The conclusion is that both physical interventions are eliminating a factor, retained in cholestasis, which increases transcription at the ATX gene and thus enzyme levels and activity (Fig. 1). One implication of this finding is that

although the evidence implicating ATX-generated LPA in the pathogenesis of pruritus in cholestasis is overwhelming, there remain upstream additional elements in the pathway that are still to be identified. So what implications does this study have for the many patients with cholestatic liver disease who remain deeply troubled by their pruritus and who have not responded to the existing limited therapies? The first and most obvious conclusion is that identifying learn more the final common pathway for pruritus generation offers the opportunity to develop novel therapies that can use mechanistic GSI-IX understanding to optimize therapeutic effect. Obvious targets include ATX or LPA themselves.15 Understanding the role played by ATX, its regulation and function, and its generation of LPA in pruritus pathogenesis will allow us to optimize therapy by increasing the effects rifampicin gives while removing its unwanted effects. Furthermore, the importance of the

association between ATX function and pruritus gives an objective biological marker that may prove useful in early evaluation of potential therapies and may offer a tool for the dissection of the relative contribution of cholestasis to pruritus in patients with more than one potential pruritic etiology (for example, cholestasis and skin disease). Given the scale of the residual problem Ribociclib order with pruritus in cholestasis, our understanding of the biology of ATX and LPA now points to the targeting of these entities as a top priority for therapy development. Although the identification of the ATX pathway as a key factor in cholestatic itch represents a real

opportunity for therapy development, important questions remain unanswered. One issue is the paradox that ATX elevation can also occur in a number of noncholestatic inflammatory diseases and disease models in which pruritus is not a feature,16 suggesting that the relationship between ATX levels and pruritus in cholestasis is not a simple causal one, and that cofactors must play a role (Fig. 1). A further issue is the cell of origin of ATX in cholestasis. This could plausibly be the biliary epithelial cells or hepatocytes directly impacted by retained hydrophobic bile acids. An alternative would be third-party cells on which the as-yet unidentified upstream factor driving ATX production and which is removed from the circulation in MARS and nasobiliary drainage acts. A final issue not addressed in the work of the Beuers group, and potentially the most important outstanding issue, is the biological reason for ATX elevation in the first place.