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Carstens E, Akiyama T, editors. Itch: Mechanisms and Treatment. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Itch: Mechanisms and Treatment.

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Chapter 6Pruritus of Cholestasis

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Cholestasis is defined as impaired secretion of bile.1 Pruritus is a complication of cholestasis including that associated with mutations in genes that code for transporters in the hepatocyte2,3 and from inflammatory liver diseases.4,5 In this regard, pruritus is more common in conditions characterized by bile duct inflammatory destruction and ductopenia including primary bile cirrhosis primary biliary cirrhosis (PBC)5 than in those characterized by hepatocellular injury such as chronic viral hepatitis.4 The pruritus of cholestasis tends to be generalized. It leads to scratching, sometimes violent, resulting in excoriations and prurigo nodularis. This type of pruritus can lead to sleep deprivation, and in some patients, to suicidal ideations. Intractable pruritus from liver disease is an indication for liver transplantation even in the absence of liver failure.6,7 Accordingly, pruritus is a complication of liver disease that requires specific management and intense research in an effort to design effective antipruritic medications.

Women with cholestasis of pregnancy can experience severe pruritus especially in the third trimester.8 The pruritus from cholestasis of pregnancy resolves itself after delivery; if it does not, investigations to rule out liver disease are indicated.

In patients with PBC the pruritus has not been consistently reported to correlate with biological markers of disease.9 Also, in PBC the presence of intrahepatic florid bile duct lesions and granulomata were significantly related to the severity of pruritus (and fatigue), which was assessed subjectively, on the day of the biopsy.10 This observation is interesting because, although it is difficult to infer the degree of cholestasis from a liver biopsy, as there is sampling error, the fact that patients with stage I PBC can experience severe pruritus may suggest an important release of pruritogens in association with active inflammatory destruction of biliary epithelial cells, which characterizes this stage. The pruritus can persist and remit throughout the course of the disease, and as the disease progresses to liver failure, the pruritus tends to cease,11 as if a certain degree of liver function were necessary for pruritogen(s) or its cofactors to be produced or for the sensation to be perceived. In relation with PBC, it was also reported that presentation of the disease at less than 50 years of age correlated with an increased likelihood of reporting symptoms (and not responding to ursodeoxycholic acid, the drug approved for the treatment of this disease).12

An Internet survey via the Web site supported by the PBCers organization (http://pbcers.org/) was conducted to understand how patients perceived pruritus.13 Two hundred and thirty-nine (239) subjects with a diagnosis of PBC responded to the survey; of these, 232 were women, and 69% of all subjects reported itch. Seventeen percent of the respondents reported that the itch was “relentless” or so severe that it led to wanting to “tear (the) skin off,” and 3.6% of the subjects stated that they scratched until they bled. Seventy-four percent of the 162 respondents who addressed the question reported that the itch affected sleep, 65% that the itch was worse at night, and 11% reported that nothing relieved the itch.13 The minority of respondents to the survey reported that the pruritus was addressed by their physician;13 this underscores the need to educate physicians and patients on the association between pruritus and liver disease, and the importance of investigating the cause of pruritus in patients who do not have an apparent skin condition that can explain the itch.

The prevalence of pruritus in patients with PBC determined from the survey reported above13 was 69%, close to what has been reported by others.14 From a retrospective study from a tertiary referral research institute in the United States, 5% of patients with chronic hepatitis C presented with pruritus;4 considering the high prevalence of this type of liver disease, the relevance of the pruritus of cholestasis in medicine is substantial. This inference is supported by a recent publication, also retrospective in nature, from one center in Europe reporting that 40% of the patients with chronic pruritus from liver disease had chronic viral hepatitis B or C.15

6.1. PATHOGENESIS OF THE PRURITUS OF CHOLESTASIS

It has been inferred that the pruritogen(s) that mediates the pruritus is made in the liver and excreted in bile and that, as a result of cholestasis, accumulates in body tissues and by some mechanism triggers the sensation of itch. The following observations support a liver origin of the pruritogen(s): (1) in patients with cholestasis, the cessation of itch portends liver failure,11 (2) patients with pruritus report the disappearance of their symptom after liver transplantation,16 and (3) relief of cholestasis from mechanical obstruction (e.g., common duct stones) is associated with decrease or disappearance of pruritus.17 The nature of the pruritogen, however, is unknown.

Bile acids accumulate in the tissues of patients with cholestasis.11,18 Under experimental conditions, bile acids were reported to trigger local “itch” when injected intracutaneously in normal volunteers;19 this, however, is not a model of the pruritus of cholestasis. The oral administration of cholylsarcosine, a synthetic bile acid, to four patients with PBC was reported to be associated with pruritus in one patient and worsening pruritus in another.20 As pruritus is intermittent in cholestasis, this observation cannot be interpreted as evidence in support of a role of bile acids in the pruritus of cholestasis because pruritus tends to be intermittent; in addition, the intake of certain foodstuffs, usually patient specific, is sometimes reported to increase or to worsen the pruritus. Three observations do not support a role of bile acids in the mediation of the pruritus of cholestasis: (1) in liver failure, when bile acids are maximally elevated, pruritus tends to disappear,11 (2) not all patients with cholestasis report pruritus, in spite of marked elevations of serum bile acids, and (3) pruritus can fluctuate independently from the serum concentration of bile acids. It is possible, however, that a certain profile of serum bile acids is necessary for these substances to mediate the pruritus. A recent clinical study published in abstract form reported that the administration of obeticholic acid, in contrast to the placebo drug, to patients with PBC was associated with pruritus, was severe in some patients, for which the drug had to be stopped, and in others sufficiently inconvenient to require dose reduction. Obeticholic acid is a synthetic derivative of chenodeoxycholic acid that is an agonist at the farsenoid nuclear receptor (FXR) and that has choleretic properties.21 FXR is a bile acid sensor associated with a decrease in bile acid production.22 The relevance of this observation in the pathogenesis of the pruritus of cholestasis is unknown.

