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Summary

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

Pruritus is often the most troublesome symptom in patients with chronic liver disease, particularly when cholestasis is a prominent feature.

The exact pathogenesis is unknown, but empirical treatment, such as cholestyramine, based on a liver-based origin of pruritus, has been used for many years. Recently, evidence for a central mechanism for pruritus has been obtained and opioid antagonists have been tried clinically with some benefit, but their use is not widespread. In addition, the pruritus associated with intrahepatic cholestasis of pregnancy can now be alleviated in many cases by ursodeoxycholic acid. As it also improves foetal outcome, this should become first-line therapy.

We review the pathogenesis and therapy of pruritus, highlighting practical aspects to help with patients with seemingly intractable pruritus.


Introduction

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

Pruritus (from the Latin verb prurire, to itch) is a common and potentially distressing manifestation of prolonged cholestasis, and is also experienced by patients with non-cholestatic liver disease. Primary biliary cirrhosis (PBC) has traditionally been the model for the study of pruritus, itching being the index symptom in the majority of patients. Pruritus, together with fatigue, is the usual presenting symptom and affects nearly 70% of PBC patients by 10 years after diagnosis. Itching may first present during pregnancy and does not resolve in the postpartum period, differentiating it from the pruritus of pregnancy. Once pruritus occurs in a patient with PBC, it is unusual for it to disappear spontaneously. Its perception appears to vary considerably amongst patients; it can be persistent or intermittent, generalized or localized to specific parts of the body, usually the palms and the soles. It is more troublesome at night, under tight, constricting clothes and in hot, humid weather. Physical processes, such as the pre-menstrual state in women, and psychological factors, such as excitation, can transiently exacerbate pruritus. Pruritus in PBC is not associated with any definable primary skin lesion; however, chronic, vigorous scratching can result in cutaneous complications, such as excoriations, folliculitis, prurigo nodularis and lichenification. Itching, when mild, can usually be managed with simple interventions, but it can be disabling, interfering with daily activities, and occasionally is refractory, leading to sleep deprivation or contributing to significant psychological disturbances with serious adverse effects on the quality of life. The management of the pruritus of cholestasis is a difficult clinical problem and may be unsatisfactory, causing distress and exasperation to the patient as well as to the doctor. This frustration originates from the subjective nature of the pruritus, the lack of a uniformly used objective evaluation and its undefined pathogenesis. Current anti-pruritic treatments are empirical and not consistently effective.

Pathogenesis

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

Many physical and chemical stimuli are able to induce pruritus, acting directly on the nerve endings or indirectly via histamine release. ‘Itch points’ are found throughout the body surface where numerous free unmyelinated nerve endings in the superficial papillary dermis, just below the epidermis, form a finely arborescent network.1 Typically, the itch sensation starts with a delay of 30–60 s following histamine stimulation, reaching a maximum after 2–3 min and lasting roughly 10 min. Recently, Andrew and Craig identified ‘itch-specific’ neurones in cat spinal cord; they responded to histamine with a time course similar to that of the itch sensation and were insensitive to noxious and thermal stimuli.2 The pathway for pruritus involves the dorsal horn, the contralateral anterolateral spinothalamic tract and the thalamus. In addition to the peripherally acting stimuli, central mediators of pruritus have been postulated, as intrathecal or intraventricular injection of morphine in the brain induces pruritus.3 The relationship between pruritus and pain has been studied; opiate administration in humans reduces pain, but can cause itching,4 and painful stimuli can abolish itching, the success of scratching being the best-known example. This suggests that itching and pain are distinct sensations that interact.2, 5

