Chronic itch, as commonly experienced by PSC patients, likely involves non-histaminergic peripheral nerve pathways from the skin, where the pruritogen(s) in PSC is postulated to act, to the dorsal horn of the spinal cord where these nerves synapse with other neurons (Fig. 10.1). Pruritogenic stimuli carried in this pathway may in turn be significantly modulated in the spine by interactions with stimuli carried in the histaminergic and pain nerve pathways, from itch-modulating spinal interneurons involving a number of neurotransmitters and receptors and/or from descending inhibitory neural pathways from the brain. Therefore, itch is a very complex sensory response that is even more challenging to understand in the context of a chronic disease such as PSC, which in turn has its own complex pathophysiology. However, the multiple levels through which pruritogenic nerve stimuli can be modulated would seem to offer a significant number of potential targets for therapeutic interventions designed to ameliorate itch in PSC patients.

The peripheral and central pathways involved in the generation of cholestatic itch, and its regulation, are poorly understood. Moreover, a specific pruritogen(s) has not been identified in cholestatic patients; however, the accumulation or creation of the cholestasis-related pruritogen must in some way be related to an impairment of bile flow into the gut lumen as this is by definition a central component of the cholestatic syndrome. In addition, it is quite possible that different pruritogenic pathways may be primarily responsible for the generation of itch in different cholestatic syndromes (e.g., ICP, BRIC, PBC, PSC). Many studies have been published examining different therapeutic approaches to cholestatic itch. Unfortunately, no single effective therapy for all patients with cholestatic itch has been identified to date. However, these studies, when evaluated together, do provide insight into the pathophysiology of cholestatic itch and allow for the generation of novel hypotheses that can be tested which may lead to therapies that are more specific and effective for cholestatic patients in general and PSC patients specifically.

Cholestasis is associated with elevated circulating histamine levels [31], suggesting that mast cells are likely activated in cholestatic patients. However, cholestatic itch is not associated clinically with a classical histamine-related wheal and flare reaction in the skin, and antihistamines are poorly effective in treating cholestatic itch [1, 2]. Mast cells are a rich source of histamine, but also secrete proteases (e.g., tryptase) which are strong activators of PAR-2 [32] which, as outlined earlier, plays an important role in modulating the activity of the non-histaminergic itch pathway. Therefore, it is plausible that mast cell stabilizers may be beneficial in treating cholestatic itch by decreasing mast cell release of PAR-2 activating proteases and warrants further study.

Bile acids have historically been most commonly implicated as the causative pruritogen in cholestasis. However, serum and skin bile acid levels correlate poorly with itch in cholestatic patients, and in PBC patients with advanced disease, pruritus often decreases or disappears completely despite the persistence of high serum bile acid levels [2]. Cholestyramine is widely used to treat cholestatic itch, presumably based on its ability to bind bile acids in the gut lumen [33]. However, the highly potent oral bile acid sequestrant colesevelam was not effective in treating cholestatic itch (including 14 patients with PSC) [34]. These findings suggest that the clinical efficacy of cholestyramine in treating cholestatic itch is likely distinct from its ability to bind bile acids and is consistent with cholestyramine potentially binding some other unknown pruritogen or pruritus-regulating substance in the gut lumen. Furthermore, obeticholic acid, a bile acid that is a strong farnesoid X receptor (FXR) agonist, induces itch but reduces levels of circulating bile acids in PBC patients [35]. Therefore, circulating bile acids do not appear to be primary mediators of cholestatic itch. Recently, a role for bile acids in cholestatic itch was supported by the finding that the TGR5 receptor, which is expressed in primary sensory neurons, can be activated by bile acids to induce itch through activation of TRPA1 channels [36, 37]. In contrast to the suggestion that bile acids are acting as pruritogens in cholestatic patients, another possibility is that altering the bile acid composition within the gut lumen, as part of the cholestatic syndrome or after treatment with obeticholic acid or cholestyramine, in turn alters the gut microbiota in such a way to either enhance or reduce specific bacterial species within the gut that facilitate or inhibit the generation of a pruritogenic substance. The concept that the pruritogen in cholestasis is secreted in the bile has led to other approaches to divert bile flow away from the gut, in an attempt to treat cholestatic itch. Nasobiliary drainage has been used in this regard and has been highly effective in treating refractory cholestatic itch in patients with BRIC and to a lesser extent in patients with PBC [38, 39]. However, it remains unclear whether nasobiliary drainage is an effective therapy for intractable itch associated with PSC.

The concept of a potential gut-derived pruritogen as a driver of cholestatic itch, which is created as a result of cholestasis-related changes in the gut microbiota, is supported by a number of other clinical observations. Specifically, rifampin is an antibiotic widely used to effectively treat cholestatic itch, including patients with PSC [40, 41]. Although the mechanism whereby rifampin alleviates cholestatic itch remains unknown, it is clear that rifampin has broad spectrum antimicrobial properties, and therefore ingestion of rifampin likely profoundly alters the gut microbiota [42]. Consistent with this possibility, treatment of PSC patients with high doses of the antibiotic metronidazole significantly decreased pruritus [43, 44]. The bile acid obeticholic acid is a powerful FXR agonist, and its administration to both cholestatic and non-cholestatic patients causes itch [35]. However, it is clear that FXR activation also strongly induces the production of a number of antimicrobial peptides [45], significantly altering the gut microbiome [46]. These FXR-mediated effects could potentially drive the gut microbial community to generate more pruritogenic substances. In contrast to the antipruritic effects of antibiotics, treatment of PSC patients with a probiotic mixture did not improve pruritus [47].