Histamine was reported to be increased in patients with liver disease and pruritus;23 indeed, 16% of patients with PBC who participated in the Internet survey conducted through the PBCers13 reported that hydroxyzine, an antihistamine, was frequently prescribed to treat their pruritus, and provided some relief in some patients.13 The skin of patients with cholestasis and pruritus is devoid of the classic histamine mediated reaction consisting of erythema and edema, which does not support a major role of this pruritogen in the mediation of this type of pruritus; however, the sedative effect of antihistamines, and not an antipruritic effect, may be responsible for some of the relief in association with this type of drugs.

Substance P is an excitatory neurotransmitter that acts through the NK-1 receptor synthesized by primary afferent nociceptors and released into the spinal cord after noxious stimuli.24 The central administration of substance P is associated with scratching behavior.25 In addition, in animal studies, increased opioidergic tone secondary to the administration of morphine activates mechanisms that promote pain (i.e., nociception), instead of analgesia, mediated, in part, by the NK-1 receptor;26 furthermore, the expression of substance P in the dorsal root ganglia, which are involved in the transmission of nociceptive stimuli,24 is increased in association with prolonged administration of opiates.24 Analogous to the activation of mechanisms that promote pain mediated by substance P associated with chronic opiate administration, the increased opioidergic tone, which is associated with cholestasis,27 may also contribute to a state of enhanced nociception that may be perceived as pruritus mediated, in part, by substance P. In this context, the mean serum concentration of substance P was 12-fold higher in patients with liver disease and pruritus than in patients with liver disease without pruritus, and that of a control group of subjects.28 These data suggest that substance P may mediate some of the manifestations of liver disease, including pruritus; however, in primates, which seem to respond to the central administration of pruritogens similarly to human beings, the administration of substance P was not associated with scratching.29

In animal studies, it has been reported that lipophosphatidic acid (LPA) induces nociception through substance P release from peripheral nerve endings,30 and it has been implicated as a mediator in animal and in in vitro neural models that explore signals associated with pain.3133 A role of LPA and the enzyme that generates its production, autotaxin, has been recently proposed in the pruritus of cholestasis.34,35 The concentration of several LPA species was reported to be significantly higher in the sera from patients with cholestasis of pregnancy than in the sera from pregnant women matched for gestation term.34 In C57BL/6J female mice, LPA injections were reported to cause scratching behavior, which was interpreted as evidence for a pruritogenic role of LPA in cholestasis;34 however, this finding is not relevant in the study of the pruritus of cholestasis as scratching behavior in association with the intradermal injection, as given in this study, of substances, including LPA, is not a model of scratching in cholestasis.34 The activity of autotaxin was reported to be higher in the serum from women with cholestasis of pregnancy, and that of patients with cholestasis and pruritus from liver diseases and not in the serum of patients with pruritus from uremia, Hodgkin’s “disease,” and atopic dermatitis.35 The serum activity of autotaxin was also reported to have decreased in the serum of patients with liver disease and pruritus who had responded to the antibiotic rifampicin.35 Autotaxin activity was not decreased in the serum from patients with cholestasis and pruritus who had participated in a controlled trial of colesevalan, a nonabsorbable resin that binds bile acids in the gut, versus placebo, in which the resin was reported not to relieve pruritus. The activity of autotaxin was also reported to correlate with a decrease in the severe pruritus of patients who had undergone dialysis with Molecular Adsorbent Recirculating System (MARSTM), or nasobiliary drainage.35 Nasobiliary drainage facilitates bile flow, and the MARSTM procedure is associated with removal of vasoactive substances and with important changes in blood flow, which may also increase bile flow;36 the effects of these two interventions thus, may decrease the degree of cholestasis and hence the pruritus associated with it. Autotaxin was not found in the bile of patients treated with nasobiliary drainage and who had responded to the treatment with a decrease in pruritus, although it was reported to have returned to pretreatment serum levels when the pruritus recurred.35 The changes in the activity of autotaxin in relation with improvement or worsening of the pruritus may reflect changes in the degree of cholestasis and do not necessarily imply a pruritogenic effect of this enzymatic pathway. The antibiotic rifampicin induces drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor (PXR).37,38 The idea that the reported antipruritic effect of this drug results from either the enhanced metabolism of the “pruritogens” or its transport has been suggested.39 The inhibition of the expression of autotaxin by rifampicin in vitro, in HepG2 hepatoma cells, and in hepatoma cells overexpressing PXR, and not on cells in which PXR had been knocked out, was interpreted to suggest that a decrease in autotaxin by rifampicin may be the mechanism by which this antibiotic decreases pruritus in patients with cholestasis;40,41 however, the lack of effect of rifampicin in some patients was not explained in this context.42 The effect of rifampicin in vitro as measured in this study35 cannot be interpreted in the context of the pruritus of cholestasis as the model does not reflect the cholestatic milieu in human beings. It was concluded from these studies that autotaxin may be a therapeutic target for the treatment of the pruritus of liver disease.35 Whether autotaxin or LPA mediate the pruritus of cholestasis and the potential neurophysiologic and/or neuropathophysiologic mechanisms by which these substance may mediate pruritus are unknown.

