The pruritus of cholestasis

Abstract

Why do patients with cholestasis itch? The answer to this fundamental question is unknown. It is inferred that substances that accumulate in plasma and other tissues, as a result of cholestasis, cause pruritus; however, the specific nature of the substances and the mechanism by which they cause pruritus has not been discerned. The absence of a clear rationale in studies of pruritus and the lack of techniques to study pruritus in human beings, and specifically, in patients with cholestasis have contributed to the vacuum of information on the pathophysiology and pathogenesis of the pruritus of cholestasis. Over the past 15 years, however, progress has been made in the study of pruritus by advancing the philosophy that research in pruritus, like in any other type of scientific area, requires valid methodology that provides objective data to be analyzed. In this context, the development of a system that allows for the conduct of behavioral studies of scratching activity, the behavioral manifestation of the sensation of itch, has satisfied the requirement of methodology. With the use of this technique, the role of the endogenous opioid system in the pathogenesis of the pruritus of cholestasis has been demonstrated. The definition of pruritus is that of an unpleasant sensation that triggers the need to scratch [[1]Greaves M.W. Wall P.D. Pathophysiology of itching.Lancet. 1996; 348: 938-940Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar]. In a study of 100 patients with atopic dermatitis the majority of the patients reported that scratching stopped with a feeling of satisfaction, disappearance of itch and appearance of pain [[2]Aoki T. Pleasure of ‘scratch’ is a complex sensation of itch and pain. In: second international workshop for hte study of itch, Toyama; 2003. p. 11.Google Scholar]. These data may be relevant to patients with cholestasis who can also suffer from chronic pruritus and may suggest that scratching may be perpetuated by the pleasure it generates and inhibited by the pain it generates in conditions characterized by chronic pruritus. The reported use of potentially harmful scratching tools (e.g. forks and knives) that cause harm do support the view that itch can transiently cease when pain is elicited by scratching. It is inferred that pruritus evolved as a sensation to lead to the protective reflex of scratching, as protection from a potentially harmful stimulus. Pruritus can result from the stimuli of polymodal (i.e. that respond to more than one type of stimuli) nociceptors (i.e. sensory fibers that respond to nociceptive stimuli). The stimulus associated with the sensation of pruritus is transmitted by unmyelinated C-fibers, which also transmit pain [[3]LaMotte R.H. Subpopulations of ‘nocifensor neurons’ contributing to pain and allodynia, itch and alloknesis.Am Pain Soc J. 1992; 1: 115-126Google Scholar] (for review); however, neurons that respond only to histamine have been identified in human beings and have been defined as itch transmitting [[4]Schmelz M. Schmidt R. Bickel A. Handwerker H.O. Torebjörk H.E. Specific c-receptrs for itch in human skin.J Neurosci. 1997; 17: 8003-8008PubMed Google Scholar]. Electrophysiologic studies in animals identified single neurons that respond to histamine alone and neurons that respond to histamine and to mechanical stimulation, also involved in pain transmission [[5]Andrew D. Craig A.D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch.Nat Neurosci. 2001; 4: 72-77Crossref PubMed Scopus (461) Google Scholar]. These studies tend to support the existence of ‘two separate nociceptive channels’ [[5]Andrew D. Craig A.D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch.Nat Neurosci. 2001; 4: 72-77Crossref PubMed Scopus (461) Google Scholar], one for itch and one for pain. In this context, the importance of an animal model to study scratching behavior and to explore the pathophysiological mechanisms that support this behavior by the use of similar electrophysiological techniques seems to be a reasonable research goal. Pruritus can be of central origin, as that associated with cerebral strokes [6Massey E. Unilateral neurogenic pruritus following stroke.Stroke. 1984; 15: 901-903Crossref PubMed Google Scholar, 7Shapiro P. Braun C. Unilateral pruritus after a stroke.Arch Dermatol. 1987; 123: 1521-1530Crossref PubMed Scopus (42) Google Scholar] and multiple sclerosis [[8]Osterman P. Paroxysmal itching in multiple sclerosis.Br J Dermatol. 