The pathogenesis of pruritus in cholestasis and non-cholestatic liver disease remains elusive, and the causative factor or factors have not been conclusively proven. It is thought that pruritus in the presence of any type of liver disease has the same pathogenesis, and it has been traditionally assumed that it arises from pruritogenic substances that accumulate as a consequence of impaired secretion of bile. These substances interact with the nerve endings of the skin and induce the sensation of itching. Bile acids (BA) have been most thoroughly tested as putative pruritogens. Skin tissue concentrations of BA are elevated in patients with cholestasis and are linearly related to serum levels.6 In addition, experiments with the instillation of bile salts (BS) induce pruritus.7 Furthermore, the binding resin cholestyramine enhances the elimination of BS and relieves pruritus. Finally, biliary drainage reduces pruritus in patients with extrahepatic biliary obstruction8 and intrahepatic cholestasis,9 and external biliary diversion has recently been used with success for intractable pruritus.10 However, there is evidence against the role of BA as pruritogens via the peripheral nervous system. Ghent et al. reported that concentrations of BA, although elevated in skin tissue and serum in patients with cholestasis, could not be used to differentiate between patients with and without pruritus.6 Similarly, Bartholomew et al. found no correlation between serum or interstitial fluid total BA or individual BA concentrations and pruritus.11 Nevertheless, this argument can be challenged by considering the diurnal fluctuation of plasma BA, their complex composition in cholestasis and their possible slow or synergistic action on peripheral or central receptors.12 In experiments by Varadi, it was the instillation of crude, not purified, human BS at high artificial concentrations that induced pruritus.7 On the other hand, cholestyramine has been reported to relieve pruritus in polycythaemia rubra vera13 and uraemia,14 suggesting that it has complex effects on the absorption of substances other than BS with pruritogenic properties. Interestingly, testosterone may relieve pruritus whilst causing a further rise in the serum concentration of BS.15

The inconsistencies in the theory of the BS–peripheral nerve endings–pruritus interaction have prompted the hypothesis that BS may act on the hepatocyte to release a ‘pruritogenic’ factor. Hydrophobic BS accumulate in the liver due to cholestasis, alter the membrane fluidity and induce shedding of the plasma membrane and the release of a pruritogen (or pruritogens). The ‘pruritogenic’ compound thereafter acts within the peripheral or central nervous system to promote the perception of itching.16 This theory is consistent with the beneficial effects of cholestyramine, testosterone and biliary drainage on pruritus. However, the discrepancy between the levels of BS and the severity of pruritus remains unsolved by either of the above theories, although the role of individual BA on hepatocytes and the ratio of hydrophobic to hydrophilic BA may be a possible explanation.

In the last decade, a theory that implicates endogenous opioids, such as met-enkephalins, as central mediators of pruritus has been suggested. More specifically, increased opioidergic tone (neurotransmission/neuromodulation) has been shown to contribute to the pruritus of cholestasis.17 There is considerable evidence that supports this concept. In particular, experiments in animals, as well as in humans, have shown that opioid agonists, such as morphine, induce pruritus.18, 19 The oral administration of a potent opioid antagonist to cholestatic patients, but not to healthy subjects, induces an opioid withdrawal-like reaction.20 In a rat model of cholestasis, total opioid activity in plasma is increased, the density of mu-opioid receptors is down-regulated and a state of anti-nociception (analgesia) can be demonstrated and reversed by naloxone.21–23 Spivey et al., on the other hand, have demonstrated that serum met-enkephalin levels in patients with PBC correlate with the severity of the disease, but not with pruritus.24

The serotonin neurotransmitter system has also been implicated in the pathogenesis of pruritus in cholestasis. It has been reported to modulate nociception (pain perception) in rats,25 and, in analogy with the opioid system, may modulate the perception of pruritus. Increased serotonin release leads to elevated met-enkephalin levels in the hypothalamus,26 and ondansetron, a 5-hydroxytryptamine-3 serotonin receptor subtype antagonist, has been reported to ameliorate pruritus.27, 28 However, data supporting changes in the serotoninergic neurotransmission in cholestatic patients are lacking.

It appears that more than one factor contributes to the pathogenesis of pruritus in cholestatic and non-cholestatic liver diseases. Whether the primary event is an as yet unidentified substance that lies peripherally within the skin, targets the hepatocyte itself or modulates central mechanisms remains to be proven. The current treatment options are based on the premise that BS or endogenous opioids are the principal mediators of pruritus in cholestasis.