The landmark publication by Thornton and Loswoski in 1988 focused on the role of the endogenous opioid system in the clinical manifestations of patients with liver disease by assessing their response to the opiate antagonist nalmefene.43 It was reported that the administration of nalmefene to patients with cholestasis was associated with an opiate withdrawal-like reaction; in addition, the patients experienced a disappearance of their pruritus.43 The reaction included high blood pressure, insomnia, and abdominal pain, in sharp contrast to the absence of any reaction in normal volunteers who, in other studies, had taken 60 times the dose of nalmefene than that used in this study.43 The reaction that the patients experienced after the intake of nalmefene was interpreted to result from cerebral dependence to opioids due to their high serum concentration, which allowed them to cross the blood brain barrier. The relief of the pruritus was interpreted to result from the opiate antagonist inhibiting opioid peptides from causing pruritic substances to be liberated.43 Indeed, the opiate withdrawal-like reaction experienced by the patients with cholestasis suggests that, in the absence to exposure to opiate drugs, they had endogenously increased opioidergic tone.27 Furthermore, the reported relief of pruritus in association with nalmefene by the patients in this study suggested a relationship between central opioid receptors and pruritus.27 This alternate interpretation is supported by the naloxone reversible pruritus in human beings44,45 and the scratching behavior in laboratory animals4648 in association with the pharmacological increase in opioidergic tone by morphine and other drugs with agonist activity at the opioid receptors. These observations provided support for a hypothesis: the pruritus of cholestasis is mediated by increased central opioidergic tone.27 Three lines of evidence suggest that in cholestasis there is increased opioidergic tone: (1) the opiate withdrawal like reaction triggered by an opiate antagonist in patients with cholestasis,43,4952 (2) the state of stereospecific, opiate antagonist reversible antinociception in an animal model of cholestasis,53 and (3) the downregulation of mu (and delta) opioid receptor in brain membranes of rats with cholestasis.54 The reason for increased opioidergic tone is cholestasis is unknown; however, several findings provide potential explanations: (1) the de novo production of endogenous opioids by the liver in a rat model of cholestasis is suggested by the expression of the mRNA of the gene that codes for Met and Leu-enkephlins and for enkephalin containing endogenous opioids, preproenkephalin mRNA,55 (2) the concentration of two pentapeptide endogenous opioids, Met-enkephalin and Leu-enkephalin, and that of Met-enkephalin containing opioids is significantly higher in liver extracts from rats with cholestasis secondary to bile duct resection than from those of sham resected controls,56 (3) the serum concentration of Met-enkephalin is increased in animal models of cholestasis57 and in some patients with liver disease,43,58 and (4) endogenous opioids accumulate in the liver of patients with liver disease including PBC and chronic hepatitis C, as evidenced by the expression of hepatic Met-enkephalin immunoreactivity59,60 and by its detection in bile.61 One question that arises is whether the enhanced expression of Met-enkephalin immunoreactivity in liver disease is related in any way to the increased central opioidergic tone. In this context, some transport proteins that can transport opiates in vitro are common to the basolateral domain of the hepatocyte, to the choroid plexus, and to the blood–brain barrier;62 accordingly, it is plausible that they can also transport periphery-derived opioids into the central nervous system (CNS). Furthermore, it has been reported that increased availability of opioid peptides in the periphery may facilitate their entrance into the CNS.63 The hypothesis that increased opioidergic tone contributes to the pruritus of cholestasis,27 however, does not depend on serum levels of endogenous opioids including Met-enkephalin, or their hepatic expression; it is, in contrast, supported by (1) the opiate withdrawal-like reaction that can be precipitated by opiate antagonists,43,4952 and (2) the ameliorating effect of opiate antagonists on the pruritus of cholestasis.43,4952,6468 Indeed, in short-term studies, opiate antagonists were associated with a decrease in hourly scratching activity in an average of 89% of the patients (range, 82.8%–100%).49,50,64,65 Opiate antagonists were also associated with a decrease in the visual analogue scale for pruritus in an average of 91.5% of patients from a series of clinical studies (range, 65.5%–100%).43,4951,6467 In a placebo-controlled study, the opiate antagonist naltrexone was associated with a 50% reduction in the visual analogue scale for pruritus in 13 of 34 patients (38%);52 although changes smaller than 50% were not discernible from the publication.52 The results of a meta-analysis that included five trials of opiate antagonists; three that tested the effect of opiate antagonists administered orally (i.e., naltrexone and nalmefene) and two that tested the effects of intravenous naloxone with a reported total of 84 participants also support an ameliorating effect of this type of drug on the pruritus of cholestasis.69 Opiate antagonists were associated with a decrease in pruritus more significantly than the control intervention, with a standard mean difference (SMD) of –0.68, 95% –1.19 to –0.17, and to decrease scratching activity with a SMD of –0.64, 95% –1.28 to 0.01.69 Thus, increased opioidergic tone contributes to the pathogenesis of the pruritus of cholestasis and opiate antagonists are available to treat this type of pruritus.70