1976; 95: 555-558Crossref PubMed Scopus (43) Google Scholar]. Increased neurotransmission via the endogenous opioid system can result in pruritus. The classic example of this phenomenon is the pruritus that results from the central (e.g. intrathecal) administration of morphine [9Ballantyne J.C. Loach A.B. Carr D.B. The incidence of pruritus after epidural morphine.Anaesthesia. 1989; 44: 863Crossref PubMed Scopus (34) Google Scholar, 10Dailey P.A. Brookshire G.L. Shnider S.M. Abboud T.K. Kotelko D.M. Noueihid R. et al.The effects of naloxone associated with the intrathecal use of morphine in labor.Anesth Analg. 1985; 64: 658-666Crossref PubMed Scopus (55) Google Scholar]. Morphine binds to opioid receptors, in particular to the mu opioid receptor. Opiate antagonists (e.g. naloxone) can effectively relieve morphine-induced pruritus, supporting that the pruritus is opioid receptor mediated [9Ballantyne J.C. Loach A.B. Carr D.B. The incidence of pruritus after epidural morphine.Anaesthesia. 1989; 44: 863Crossref PubMed Scopus (34) Google Scholar, 10Dailey P.A. Brookshire G.L. Shnider S.M. Abboud T.K. Kotelko D.M. Noueihid R. et al.The effects of naloxone associated with the intrathecal use of morphine in labor.Anesth Analg. 1985; 64: 658-666Crossref PubMed Scopus (55) Google Scholar]. In laboratory animals (e.g. monkeys and rats), the microinjection of morphine into the medullary dorsal horn [11Thomas D.A. Williams G.M. Iwata K. Kenshalo D.J. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 12Oliveras J. Maixner W. Dubner R. Bushnell M. Kenshalo Jr, D. Duncan G. et al.The medullary dorsal horn: a target for the expression of opiate effects on the perceived internsity of noxious heat.J Neurosci. 1986; 6: 3086-3093PubMed Google Scholar, 13Thomas D.A. Hammond D.L. Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching.Brain Res. 1995; 695: 267-270Crossref PubMed Scopus (46) Google Scholar] is associated with scratching behavior, which has been interpreted to result from ‘pruritus’ in the animals. This behavior can be prevented by the administration of opiate antagonists again supporting that the scratching behavior is opioid receptor mediated [11Thomas D.A. Williams G.M. Iwata K. Kenshalo D.J. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 13Thomas D.A. Hammond D.L. Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching.Brain Res. 1995; 695: 267-270Crossref PubMed Scopus (46) Google Scholar]. Technical progress has allowed for studies from single-unit recordings in superficial lumbar dorsal horn neurons in rats, which have revealed that the intrathecal administration of morphine facilitated or depressed the response of some units to the intracutaneous injection of histamine and in some, the effect was naloxone reversible [[14]Jinks S.L. Carstens E. Superficial dorsal horn neurons identified by intracutaneous histamine: chemonociceptive responses and modulation by morphine.J Neurophysiol. 2000; 84: 616-627PubMed Google Scholar]. In summary, behavioral and electrophysiological data support a role of the endogenous opioid system in pruritus of central origin. In cholestasis, there is evidence to suggest that central opioidergic tone is increased. The evidence can be summarized as follows: (i) patients with cholestasis can experience an unpleasant constellations of symptoms and signs suggestive of an opiate withdrawal reaction when administered opiate antagonists; this reaction in cholestasis has been termed ‘opiate withdrawal-like syndrome’ [[15]Thornton J.R. Losowsky M.S. Plama methionine enkephalin concentration and prognosis in primary biliary cirrhosis.Br Med J. 1988; 297: 1241-1242Crossref PubMed Scopus (67) Google Scholar], (ii) a stereospecific naloxone reversible state of antinociception (analgesia) can be displayed by rats with cholestasis secondary to bile duct resection [[16]Bergasa N.V. Alling D.W. Vergalla J. Jones E.A. Cholestasis in the male rat is associated with naloxone-reversible antinociception.J Hepatol. 1994; 20: 85-90Abstract Full Text PDF PubMed Scopus (104) Google Scholar], and (iii) there is down regulation of mu opioid receptors in rats with cholestasis secondary to bile duct resection [[17]Bergasa N.V. Rothman R.B. Vergalla J. Xu H. Swain M.G. Jones E.A. Central mu-opioid receptors are down-regulated in a rat model of cholestasis.J Hepatol. 1992; 15: 220-224Abstract Full Text PDF PubMed Scopus (114) Google Scholar]. It was hypothesized that increased opioidergic tone in cholestasis mediates the pruritus; a central mechanism was proposed [[18]Jones E.A. Bergasa N.V. The pruritus of cholestasis: from bile acids to opiate agonists.Hepatology. 