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Cholestatic liver disease can be associated with significant impairment of quality of life1 with one of the key contributing factors being characteristic and often severe pruritus.2 Pruritus impacts patients both directly and through secondary effects on sleep, which can in turn contribute to fatigue and cognitive symptoms.3 Intriguingly, patients with similar severities of liver disease and cholestasis can have markedly different degrees of pruritus for reasons which are at present unclear. A number of therapeutic approaches have been described for cholestatic pruritus and treatment guidelines have begun to suggest pathways for structured intervention.4 The identification of agents populating these pathways has, however, been largely empirical to date and their effects are far from universal. Furthermore, they can be associated with significant and often limiting side effects.5, 6 Thus, pruritus remains a substantial practical problem in cholestasis and one where improved therapy is needed.

Until recently, relatively little progress had been made in our understanding of the pathogenesis of cholestatic pruritus, and as a consequence mechanism-directed therapy has yet to be developed. Theories of pathogenesis are diverse and include pruritic action of retained bile acids and increased endogenous opiate activity (models develop in light of the observed antipruritic actions of bile acid sequestrants and opiate antagonist drugs, respectively).7, 8 It should be noted, however, that none of these models are mutually exclusive.

A key step forward in our understanding of the pathogenesis of cholestatic pruritus came with the observation that lysophosphatidic acid (LPA) levels are significantly elevated in the serum of patients with cholestatic itch, and that the level of elevation is significantly associated with severity of itch.9 Moreover, injection of LPA into experimental mice resulted in scratching activity, suggesting that this molecular entity was a direct cause of pruritus.10 LPA arises as a consequence of the actions of the lysophospholipase D enzyme autotaxin (ATX),11 an enzyme also found to be elevated in the serum of cholestatic patients with pruritus, with levels again correlating directly with severity of pruritus. ATX acts through the cleavage of choline from lysophosphatidylcholine.11 These findings led to the hypothesis that increased ATX levels/activity occurred as a consequence of the biology of cholestasis (by an undefined mechanism), and the increased enzyme functionality generated increased LPA, which was a direct mediator of pruritus (Fig. 1). This intriguing hypothesis generated a number of important questions, several of which have been addressed in a study in the current edition of HEPATOLOGY by Kremer et al.12 Their study makes a number of important observations that help to shed light on the biology of cholestatic itch, along the way potentially answer a long-standing unanswered question, and open up potentially exciting new directions for therapy.

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Figure 1. Model for the pathogenesis of pruritus in cholestasis. An as-yet unidentified factor (“Factor X”) is retained in cholestasis (1) and can upregulate transcription of autotaxin (ATX) (2) (the data would also be compatible with “Factor X” impairing natural breakdown of ATX). The resulting increased circulating levels of ATX result in increased cleavage of lysophosphatidylcholine (LPC), generating increased levels of lysophosphatidic acid (LPA) (3). LPA has a direct action on puritoceptive nerve fibers (4), potentially acting in conjunction with a second factor retained at increased levels in cholestasis (“Factor Y (5)). The existence of this second cholestatic factor, which is necessary but not sufficient for the development of cholestatic pruritus, would explain why elevation of ATX in other disease states is not associated with pruritus. The combined effects of LPA and ”Factor Y“ would trigger the pruritic signaling pathway. In this model MARS and nasobiliary drainage would have their action at site 1, removing ”Factor X“ and thus blocking the ATX augmentation arm. Rifampicin would act at site 2, acting as a PXR agonist, down-regulating ATX gene transcription, thereby achieving the same effect. We could postulate that naltrexone has its effects downstream at the level of signaling (site 6). It is even conceivable that endogenous opiates produced in excess by cholestatic biliary epithelium are in fact ”Factor Y.“ We could also postulate that bile salts play a role at site 5, explaining the actions, such as they are, of bile acid sequestrant drugs. Sites 3 and 4, ATX and LPA themselves, represent exciting novel targets for antipruritic drug development.

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The first key observation is that the elevation of ATX in patients with pruritus is limited to pruritus of cholestatic origin. Although this does not preclude a role for LPA in the pathogenesis of pruritus in other conditions (such as uremia and Hodgkin's disease), it would suggest that the mechanism of generation by way of serum ATX is a cholestasis-specific phenomenon. A second, and striking, observation is that in patients treated with a number of therapeutic modalities for cholestatic pruritus (including conventional therapies such as bile acids sequestrants and rifampicin,7, 13 and physical intervention therapies such as Molecular Adsorbents Recirculating System [MARS] and nasobiliary drainage14) the effect of the therapy on the perception of itch severity correlated directly with lowering of serum ATX levels, with the same relationship being seen for all therapeutic modalities (i.e., for all modalities the degree of lowering of ATX levels predicted the antipruritic effect seen). This provides further support for the concept that, in cholestasis at least, it is the increase in ATX functionality in the circulation which is a direct mechanistic factor in pruritus expression.

In exploring the biology of therapeutic interventions for cholestasis some intriguing further observations are made. The first is that rifampicin, a well-established second-line therapy for the treatment of cholestatic pruritus but one for which the mechanism of action has remained unknown for decades13 significantly reduces ATX levels in vivo, and in cell-based studies exerts this effect through agonism of the pregnane x receptor (PXR). The conclusion is that rifampicin has its actions on pruritus through PXR-mediated down-regulation of ATX transcription (Fig. 1). This provides the first plausible mechanistic explanation for the well-described clinical actions of rifampicin. The second intriguing observation is that in neither of the two very disparate physical therapies studied (MARS and nasobiliary drainage, where reduction in serum ATX levels correlated with an antipruritic effect) was the effluent from the physical system (the drained bile in the case of nasobiliary drainage and the MARS system effluent) found to contain either ATX protein or activity, meaning that the ATX-lowering effect, and resulting antipruritic actions, cannot be explained simply by physical depletion of ATX by the drainage process. 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 the final common pathway for pruritus generation offers the opportunity to develop novel therapies that can use mechanistic 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 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. This enzyme is implicated in cell survival pathways and LPA plays an important role in cell proliferation, including in the context of cancer.17 In recent years it has become clear that the biology of the biliary epithelial cells, the loss of which is integral to the development of cholestatic disease, is complex. In contrast to simple models in which the mechanism of injury (be it immune, toxic, or apoptotic) is associated with irreversible loss of the biliary epithelial cells, rather a period of homeostatic proliferation occurs in which the injury and insult triggers an attempt by the body to regenerate the epithelium. The evidence regarding senescence of epithelial cells in the context of cholestatic disease would suggest that it is only when this adaptive response ultimately fails due to exhaustion of proliferative capacity that ductopenia occurs, leading to the biological effects of cholestasis.18, 19 It is plausible, therefore, that ATX elevation occurs in the context of cholestasis as part of this homeostatic response. In simple terms, ATX production might represent an element in the body's attempt to mitigate against biliary epithelial cell injury through up-regulating proliferative capacity. Although this is only a hypothesis, its important implication might be that modulating ATX function with the aim of reducing pruritus might limit the body's reactive response to cholestasis. The potential effect would be that an ATX-directed therapy might improve cholestatic pruritus at the cost of worsening cholestatic biology. Until we fully understand role, if any, played by ATX in regenerative capacity, and the importance of this process for disease progression, this must remain a concern.

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