that the opioid antagonist, naloxone, often reduces pruritus in cholestatic patients. Itch signals coming from nerve endings of specific itch fibers are modulated in the spinal cord by interneurons between pain and itch afferents. Pain signals inhibit itch signals through these interneurons. Therefore, opioid antagonists will inhibit pruritus by a general mechanism, irrespective of the causative pruritogen(s). The observation that injection of plasma extracts from cholestatic patients with itch into the medullary dorsal horn of primates causes facial scratching is as much an indication for a role of LPA as for a role of endogenous opioids. A tight correlation exists between serum ATX activity and the extent of itch in cholestasis.1 Thus, also in intrahepatic cholestasis of pregnancy (ICP) we find increased serum ATX activity, compared to healthy pregnant women. In addition, we have shown that several forms of therapy that reduce itch in cholestatic patients also reduce the increased levels of ATX.3 We are not aware of a comparably elaborate screen for endogenous opioids. We are convinced that ATX is not the only potential pruritogenic factor.3 Healthy pregnant women (without pruritus) have higher serum ATX levels than cholestatic patients with pruritus. There is a relation between itch and the relative, rather than absolute, increase in serum ATX. Hence, we think that LPA produced by ATX may potentiate, rather than initiate, itch signals caused by other pruritogens.