6.2. INDIVIDUAL PREDISPOSITION TO EXPERIENCE PRURITUS BY PATIENTS WITH CHOLESTASIS

Not all patients with cholestasis report pruritus;4,13 this observation may suggest a genetic predisposition to experience this sensation in the context of cholestasis. In this regard, if the liver is the source of the pruritogen(s) and the pruritogen(s) is excreted in bile, the transporters that participate in the transport of compounds into the biliary canalicula may be relevant on how these substances are excreted. MRP2 (ABCC2) is a member of the family of ATP binding cassette (ABC) transporters expressed in various organs including the liver and the blood–brain barrier.71,72 MRP2 mediates the transport of several organic anions73 in the hepatocyte; in addition, and pertinent to the pruritus of cholestasis, opioid ligands are MRP2 substrates.74 A single nucleotide polymorphism (SNP) characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the MRP2 gene was found in heterozygosity in a group of patients with PBC.75 V1188E was significantly associated with the presence of pruritus; thus, V1188E in MRP2 may alter the pruritogen(s) or its cofactors from being transported from the hepatocyte into the bile canalicula or into the central nervous system and may favor the experience of pruritus.

The manner in which the endogenous opioid system responds to opioid ligands may also be relevant in the way the pruritus of cholestasis is perceived. The stimulation of the mu opioid receptor is the mechanism by which opiate (and morphine) induced pruritus is generated. Accordingly, the presence of genetic polymorphisms in the gene that codes for the mu opioid receptor may be relevant in the sensation of itch. In this context, the SNP Al18G in exon1 of opioid receptor mu 1 (OPRM1) gene, which predicts an Asn-to-Asp change in amino acid residue 40 in the extracellular domain of the receptor, at a putative N-glycosylation site,76 has been associated with changes in the behavioral expression from the stimulation of the mu opioid receptor in human beings,77,78 and changes in the binding profile of at least one endogenous opioid, beta-endorphin, to the receptor.79 A study from patients with PBC found A118G in heterozygosity 1.5 times more frequently in DNA samples from a group of patients without pruritus from the United States than in the rest of the samples, which included those from patients from Italy.80 These preliminary findings suggested that patients with the A118G SNP in the OPRM1 may be protected from the perception of itch from cholestasis.80 Indeed, this interpretation may be supported by the results of a study of the incidence of pruritus in patients after 24 hours of having received epidural morphine for postcesarean section analgesia that revealed that the G allele in the A118G polymorphism was associated with a decrease in the incidence of pruritus with genotype AA being associated with significant pruritus in 53% of patients, AG in 41.9%, and GG in 4.8%.81 In addition, ethnicity may inform the experience of side effects from the administration of intravenous morphine; in this regard, in a study of children pruritus (and vomiting) was significantly more common in subjects identified as Latino than in subjects identified as non-Latino Caucasian.82

The intact skin of patients with atopic dermatitis, a condition characterized by chronic pruritus, allows for the enhanced penetration of chemical solutes.83 In this regard, mutations in the gene that codes for filaggrin, a protein necessary for the formation of the stratum corneum, and hence instrumental in the maintenance of the skin as a barrier, may be relevant in the pathogenesis of this disease.83,84 Skin permeability may also be relevant in the vulnerability of patients with liver disease to experience pruritus.

It seems reasonable, accordingly, to conduct genetic studies that may identify mutations in genes including those that code for transport proteins in the hepatobiliary system and CNS, those involved in the activation of sensory neurons such as the phospholipase C B3 pathway,85 and those that code for proteins that determine skin integrity83 as certain polymorphisms may inform how patients experience itch in cholestasis.

6.3. RECEPTORS SPECIFICITY IN THE MEDIATION OF OPIOID-INDUCED PRURITUS

There is strong evidence to support that the stimulation of opioid agonist ligands is associated with pruritus and scratching that can be ameliorated and prevented by opiate antagonists in human beings44,45 and in laboratory animals.4648 Studies exploring the role of specific opioid receptors47,48,86,87 have identified an antiscratching effect of kappa agonists; in this regard, nalfurafine, an agonist at the kappa opioid receptor has been reported to decrease the sensation of pruritus in patients with uremia.8890 In this context, scratching behavior in a rat model of estrogen-induced cholestasis was prevented by the administration of nalfurafine, suggesting that stimulation of the kappa opioid receptor may be a therapeutic option in the treatment of the pruritus of cholestasis.87 In this context, butorphanol, is an antagonist at the mu opioid receptor and an agonist at the kappa receptor.91 In a patient with intractable pruritus from liver disease secondary to chronic hepatitis C, butorphanol in spray form (1 mg per application) was associated with prolonged relief of pruritus.92 It was subsequently reported that in a series of patients with PBC, butorphanol had been associated with relief of the pruritus.93 The potential addiction to butorphanol, initially considered to be low,94 is important;95 thus, the use of this drug for the treatment of the pruritus of cholestasis has to be considered carefully, i.e., short courses, in light of addiction complications. Anecdotal reports of the use of codeine, an agonist at the mu opioid receptor,96 and buprenorphine, an agonist at the mu and an antagonist at the kappa receptor,97 in association with amelioration of the pruritus of cholestasis have been published. These reports have to be reconciled with the effects of butorphanol in regards to its receptor preference.