1990; 11: 884-887Crossref PubMed Scopus (168) Google Scholar]. In this hypothesis, the pruritus of cholestasis would be analogous to the pruritus that results from the pharmacological increase in opioidergic tone by central morphine. That the pruritus of cholestasis is mediated, at least in part, by endogenous opioids, is supported by the amelioration of the pruritus by opiate antagonists. The reason for altered central neurotransmission in cholestasis is unknown, however, the liver may contribute to the increased availability of opioids in liver disease [19Bergasa N.V. Sabol S.L. Young W.S.D. Kleiner D.E. Jones E.A. Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver.Am J Physiol. 1995; 268: G346-G354PubMed Google Scholar, 20Bergasa N. Hepatic Met-enkephalin immunoreactivity is enhanced in primary biliary cirrhosis.Liver. 2002; 22: 107-113Crossref PubMed Scopus (61) Google Scholar]. In this context, increased plasma levels of Met and Leu-enkephalins, two of the endogenous opioid peptides, have been reported in patients with liver disease, including those with primary biliary cirrhosis [[21]Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (264) Google Scholar]. It is not known whether opioids derived from the liver in cholestasis mediate what has been interpreted as centrally increased opioidergic neurotransmission; however, transport proteins found in the basolateral domain of the hepatocyte are also found in the choroid plexus and in the blood brain barrier and can transport opiates in vitro [22Regina A. Demeule M. Laplante A. Jodoin J. Dagenais C. Berthelet F. et al.Multidrug resistance in brain tumors: roles of the blood-brain barrier.Cancer Metastasis Rev. 2001; 20: 13-25Crossref PubMed Scopus (124) Google Scholar, 23Dagenais C. Ducharme J. Pollack G.M. Uptake and efflux of the peptidic delta-opioid receptor agonist.Neurosci Lett. 2001; 301: 155-158Crossref PubMed Scopus (64) Google Scholar] and may potentially transport periphery-derived opioids into the central nervous system (CNS). Furthermore, increased availability of opioid peptides in the periphery may facilitate their entrance into the CNS [[24]Banks W.A. Kastin A.J. Peptide transport systems for opiates across the blood-brain barrier.Am J Physiol. 1990; 259: E1-E10PubMed Google Scholar]. An alternative and/or concomitant mechanism involving the central nervous system and that could support the chronic pruritus of cholestasis is central sensitization for itch. Central sensitization for pain or allodynia is recognized in patients with chronic pain, and it defines a state in which a non-painful stimulus around an injured area is perceived as painful [[3]LaMotte R.H. Subpopulations of ‘nocifensor neurons’ contributing to pain and allodynia, itch and alloknesis.Am Pain Soc J. 1992; 1: 115-126Google Scholar]. In the context of pruritus, studies in subjects with atopic dermatitis, a condition characterized by chronic pruritus, have provided evidence for central sensitization for itch. In these studies, noxious stimuli (e.g. heat and mechanical, electrical and chemical stimulations) evoked pain in control subjects; in contrast, in patients with atopic dermatitis, the stimuli were perceived as itch [[25]Ikoma A. Fartasch M. Heyer G. Miyachi Y. Handwerker H. Schmelz M. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch.Neurology. 2004; 62: 212-217Crossref PubMed Scopus (181) Google Scholar]. Furthermore, sensitization to histamine, achieved by perfusion of this pruritogenic substance by microdialysis into the skin of a defined area of the forearm in normal control subjects, was associated with pruritus from chemical stimuli, although pain was still the dominant sensation, suggesting that chronic pruritogenic stimuli facilitate the perception of itch [[25]Ikoma A. Fartasch M. Heyer G. Miyachi Y. Handwerker H. Schmelz M. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch.Neurology. 2004; 62: 212-217Crossref PubMed Scopus (181) Google Scholar]. The triggering of itch by noxious stimuli was interpreted as resulting from central sensitization for itch, which would result from the constant pruritogenic (i.e. pruriceptive) input and which would not allow nociceptive stimuli to inhibit itch but to facilitate it. The timing of the appearance of itch, as described in these studies by patients with atopic dermatitis, has suggested that its mediation is via C-nociceptors [[25]Ikoma A. Fartasch M. Heyer G. Miyachi Y. Handwerker H. Schmelz M. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch.Neurology. 