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    • The molecular mechanisms involved in

    2023-01-13

    The molecular mechanisms involved in the pathogenesis of cholestatic pruritus remain unknown [45], [46]. Indeed, there has been an enormous effort at understanding the etiology of PBC-related pruritus, including work at the cellular and molecular level, but such efforts have not been translated into unique therapeutic agents [47], [48], [49], [50], [51], [52], [53], [54], [55], [56]. Many theories have been offered to explain pruritus, including increased opioidergic neurotransmission [57] or a unique component of bile [58]. While bile acids have been strongly suspected as etiological factors, they do not correlate with the intensity of pruritus [59]. Ursodeoxycholic TCS 2002 (UDCA), a naturally occurring bile acid, is the only FDA-approved therapy for PBC by virtue of its ability to slow progression of the liver disease, but has little or no impact on pruritus. Interestingly, when the farnesoid X receptor (FXR) agonist obeticholic acid is used in patients with PBC, it reduces serum bile acid levels but increases pruritus. Guidelines from the American Association for the Study of Liver Disease recommend a stepwise approach for the treatment of PBC-related pruritus [60], including bile acid sequestrants as initial therapy, followed by the pregnane X receptor (PXR) agonist rifampicin, oral opiate antagonists, and sertraline for pruritus refractory to bile acid sequestrants. Other agents that have been used include phenobarbital, doxepine, and antihistamines. Current clinical trials in PBC-associated pruritus include the use of inhibitors of the intestinal apical sodium-bile acid transporter (iASBT) that block the enterohepatic circulation of bile acids (NCT01904058, NCT02360852 and NCT01899703). A link between the ATX-LPA axis and cholestatic pruritus came when Kremer and colleagues [21] found that intradermal LPA induced a scratch responses in mice. In addition, LPA concentrations were increased in cholestatic patients with pruritus and ATX was markedly increased in cholestatic patients with pruritus compared to those without pruritus. Further, ATX activity correlated with the intensity of pruritus. Nasobiliary drainage in PBC patients decreased the itch intensity and serum ATX activity which returned to pre-drainage levels after drain removal. Other evidence suggested that [Ca2+] i, a key mediator of the neuronal secretory response, may be a biomarker of neuronal activation though the ATX-LPA pathway. Thus, LPA and ATX may be potential pruritogens by virtue of their accumulation in sera of cholestatic patients and their ability to activate sensory neurons. Subsequently, Kremer et al. [61] reported that the increased ATX levels were specific to pruritus from cholestasis and not found in other forms of pruritus. In addition, while treatment with the bile salt sequestrant, colesevelam, decreased serum bile acid levels, it only marginally reduced pruritus intensity and serum ATX activity. However, in patients treated with rifampin, both itch intensity and ATX activity were reduced. Another approach to relieving pruritus associated with cholestasis has been apheresis or a similar procedure using the molecular absorbance recirculating system (MARS), an extracorporeal liver dialysis system capable of removing albumin-bound molecules [62]. ATX activity is reduced in MARS-responsive patients and reduced itch intensity was linearly correlated with reduction of ATX [61]. Bellmann et al. [63] reported similar data using MARS to treat patients with refractory cholestatic pruritus after liver transplantation. After MARS treatment, albumin-bound pruritogens including the ATX substrate LPC, were reduced, but ATX activity rebounded to levels greater than pretreatment levels after stopping treatment. LPA receptors are present in various tissues including the nervous system [34], and LPA can induce neuropathic pain via LPA receptors [34], [64]. However, the molecular mechanisms of LPA-induced scratching behavior is still unclear [65]. LPA can also directly activate the intracellular transient LPA receptor TRPV1 [66]. Activation of IL-13 [66], [67] receptors have been implicated in the onset of pruritus [68] as well as alterations in the transient receptor potential (TRP) receptors, i.e. TRPV1 on sensory neurons [64], [69]. We should note that, in contrast to the finding of Kremer et al. suggesting that the ATX-LPA pathway is unique to cholestasis-associated pruritus, serum ATX levels in atopic dermatitis patients were significantly higher compared to healthy individuals; serum ATX levels significantly correlated with atopic dermatitis severity [70]; and ATX levels decreased when patients were treated with prednisolone [70], [71].