Gastrin-releasing peptide receptor (GRPR) was proposed to mediate scratching behavior from pruritogenic stimuli in mice.98 Morphine-induced scratching behavior does not occur in genetically engineered mice lacking GRPR or the mu opioid receptor (MOR), to which morphine binds. By the use of exon-specific knockdown, an MOR 1 D isoform was identified.99 MOR 1 D was reported to be essential for scratching behavior, interpreted as a response to itch, whereas the MOR 1 was involved in the mediation of antinociception (i.e., analgesia); no cross-reactivity between the two behaviors, scratching and anticociception, was appreciated.99 Double immunostaining revealed coexpression of GRPR and of MOR 1 D, defined as constitutive heterodimers; there was no coexpression of GRPR and MOR. The addition of morphine to the experimental preparation was associated with internalization of GRPR and of MOR 1 D; the addition of gastrin releasing peptide was associated with internalization of GRPR but not with the internalization of MOR 1 D or of MOR. The results of these experiments were interpreted as evidence in support of a unidirectional cross-activation of GRPR signaling with MOR 1 D by formation of heterodimers, and also that the scratching due to morphine is an independent effect from the antinociception effect (i.e., analgesia).99 It is unknown whether these interesting findings relate to the pruritus of cholestasis; however, the revelation of MOR 1 D as the responsible receptor in the mediation of opioid-mediated scratching in the animals studied and its connection with the GRPR may suggest that GRPR may also be relevant in pruritus in human beings and may further support the role of the endogenous opioid system in the pruritus of cholestasis. The demonstration that MOR 1 D can combine with GRPR seems to support the idea that opioid receptors can form complexes that, when activated by specific ligands, mediate synergistic effects, including potentiation of analgesia100 and, as now suggested,99 the specific transmission of itch signals. In addition, the combination of opioid receptors with other receptors may be a way by which the binding of nonpruritic substances to the complex may induce pruritus; this possibility may be relevant in cholestasis, as a result of which numerous substances accumulate in various tissue compartments.

6.4. PRURITUS OF CENTRAL ORIGIN

There is strong evidence in support of pruritus of central origin, including the pruritus from increased opioidergic tone.44,45 It is also considered that the pruritus complicating neurological disease including cerebrovascular accidents101,102 and multiple sclerosis103 is of central origin. In the context of centrally mediated pruritus, it has been suggested that conditions associated with chronic pruritus may also be associated with central sensitization for itch. Studies in patients with pruritus secondary to atopic dermatitis experienced noxious stimuli like heat and pressure, and electrical and chemical stimulations as itch, in contrast to the pain experienced by the control subjects.104 It was proposed that the central sensitization for itch results from constant pruritogenic (i.e., pruriceptive) input, enabling nociceptive stimuli to facilitate itch instead of inhibiting it. Microneurographic recordings in a patient with chronic pruritus and prurigo nodularis secondary to chronic scratching revealed spontaneously active itch fibers;105 thus, in addition to a genesis of central opioid-mediated pruritus in cholestasis, it is conceivable that the chronicity of the pruritus in liver disease and uremia, for example, results in central sensitization for pruritus, leading to nonpruritogenic stimuli resulting from the constant stimuli of C-pruriceptors (e.g., by toxic substances retained as a result of cholestasis) to be perceived as pruritus.

In this regard, the results of brain scans by single photon emission computed tomography and functional magnetic resonance imaging methodology in patients with pruritus of cholestasis during periods of itch and no itch have been published in abstract form.106 It was reported that itch was not associated with sensory cortex activation; there was a correlation between increasing itch severity with activity in the prefrontal cortex, orbital frontal cortex, putamen, globus pallidus, insular cortex, and orbital anterior and posterior cingulate cortices. It was concluded, based on the pattern of activation, that the limbic system is the primary central nervous system pathway involved in the perception of itch and that the findings support a central origin for this type of pruritus or itch.106 These preliminary studies are consistent with the hypothesis stating that the pruritus of cholestasis is centrally mediated.27

The pruritus of cholestasis may also have a peripheral component mediated by the stimulation of peripheral receptors that respond to the pruritogens that may accumulate in body tissues as a result of cholestasis.

6.5. SCRATCHING ACTIVITY IN PATIENTS WITH THE PRURITUS OF CHOLESTASIS: LESSONS FROM BEHAVIORAL STUDIES

The problem with studies of the pruritus of cholestasis is, in part, the methodology that had been used traditionally, i.e., the measurements of substances that accumulate in plasma as a result of cholestasis. Evidence to explain how any of the proposed substances mediate the neurophysiological changes required for the sensation of the pruritus of cholestasis to be transmitted has not been provided18,23,28,35 except for what has been documented for substances with agonist activity at the mu opioid receptor.4448