2004; 62: 212-217Crossref PubMed Scopus (181) Google Scholar]. Analogous to patients with atopic dermatitis, patients with chronic pruritus from cholestasis may undergo central sensitization for itch, so that noxious stimuli are experienced as pruritus by these patients. In this scenario, constant pruritogenic stimuli would result in continuous activation of C-pruriceptors, perhaps by pruritogens retained as a result of cholestasis. Indeed, spontaneously active itch fibers have been identified in a patient with chronic pruritus and prurigo nodularis in microneurographic recordings [[26]Schmelz M. Hilliges M. Schmidt R. Orstavik K. Vahlquist C. Weidner C. et al.Active ‘itch fibers’ in chronic pruritus.Neurology. 2003; 61: 564-566Crossref PubMed Scopus (98) Google Scholar]. Very interesting data emerging from a model of opiate-induced scratching in monkeys may provide some insight into central opioid-mediated pruritus and scratching behavior [27Ko M.C. Song M.S. Edwards T. Lee H. Naughton N.N. The role of central mu opioid receptors in opioid-induced itch in primates.J Pharmacol Exp Ther. 2004; 310: 169-176Crossref PubMed Scopus (122) Google Scholar, 28Ko M.C. Lee H. Song M.S. Sobczyk-Kojiro K. Mosberg H.I. Kishioka S. et al.Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys.J Pharmacol Exp Ther. 2003; 305: 173-179Crossref PubMed Scopus (92) Google Scholar]. The scratching behavior associated with the administration of morphine into the MDH of monkeys was decreased by the co-administration of U50488H, a selective kappa agonist [27Ko M.C. Song M.S. Edwards T. Lee H. Naughton N.N. The role of central mu opioid receptors in opioid-induced itch in primates.J Pharmacol Exp Ther. 2004; 310: 169-176Crossref PubMed Scopus (122) Google Scholar, 28Ko M.C. Lee H. Song M.S. Sobczyk-Kojiro K. Mosberg H.I. Kishioka S. et al.Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys.J Pharmacol Exp Ther. 2003; 305: 173-179Crossref PubMed Scopus (92) Google Scholar]. In addition, the administration of a kappa agonist prevented mu opioid receptor-mediated scratching in mice [[29]Togashi Y. Umeuchi H. Okano K. Ando N. Yoshizawa Y. Honda T. et al.Antipruritic activity of the kappa-opioid receptor agonist, TRK-820.Eur J Pharmacol. 2002; 435: 259-264Crossref PubMed Scopus (187) Google Scholar]. The intrathecal administration of morphine inhibits pain but is associated with pruritus. This type of pruritus does not involve the stimulation of afferent (i.e. peripheral) pruriceptors and is, by definition, pruritus of central origin. It has been noted in experiments of neural recordings from single neurons [[30]Andrew D. Craig A.D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch.Nat Neurosci. 2001; 4: 72-77Crossref PubMed Scopus (299) Google Scholar] that spinal neurons that transmit pruritus information to the thalamus are not spontaneously activated [[30]Andrew D. Craig A.D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch.Nat Neurosci. 2001; 4: 72-77Crossref PubMed Scopus (299) Google Scholar], in contrast to the pain transmitting neurons, which are spontaneously active. It has been suggested that spontaneous activation of the pain pathway suppresses the activity of the neurons that transmit pruritus (i.e. inhibition) [[31]Ikoma A. Rukwied R. Stander S. Steinhoff M. Miyachi Y. Schmelz M. Neurophysiology of pruritus: interaction of itch and pain.Arch Dermatol. 2003; 139: 1475-1478Crossref PubMed Scopus (101) Google Scholar]. If the pain pathway is suppressed, by the administration of morphine (i.e. the pharmacological increase in opioidergic tone) the pruritus pathway may become activated and pruritus may be perceived. This switch in neurotransmission may explain central morphine-mediated pruritus. In cholestasis, increased central opioidergic tone may suppress the stimulation of pain-transmitting neurons and activate the central pruritus pathway (i.e. desinhibition). In this model, the administration of opiate antagonists would decrease pruritus. Indeed, the amelioration of the pruritus of cholestasis by opiate antagonists has been demonstrated in clinical trials that applied objective methodology, which tends to support the hypothesis that increased opioidergic tone, contributes to the pruritus of cholestasis [32Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 33Bergasa N.V. Alling D.W. Talbot T.L. Swain M.G. Yurdaydin C. Schmitt J.M. et al.Naloxone ameliorates the pruritus of cholestasis: results of a double-blind randomized placebo-controlled trial.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (320) Google Scholar, 34Bergasa N.V. Talbot T.L. Schmitt J.P. Alling D.W. Swain M.G. Turner M. et al.Open label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar, 35Bergasa N.V. Alling D.W. Talbot T.L. Wells M. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar]. In addition, central sensitization for itch, which could occur in cholestasis by the continuous stimulation of C-pruriceptors, may allow for non-pruritogenic stimuli to be perceived as pruritogenic, thus leading to chronic pruritus. The model proposed here involves peripheral and central events as possible mediators of the pruritus of cholestasis and support the implementation of therapeutic interventions that switch opioidergic tone to the non-pruritic mode (i.e. central mechanism) and that increase the threshold to the perception of noxious stimuli (i.e. peripheral mechanism). Bile acids accumulate in the tissues of patients with cholestasis [36Lloyd-Thomas H.G.L. Sherlock S. Testosterone therapy for the pruritus of obstructive jaundice.Br Med J. 1952; 2: 1289-1291Crossref PubMed Google Scholar, 37Kirby J. Heaton K.W. Burton J.L. Pruritic effect of bile salts.Br Med J. 1974; 4: 693-695Crossref PubMed Scopus (87) Google Scholar]. Bile acids were reported to elicit local ‘itch’ when injected intracutaneously in normal volunteers [[38]Varadi D.P. Pruritus induced by crude bile and purified bile acids. Experimental production of pruritus in human skin.Arch Dermatol. 1974; 109: 678-681Crossref PubMed Scopus (81) Google Scholar]; however, this model does not appear to be a model of the pruritus of cholestasis. Also, the oral administration of cholylsarcosine, a synthetic bile acid, to four patients with primary biliary cirrhosis (PBC) whose treatment with ursodeoxycholic acid (UDCA) had not been associated with normalization of serum activity of liver enzymes was reported to be associated with pruritus in one patient and worsening pruritus in another one [[39]Ricci P. Hofmann A.F. Hagey L.R. Jorgensen R.A. Dickson E.R. Lindort K.D. Adjuvant cholylsarcosine during ursodeoxycholic acid treatment of primary biliary cirrhosis.Dig Dis Sci. 1998; 43: 1292-1295Crossref PubMed Scopus (31) Google Scholar]. This observation cannot be considered as evidence of a role of bile acids in the pruritus of cholestasis as pruritus tends to be intermittent in cholestasis; furthermore, patients report exacerbations of pruritus in cholestasis after the intake of several substances including chocolate and meals rich in carbohydrates (NVBergasa, unpublished). The reported improvements of pruritus after invasive procedures (discussed under treatments) that remove substances from the circulation cannot be attributed to bile acid depletion because it is uncertain that only bile acids are removed. Furthermore, (i) in liver failure, when bile acids are maximally elevated, pruritus may cease [[36]Lloyd-Thomas H.G.L. Sherlock S. Testosterone therapy for the pruritus of obstructive jaundice.Br Med J. 1952; 2: 1289-1291Crossref PubMed Google Scholar], (ii) some patients with cholestasis and striking elevations of serum bile acids do not experience pruritus throughout the course of their disease, (iii) pruritus can fluctuate and even remit spontaneously without concomitant changes in serum bile acid concentrations and (iv) some patients with liver disease experience pruritus in the absence of increased concentration of bile acids in serum (at the time of that measurement). It is possible that a certain profile of serum bile acids is necessary for these substances to mediate pruritus but, based on current data, a role of bile acids in the mediation of the pruritus of cholestasis has not been proven. Not all patients with cholestasis report pruritus, regardless of the degree of cholestasis. This observation may suggest that the ability to perceive pruritus varies among individuals and that perhaps a genetic component is involved. In this context, genetic polymorphisms have been described in genes that code for hepatobiliary transport proteins. Studies aimed at the identification of genetic polymorphism in multidrug resistance protein (MRP) 2, which regulates the transport of organic compounds including dianionic conjugated bile salts [40Keppler D. Leier I. Jedlitschky G. Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2.Biol Chem. 1997; 378: 787-791PubMed Google Scholar, 41Meier P.J. Stieger B. Bile salt transporters.Annu Rev Physiol. 2002; 64: 635-661Crossref PubMed Scopus (466) Google Scholar] identified a single nucleotide polymorphism in MRP2 in patients with PBC and pruritus (Annarosa Floriani, 2005, personal communication). The relevance of this finding in the pathogenesis of the pruritus of cholestasis remains to be established. The nuclear receptor pregnane X (PXR) mediates the induction of some of the cytochrome P450 (CYP) enzymes including CYP3A4 [[42]Bertilsson G. Heidrich J. Svensson K. Asman M. Jendeberg L. Sydow-Backman M. et al.Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.Proc Natl Acad Sci USA. 1998; 95: 12208-12213Crossref PubMed Scopus (785) Google Scholar], of which bile acids are endogenous ligands, and the transporters MDR1 in the intestine [[43]Geick A. Eichelbaum M. Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.J Biol Chem. 2001; 276: 14581-14587Crossref PubMed Scopus (762) Google Scholar] and MRP2 [[44]Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. 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The elucidation of pathways that control the gene expression of enzymes that metabolize xenobiotics, including cytochrome P450, transferases and transporters has facilitated the understanding on drug interactions in human beings [[46]Tirona R.G. Kim R.B. Nuclear receptors and drug disposition gene regulation.J Pharm Sci. 2005; 94: 1169-1186Crossref PubMed Scopus (181) Google Scholar]; however, any relationship that these findings (many of which have been derived from animal and in vitro experiments) may have to the pathogenesis and/or treatment of the pruritus of cholestasis has not been defined. Pruritus tends to be associated with cholestasis [[47]Sherlock S, Dooley J. Cholestasis. In: Diseases of the liver and biliary system. 9th ed. London: Blackwell; 1991. p. 214–35.Google Scholar], as measured by increased activity of liver-derived alkaline phosphatase and plasma concentrations of bile acids; however, not all patients with cholestasis report pruritus, suggesting that a subject-dependent factor is necessary but, at present, unknown. Primary biliary cirrhosis (PBC) is one of the liver diseases characterized by pruritus [[47]Sherlock S, Dooley J. Cholestasis. In: Diseases of the liver and biliary system. 9th ed. London: Blackwell; 1991. p. 214–35.Google Scholar]. An internet-based survey of patients with PBC was conducted via the PBCers Organization, based in the United States with international membership, to identify patterns in the characteristics of pruritus (and fatigue). 242 subjects responded, 164 (68%) of whom reported pruritus (itch); 120 (74%) reported that their itch interfered with their sleep and 19 (11%), an important proportion, reported that nothing relieved the itch (Rishe and Bergasa 2002, unpublished). A recent publication reported pruritus in 55 and 56% of patients with PBC enrolling in each of the two arms of a clinical trial of ursodeoxycholic acid (UDCA). [[48]Talwalkar J.A. Souto E. Beigley C.S. Petterson T.M. Jorgensen R.A. Lindor K.D. Natural history of pruritus in primary biliary cirrhosis.J Clin Gastroenterol Hepatol. 2003; Google Scholar]. It was reported in this publication that treatment with UDCA was not associated with a significant impact on the percentage of patients experiencing pruritus as compared to treatment with placebo. In a three-UDCA dose comparison study, which included 155 patients with PBC, 37% reported pruritus prior to enrollment into the study [[48]Talwalkar J.A. Souto E. Beigley C.S. Petterson T.M. Jorgensen R.A. Lindor K.D. Natural history of pruritus in primary biliary cirrhosis.J Clin Gastroenterol Hepatol. 2003; Google Scholar]. In this publication, it is reported that serum activity of alkaline phosphatase and Mayo risk score were independent predictors of the reporting of pruritus at baseline [[48]Talwalkar J.A. Souto E. Beigley C.S. Petterson T.M. Jorgensen R.A. Lindor K.D. Natural history of pruritus in primary biliary cirrhosis.J Clin Gastroenterol Hepatol. 2003; Google Scholar]. In one study, the intrahepatic florid bile duct lesion and granulomata correlated with pruritus in patients with PBC [[49]Poupon R. Chazouilleres O. Balkau B. Poupon R.E. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC group.J Hepatol. 1999; 30: 408-412Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Pruritus can also be reported by patients with liver disease not typically associated with a ‘serum liver profile’ classic of cholestasis, including liver disease secondary to alcohol [[50]Woolf G.M. Reynolds T.B. Failure of rifampin to relieve pruritus in chronic liver disease.J Clin Gastroenterol. 1990; 12: 174-177Crossref PubMed Scopus (34) Google Scholar] and chronic hepatitis C [51Lebovics E. Seif F. Kim D. Abdelmonem E. Dworkin B.M. Casellas A. et al.Pruritus in chronic hepatitis C.Dig Dis Sci. 1997; 42: 1094-1099Crossref PubMed Scopus (46) Google Scholar, 52Fisher D.A. Wright T.L. 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