Treatment

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

As the aetiology of the pruritus of cholestasis remains unknown, its treatment has been largely empirical. Numerous interventions have been used to manage pruritus with varying efficacy. Treatment evaluation is difficult; pruritus is an intrinsically subjective perception and cannot be quantified directly. The comparison and interpretation of the results of clinical trials have been limited by the small sample sizes, open-label designs and the use of various subjective scales to ‘quantify’ pruritus. In an attempt to apply an objective method to assess pruritus, which can be used at the same time as a primary efficacy end-point, the measurement and monitoring of the scratching activity has been introduced. The devices that measure scratching activity involve the application of piezofilm technology to generate a scratch transducer which is attached to the fingernail.29, 30 On the other hand, it can be argued that scratching is merely a consequence of pruritus and cannot accurately convey the sensation of itching. The perception of itching has been assessed using subjective scales, such as visual analogue scales, that have been validated in clinical practice.31

Therapies of the primary disease — ursodeoxycholic acid (UDCA). Treatment of the underlying cholestatic disease should ameliorate pruritus. Currently, the only approved treatment for PBC is UDCA. From the considerable amount of literature on its use in PBC, only five studies have suggested that UDCA significantly decreases the severity of pruritus.32–36 These include a publication in abstract form32 and a trial with only 10 patients.33 In a multi-centre controlled trial of UDCA, pruritus was significantly decreased only in patients completing the study, but not in an intention-to-treat analysis.34 In two double-blind, multi-centre trials, decreased pruritus following the administration of placebo was observed.35, 36 A beneficial effect of both UDCA and colchicine has been reported in a placebo-controlled trial comparing the two drugs, but not in an intention-to-treat analysis.37 The role of UDCA in pruritus has been clarified by recent meta-analyses of randomized controlled trials of UDCA therapy in PBC, which show no favourable effect on symptoms, including pruritus, in patients with PBC.38, 39

Prednisolone, ciclosporin and methotrexate have also been assessed in trials for the treatment of PBC. In a 3-year placebo-controlled trial of prednisolone in PBC, 15 of 19 patients reported improvement of itching at the higher doses of prednisolone (> 10 mg/day). However, this was not a quantitative assessment and was single-blind.40 Pruritus has been stabilized and even improved in trials with ciclosporin in PBC patients, but the limited efficacy of the drug is counterbalanced by its predictable toxicity.41 In a pilot study of nine patients with PBC treated with methotrexate, pruritus improved or resolved.42 When the drug was compared with colchicine in a randomized controlled trial with 85 patients, it was found to reduce significantly the severity of itching [mean pruritus score reduced from 1.63 to 1.12 (P = 0.04) with colchicine and from 1.25 to 0.44 (P = 0.0001) with methotrexate].43 However, Hendrickse et al. reported a non-significant trend towards lower pruritus scores with methotrexate treatment in a double-blind, randomized controlled trial.44 Interstitial pneumonitis is a serious complication of methotrexate treatment in PBC patients and occurred in 14% in one study.45

Anion exchange resins — cholestyramine. The most widely used conventional treatment for the pruritus of cholestasis is the anion exchange resin cholestyramine. Cholestyramine is a hydrophilic, water-insoluble, non-absorbable agent that binds BA, preventing their absorption from the terminal ileum through the enterohepatic circulation. Cholestyramine has been reported to relieve the pruritus of polycythaemia rubra vera13 and uraemia,14 and, as it has complex effects on the absorption of a variety of compounds, its effectiveness is not attributed entirely to the depletion of the serum BS pool.46 There has been no randomized study on the effectiveness of cholestyramine. However, the clinical experience is extensive and the drug appears to relieve or ameliorate pruritus in the majority of patients within the first 2 weeks from the initiation of treatment. In a substantial proportion of patients, the response is transient. According to initial studies, 80–85% of patients completely or partially respond to cholestyramine treatment (3.3–10 g/day; 1.7 g/day for children aged < 10 years) within 4–11 days.47, 48 The relief of pruritus was maintained for up to 32 months on therapy in a placebo-controlled trial with 23 patients treated for 6–32 months.48