Oral reports from patients on the effect of drugs on their pruritus are extremely relevant. In the context of clinical trials, for example, patients can say yes or no in response to the question of relief, with responses to be interpreted as a measure of effectiveness versus lack of effect; however, that is not how response to study drugs is assessed in studies of pruritus, as numbers, generated by questionnaires and visual analogue scales for pruritus have a certain appeal. The problem with the use of this type of methodology is that pruritus is a perception, and as a perception, it cannot be directly quantitated; accordingly, the meaning of the data collected by the above stated methods is uncertain. In contrast, scratching, the behavior that results from the sensation of pruritus, can be quantitated by appropriate methodology, providing the unique opportunity to study this well-conserved protective reflex that results from a symptom of disease. A scratching activity monitoring system was specifically developed to record scratching behavior independent from gross body movement in patients with cholestasis,107 a need that has been identified by other investigators in the field of pruritus.108,109 The use of this scratching activity monitoring system allowed for continued recording of scratching from patients with cholestasis and pruritus over consecutive 24-hour periods in clinical trials that evaluated treatment of patients with pruritus from liver disease. In addition to providing evidence for a decrease in scratching by opiate antagonists,49,50,64,65 unique information was revealed by these recordings: (1) 96 hours of recording revealed a 24-hour rhythm in scratching behavior in some patients with maximum activity between 1200 and 1800 hours, and the nadir during hours of sleep (Figure 6.1).65 This finding underscores the uncertainty of randomly collected data, as time of day or night can affect the data themselves; in addition, the presence of a rhythm suggested the possibility of circadian regulation of itch and scratching, (2) the effect of bright-light phototherapy (10,000 lux) indirectly projected toward the eyes was associated with a decrease in the outbursts of scratching,110 suggesting some value of this type of therapy on the pruritus of cholestasis, perhaps in combination with other interventions; these results also offered support for a potential role of light, which regulates circadian rhythms,111 on the itch sensation, and (3) in contrast to gabapentin (Figure 6.2a and c), the placebo intervention was associated with a marked and significant decrease in scratching activity (Figure 6.2b and d) in patients with chronic liver disease in a double-blind, randomized, placebo-controlled trial.112 These striking results highlight the importance of placebo on the pruritus and scratching, enticing investigators to explore the physiology of the placebo effect in the treatment of this symptom. In this regard, as the magnitude of the placebo effect depends on the subject’s expectations for an effect, a practical lesson from this study is that the design of clinical trials of interventions to treat the pruritus of cholestasis, and probably any type of pruritus, must include the assessment of the subjects’ expectations, prior to entrance into a study.113,114 Accordingly, clinical trials for the treatment of pruritus in the twenty-first century should include behavioral methodology,115 preferably portable,116 the development of which is surely feasible in the current, continuously growing technological environment.

FIGURE 6.1. Mean hourly scratching activity during the 96-hour study period of a patient with benign recurrent intrahepatic cholestasis who participated in a study of naloxone infusions for the pruritus of cholestasis.

FIGURE 6.1

Mean hourly scratching activity during the 96-hour study period of a patient with benign recurrent intrahepatic cholestasis who participated in a study of naloxone infusions for the pruritus of cholestasis. The continuous line indicates the 24-hour rhythm (more...)

FIGURE 6.2. Hourly scratching activity (HSA) from patients with pruritus secondary to liver disease who participated in a randomized, double-blind, placebo-controlled study of gabapentin.

FIGURE 6.2

Hourly scratching activity (HSA) from patients with pruritus secondary to liver disease who participated in a randomized, double-blind, placebo-controlled study of gabapentin. All patients underwent continuous recording of scratching activity for a minimum (more...)

6.6. TREATMENT OF THE PRURITUS OF CHOLESTASIS

Patients with liver disease and pruritus often seek the attention of dermatologists. Internal medicine causes of pruritus including liver disease and malignancy (e.g., lymphoma) should be excluded in patients without dermatological diseases. The management of women with cholestasis of pregnancy is not discussed in this review. There is a consensus that ursodeoxycholic acid is associated with a decrease in the pruritus in the mothers, and with an improved prognosis in their infants;8 patients with cholestasis of pregnancy should be treated in collaboration with the obstetricians in a high risk pregnancy service.

The skin of patients with pruritus from liver disease is devoid of primary pruritic skin lesions; however, lesions secondary to scratching, including excoriations, and sometimes prurigo nodularis can be found; to avoid scratching is very difficult as pain induced by vigorous scratching is often associated with relief of the pruritus.117 The use of moisturizers, emollients, and other topical preparations have not been submitted to studies in patients with the pruritus of cholestasis; however, the skin must be protected and measures to keep it healthy applied. It has been the practice of the author to refer patients with pruritus from liver disease to a dermatologist to exclude primary skin diseases that may contribute to the pruritus.

Selected studies in patients with the pruritus of cholestasis are provided in Table 6.1, and guidelines for the treatment of patients in Table 6.2. Recommendations on the specific use of some drugs are provided below, although a rationale for the use of certain interventions to treat the pruritus is not always readily apparent.