Lysophosphatidic acid (LPA) has recently been implicated as a potential mediator of cholestatic itch [48], and LPA is formed through the action of the enzyme autotaxin. Interestingly, LPA also stimulates basophils to release histamine, and this has recently been implicated in the development of itch in a patient with PSC [49]. Importantly, autotaxin activity in the serum is increased in cholestatic patients with pruritus and is decreased in cholestatic patients who have been effectively treated with antipruritic regimens, including nasobiliary drainage and rifampin [48, 50]. Indeed, Kremer et al. have suggested that the antipruritic effect of rifampin in cholestasis can be explained, at least in part, by rifampin-related activation of pregnane X receptor (PXR) which inhibits autotaxin expression at the transcriptional level [50]. However, other clinical observations do not support this hypothesis. Bezafibrate has been increasingly used as a treatment for patients with PBC, in part, due to its effects as a PXR agonist [51, 52]. However, bezafibrate has no effect on PBC-related pruritus [40, 52]. Moreover, autotaxin activity is highest and correlates most closely with itch in women with intrahepatic cholestasis of preagnancy (ICP); however, ursodeoxycholic acidhep (UDCA) therapy is highly effective in relieving itch in ICP patients but is without effect for itch in PBC and PSC patients [1, 2, 53, 54]. Moreover, LPA has a very short biological half-life and is highly lipophilic, and its receptors are located intracellularly making the case for a significant role for LPA in cholestatic itch challenging [2]. Interestingly, serum autotaxin activity is also often significantly increased clinically in a number of non-cholestatic clinical syndromes but is not associated with the development of itch [2].

Opioids have historically been closely linked to both pain and itch pathways, as administration of opioids (e.g., morphine) relieves pain but often induces itch. Endogenous opioids accumulate in the serum of cholestatic patients [55] and have been shown to modulate pain pathways in cholestasis by acting at peripheral opioid receptors located on cutaneous nerve endings [56]. Moreover, blockade of opioid receptors with naloxone, naltrexone, or nalmefene is clinically effective in treating some patients with cholestatic itch [40, 57–59]. However, the induction of an opioid withdrawal-type reaction in pruritic cholestatic patients treated with opioid receptor blockers suggests that endogenous opioids may be acting centrally, to modulate the perception of itch, and not peripherally to generate itch [57, 59].

Inflammatory mediators, including cytokines, can modulate pain and itch pathways. In particular, TNFα can activate nociceptive primary afferent nerve fibers [60], and topical application of TNFα to peripheral nerves causes mechanical hyperalgesia [61]. In addition, TNFα modulates spinal cord dorsal horn pain-related synaptic activity [62], and TNFα increases the expression of the TRPV1 receptor in the spinal dorsal root ganglia [63]. Inhibition of TNFα using etanercept reduces pain-related behaviors in a model of neuropathy [64]. A potential role for TNFα in modulating cholestatic itch is supported by a number of clinical observations. Circulating TNFα levels are increased in cholestatic patients, and treatment of profoundly pruritic cholestatic patients with MARS is associated with a significant reduction in serum TNFα levels [65]. In addition, thalidomide treatment (which inhibits TNFα production) decreased itch in PBC patients [66]. In contrast, treatment of PSC patients with pentoxifylline (also inhibits TNFα production) did not alter pruritus; however, the patients included in this study were not significantly pruritic at the start of treatment [67]. In another study, treatment of PSC patients with the TNFα inhibitor etanercept resulted in a reduction in pruritus [68]. Activated B cells produce significant amounts of TNFα [69], and we have shown that elimination of B cells with rituximab in PBC patients resulted in a significant improvement in pruritus, without altering serum indicators of cholestasis severity [70]. These observations suggest that targeting TNFα may be a novel approach to treat pruritus in PSC patients and may be linked to therapeutic approaches for inflammatory bowel disease (IBD) which commonly coexists in these patients.

The cutaneous itch signal is transmitted to secondary neurons within the spinal cord. These secondary neurons can be extensively modulated by input from excitatory and inhibitory interneurons (Fig. 10.1) and by descending inhibitory neural pathways from the brain [10, 17]. Itch signal processing and regulation within the spinal cord and brain therefore represent potential targets for therapeutic modulation of cholestatic itch. Cannabinoids are widely used clinically for their ability to modulate pain and decrease nausea, most likely by acting on receptors within the CNS. A pilot study in three cholestatic patients with treatment refractory itch, treated with the cannabinoid dronabinol, showed an improvement in itch [71]. Interestingly, histamine-induced itch is attenuated by a peripherally administered cannabinoid receptor agonist [72]. These findings suggest that cannabinoids may be beneficial in cholestatic itch by acting both peripherally and centrally. Serotonin also regulates itch, and a role for serotonin in cholestatic itch is supported by the well-documented clinical efficacy of the selective serotonin reuptake inhibitor (SSRI) sertraline in treating patients with cholestatic itch, including patients with PSC [73]. However, it remains unclear whether the clinical effect of sertraline in improving itch in these patients is due to the effects on serotonergic neurotransmission within the brain, spinal cord, or skin. One serotonin receptor in particular, the 5-HT3 receptor, has been examined as a potential driver of cholestatic itch. However, a number of studies have been performed using 5-HT3 antagonists in patients with cholestatic itch, but no significant beneficial effects could be consistently documented [40, 74].