Cholestyramine is administered orally and should be given in escalating divided doses starting with 2–4 g/day up to 16 g/day (each sachet contains 4 g of cholestyramine). Empirically, doses up to 32 g/day have been prescribed. It is recommended that it should be adequately diluted in water or juice. The timing of ingestion of cholestyramine in relation to meals is most important. The greatest amount of BA available for binding by the resin is present in the gall-bladder before breakfast. Depending on the extraction efficiency of the liver, less may be present before lunch and even less before dinner. Therefore, in patients with an intact gall-bladder, the resin should be taken 30 min before and 30 min after breakfast. A third dose should follow lunch. This scheme of administration maximizes the efficacy and minimizes the side-effects of cholestyramine.49

The side-effects of cholestyramine are common, but usually mild. Poor compliance appears to be the major issue due to the drug's unpleasant taste. This problem seems to have been further aggravated, and more patients have found the drug to be even more unpalatable, after the recent changes in the drug's formulation; the colouring agents have been removed and the medication is now sucrose free (personal communication, from Bristol-Myers, 2002). Cholestyramine may also cause constipation, abdominal discomfort, anorexia and fat malabsorption. Hyperchloraemic metabolic acidosis and hypothrombinaemic haemorrhage have been described in case reports.50, 51 Cholestyramine interferes with the bio-availability of several drugs, such as UDCA, thyroxin, digoxin and oral contraceptive hormones; it is advisable that at least 4 h should lapse between the ingestion of cholestyramine and any other medication. Another ammonium resin, colestipol hydrochloride (5 g up to 30 g/day), has similar properties to cholestyramine and appears to be better tolerated in some patients.52 A new BA-binding polymer, colesevalem hydrochloride, initially developed as therapy for hypercholesterolaemia, has been reported to be more effective than cholestyramine and to have no gastrointestinal side-effects.53

Rifampicin. Rifampicin, a semi-synthetic antibiotic produced by Streptomyces mediterranei, has been studied for the treatment of pruritus in cholestasis. Rifampicin and phenobarbital act as rapid and strong inducers of the enzymes of the microsomal drug-oxidizing system, promoting the metabolism of endogenous ‘pruritogenic’ compounds.54 Furthermore, rifampicin competes for the uptake of BS into the hepatocyte, eliminating their detergent effect.55 It has also been suggested that rifampicin, through its antimicrobial action, modifies the synthesis of secondary BA in the intestinal lumen, and consequently reduces the amount of hepatotoxic lithocholic acid.56

Three prospective studies, two being double-blind randomized controlled trials, have suggested a subjective effect of rifampicin on the severity of pruritus in PBC patients (Table 1).57–59 Ghent and Carruthers reported a highly significant reduction of pruritus in eight of nine patients on rifampicin (P < 0.002) within the first week of treatment. Of note, the amount of cholestyramine ingested by the patients did not change whilst on rifampicin.57 Similarly, Podesta et al. reported a significant difference of pruritus response to rifampicin and placebo (P < 0.001); pruritus disappeared in the majority of patients (11 of 14).58 In both studies, there was no significant placebo response or any effect from the order of treatment. No adverse effects were observed, except for an allergic reaction in one patient.58 In an open study by Bachs et al., pruritus disappeared in 11 of 16 patients after 3 months of rifampicin treatment, and the beneficial effect was maintained up to 24 months. Rifampicin hepatitis developed in two patients (12%).59 In contrast, Woolf and Reynolds reported that a daily dose of 300 mg rifampicin was not effective in relieving pruritus in patients with a variety of chronic liver diseases (reported less itching, four patients on rifampicin and three on placebo; small fall in visual analogue scale score, two patients on rifampicin and two on placebo; three patients reported no change). However, the authors recognized the possibility of a type II statistical error (Table 1).60 In comparison with phenobarbital, rifampicin has a greater anti-pruritic effect.61 Similar to adults, the relief of pruritus has been reported in children with chronic cholestatic liver disease.62

Table 1.  Studies of rifampicin (RF) for the treatment of pruritus in patients with primary biliary cirrhosis (PBC)
ReferenceStudyNo. of patientsRF dose (mg/day)Duration of treatment (days)*Study periodPruritus score RF efficacy
  • DB RCT, double-blind, randomized controlled trial; VAS, visual analogue scale.