TABLE 6.1

TABLE 6.1

Selected Publications on the Treatment of Itch from Liver Disease

TABLE 6.2

TABLE 6.2

Treatment of Patients with the Pruritus of Cholestasis

6.6.1. Procedures Aimed at Removal of Pruritogens from the Body

The most commonly used drug to treat this form of pruritus is cholestyramine,118 a resin that is not absorbed and that binds anions in the small intestine increasing their fecal excretion, including that of bile acids and cholesterol. The mechanism by which pruritus decreases in some patients with cholestasis in association with cholestyramine is unknown. The side effects of this resin tend to be minor in most patients (e.g., bloating). It is recommended that cholestyramine be taken immediately before and after breakfast as the rationale for its use is to bind the pruritogen(s) that accumulates in the gallbladder during the overnight fast and that is poured into the small bowel after breaking the fast. Colesevalan, also a resin, was tested in a placebo-controlled study in which a positive effect on the amelioration of pruritus was defined, seemingly arbitrarily, as a 40% decrease in the visual analogue scores for pruritus; the effect of the drug was not better than that of placebo.119

A transient relief from pruritus has been reported in association with anion adsorption and plasma separation,120 and the extracorporeal liver support systems PrometheusTM and MARSTM.121125 The analysis of plasma removed from patients with what was defined as resistant pruritus via MARSTM was reported to reveal 60 proteins, one of which, SLURP1, was three times higher in the samples extracted from patients with cholestasis than in those from the control group.126 These interventions may never be submitted to controlled clinical trials because of their nature; the tremendous need to provide relief to patients with severe pruritus, however, supports the use of this type of intervention in a controlled environment, although the placebo effect of these interventions may be substantial and the relief provided temporary.122

Reports of relief of the pruritus have also been published in association with nasobiliary drainage in PBC,127 partial internal diversion of bile in patients with progressive familial intrahepatic cholestasis,128 and partial external diversion of bile129,130 and ileal diversion in children with cholestasis,131 in whom an improvement in quality of life was also reported.

6.6.2. Changes in Neurotransmission

6.6.2.1. Opiate Antagonists

The results of several clinical studies,43,4952,6467 including those that included behavioral methodology,49,50,64,65 and the rationale on which their use is based, increase opioidergic tone,27 support the administration of opiate antagonists to treat the pruritus of cholestasis. The opiate antagonists available for the treatment of the pruritus of cholestasis are naloxone and naltrexone (Tables 6.1 and 6.2). To decrease the probability of an opiate withdrawal-like reaction that some patients experience, treatment with opiate antagonists can be started with continuous intravenous infusions in the in-patient or out-patient setting (e.g., endoscopy suite, ambulatory surgery suite) for several hours prior to the introduction of the oral medication.7,132,133 If at any point of the dose increase the patient exhibits signs of withdrawal, the dose can be maintained at the prior dose for a day or two with subsequent increases, until relief of the pruritus is achieved (Table 6.2). The symptoms and signs related to the opiate withdrawal-like reaction cease on the dose that triggered it; thus, it is not necessary to stop the medication. Patients should be evaluated with blood work after the initiation of naltrexone; from a large study of patients with alcoholism in which the drug was given for 1 year, however, no hepatotoxicity was reported.134 The metabolism of naltrexone is slow in patients with compensated and decompensated cirrhosis, in comparison to that of a control group, with predominance of naltrexone over 6 β-naltrexol in the patients;135 however, pruritus tends to cease in patients with hepatic synthetic dysfunction; thus, naltrexone is not commonly needed for patients with decompensated liver disease.11

Pain was reported in three patients with inflammatory conditions and with cholestasis and pruritus who had experienced relief on naltrexone.136 This complication is not common; if it occurs, the cause of pain has to be determined and, if none found, the pain may be from the blocking the endogenous opioid system, which is a survival system that mediates endogenous analgesia.137 The dose of the opiate antagonist can be decreased or the medication stopped as necessary if pain persists.

6.6.2.2. Serotonin Antagonists

Ondansetron was reported to relief pruritus in a group of patients with pruritus from liver disease measured by subjective methodology;138140 however, it did not have a therapeutic advantage over placebo in studies that applied behavioral methodology.141,142

6.6.2.3. Serotonin Re-Uptake Inhibitors

It was reported that the review of diaries from patients who participated in a trial for the treatment of PBC revealed an association between the use of sertraline and relief of pruritus.143 In a subsequent randomized placebo-controlled study, sertraline was reported to be associated with relief of pruritus, as assessed by a visual analogue scale, and with an improvement in the skin appearance as evaluated on physical examination.144 Selective serotonin reuptake inhibitors have been reported to decrease pruritus in polycythaemia vera145 and in patients with malignancy whose pruritus was multifactorial.146,147 Mertazapine, a noradrenergic and serotoninergic antidepressant,148 and other antidepressants have been reported to relieve pruritus in a small heterogeneous group of patients with malignancy and uremia149 and in patients with nocturnal itch from skin diseases.150 These reports tend to suggest that in addition to the serotonin neurotransmitter system, noradrenaline may participate in the mediation of pruritus not limited to that associated with liver disease.

Dronabinol relieved intractable pruritus in three patients with chronic liver disease151 and was associated with marginal ameliorating effects in a small series of patients (NVBergasa, unpublished). Impaired coordination and drowsiness of various degrees were reported as side effects (Ref. 151 and NVBergasa, unpublished). Antinociception was increased in rats with cholestasis secondary to bile duct resection in association with the administration of an agonist at a cannabinoid receptor;152 thus, it can be hypothesized that the relief of pruritus in association with dronabinol in some patients with liver disease may be due to an increase in the threshold to experience nociception of which pruritus has been defined as its second order, the first one being pain.153

6.6.2.4. Antibiotics

Rifampicin was associated with relief in pruritus in patients with PBC in a study that explored the enzyme inducing capacity of this drug.154 Rifampicin stimulates PXR, which induces drug-metabolizing enzymes and transporters.37 Rifampicin has been studied in clinical trials where it was found to relieve pruritus in patients with liver disease,41,155 although it is not helpful in all patients.42 It was concluded from a meta-analysis of controlled randomized clinical trials that rifampicin was safe; however, rifampicin can be hepatotoxic.156,157 Thus, follow-up of liver profile is necessary when patients are started on this drug and stopped if there is suggestion of hepatotoxicity.

Refractory pruritus in a group of patients with PBC was reported to be ameliorated by metronidazole.158 The long-term use of metronidazole can be associated with peripheral neuropathy; thus, only short-term courses may be appropriate.

6.6.3. Miscellaneous Types of Drugs that Have Been Reported to Relief Pruritus in Cholestasis

Phenobarbital40,159,160 has been used to treat pruritus for some time, especially in children. The sedative effect of this drug may be associated with its ameliorating effect and also, its choleretic activity.159 Gabapentin may be useful in a selective group of patients with high expectations for relief from the drug.112 Pregabalin has been reported to relieve pruritus in uremia161 and in that associated with burns.162 This drug was associated with marked relief in the itch secondary to a generalized drug-induced rash at doses of 150 mg twice a day (NVBergasa, unpublished, 2012). Its effect on the pruritus of cholestasis merits investigation.

S-adenosylmethionine is an anticholestatic agent reported to decrease cholestasis and to improve pruritus in patients with intrahepatic cholestasis of pregnancy in clinical trials.163,164

Grapefruit juice has been inconsistently reported to relieve pruritus in patients with cholestasis.165,166 Grapefruit juice causes drug interactions by inhibiting CYP3A4 in the intestine167 and in the hepatocyte, in an exposure-dependent manner,168 in contrast to rifampicin, which induces this enzyme in the hepatocyte.38 It is unknown how this effect may be relevant in the relief of the pruritus; however, the effect of these compounds in some patients may be related to absorption and to metabolism of unknown pruritogens.

Controlled studies of steroids and other immunosuppressants to treat the pruritus of cholestasis have not been published. There are reports on the use of steroids to treat pruritus not associated with inflammatory skin conditions, including cholestasis;11,169 however, long-term steroid therapy can be associated with osteopenia170 to which patients with liver disease can be predisposed.171 Thus, their random use is not recommended. The use of tacrolimus to treat pruritus in PBC has also been reported but not followed up in controlled studies.172

A reduction in the visual analogue score for pruritus was reported in a small heterogeneous group of patients with cholestasis in association with skin irradiation for a period of 8 weeks.173 Phototherapy decreased in the number of epidermal and calcitonin gene related peptide-positive dermal nerve fibers in a group of patients with inflammatory skin disease associated with pruritus;174 the rationale for the use of phototherapy to the skin to treat patients with the pruritus of cholestasis, however, is not apparent. The effect of bright-light phototherapy indirectly directed toward the eyes has already been discussed.110

The administration of anesthetics including propofol175,176 and lidocaine177 have been reported to relief pruritus from liver disease. The effect of lidocaine on the pruritus of cholestasis may be related to the role of transient receptor potential vanilloid receptor-1 in the transmission of the itch sensation.178

In summary, the pathogenesis of the pruritus of cholestasis is, most likely, multifactorial, and the perception of pruritus may be informed by the genetic composition of the patient. Increased opioidergic tone contributes to the pathogenesis of the pruritus of cholestasis, at least in part; a central mechanism has been proposed.27 Substances that under physiological conditions are excreted in bile accumulate in body tissues as a result of cholestasis and may stimulate peripheral pruriceptive neurons, providing a peripheral component to the pruritus. In addition, the constant peripheral stimulation may also lead to central sensitization for itch.104

The relevance of results from cellular and from behavioral research in laboratory animals to the pruritus of cholestasis must be sought in an effort to develop effective antipruritic drugs. The incorporation of behavioral methodology in studies of pruritus offers the opportunity to learn features of scratching behavior and to define objective end points in clinical trials. In the absence of behavioral methodology, yes or no, in answer to the question of relief from patients must suffice as a measure of success.

Bile acids, which accumulate in body tissues in cholestasis, were recently reported to mediate scratching behavior in mice by mechanisms that involved gastrin releasing peptide and the mu opioid receptor, the receptor through which morphine mediates scratching behavior in non-human primates, and likely, human beings. TGR5, a G protein coupled plasma membrane receptor for bile acids, was necessary for mice to exhibit scratching behavior in association with bile acid administration. These results were interpreted to suggest a potential role of TGR5 antagonists for the treatment of the pruritus of cholestasis. Although the animal model used in these experiments is not a model of the pruritus of cholestasis, these interesting results identify the opioid receptor as mechanistically relevant in scratching behavior associated with the administration of bile acids in mice. If bile acids contribute to the pruritus of cholestasis in human beings, the mu opioid receptor may mediate the pruritogenic effect of these substances,179 supporting further a role of the endogenous opioid system in the pruritus of cholestasis.

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© 2014 by Taylor & Francis Group, LLC.
Bookshelf ID: NBK200923PMID: 24830019

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