  • Days of washout-treatment-washout-treatment-washout.

  • † 

    See text.

Ghent and  Carruthers57DB RCT cross-over 9300–45014-14-14-14-1410 weeksVASImprovement in 8
Podesta et al.58DB RCT cross-over1460015-7-7-73 weeks open  study: 8 monthsIndividual  log book  (1–100)Improvement in 3 Disappeared in 11
Bachs et al.59Open prospective1610/kg2–24 monthsScale (0 to + 3)Improvement in 5 Disappeared in 11
Woolf and  Reynolds60DB RCT cross-over12 (4 PBC)3007-15-7-15-77 weeksVASNo effect

Rifampicin has been associated with severe idiosyncratic hypersensitivity reactions, such as haemolytic anaemia, renal failure and thrombocytopenic purpura. Rifampicin as an enzyme inducer may have important implications in the disposition of concomitantly administered drugs. In this respect, it has been reported that, in heroin addicts on methadone maintenance, withdrawal symptoms frequently developed in those simultaneously given rifampicin.63 The potential hepatotoxicity of rifampicin is of concern, as Prince et al. recently described three cases of severe rifampicin hepatitis and reported an incidence of 7.3% in patients treated with rifampicin.64 The potential development of resistance to the antibiotic is also a major issue.

In conclusion, the role of rifampicin requires further assessment with studies of larger sample sizes and longer follow-up. Empirically, in patients who fail or are intolerant to the side-effects of cholestyramine, rifampicin should be used as second-line therapy. As there is no clear evidence for the dosing of rifampicin in PBC, and given the fact that hepatotoxicity tends to occur with higher doses, it is prudent to start on a daily dose of 150 mg and subsequently increase up to a maximum of 600 mg based on clinical need. Regular monitoring of liver function, especially in the first 2 months, is essential.64

Opioid antagonists. The opioid antagonists have been extensively evaluated in the treatment of the pruritus of cholestasis over the last decade, with the majority of studies showing a beneficial effect. They function by preventing binding of endogenous opioid agonists, which are elevated in cholestasis. In 1979, a subcutaneous injection of naloxone in a female patient with cholestatic sarcoidosis provided relief of itching, whilst the injection of a saline solution provided none.65 To further define the role of opioid antagonists in pruritus, several studies have been conducted which have shown a beneficial effect (Table 2, Figure 1).20, 66–69 In a double-blind, randomized controlled trial by Bergasa et al., the mean visual analogue scale score of the perception of pruritus, recorded during naloxone infusions, was 0.582, lower than that recorded during placebo infusions (P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (P < 0.001), and was greater than 1.0 in only five patients.67

Table 2.  Studies of opiate antagonists for the treatment of pruritus in patients with chronic liver disease
 Reference
2066676869
  • C, control; DB RCT, double-blind, randomized controlled trial; iv, intravenous; NR, not recorded; PBC, primary biliary cirrhosis; SA, scratching activity; SB PCT, single-blind, placebo-controlled trial; T, opioid antagonist; VAS, visual analogue scale.

  • *

     Gradually up to 120 mg/day.

  • † 

    Subsequently increased up to 0.4 µg.min/kg.

  • ‡ 

    Preceded by bolus of 0.4 mg iv.

  • § 

    Subsequently doubled every 2 days up to 240 mg/day until substantial subjective reduction of pruritus.

  • ¶ In 50% of patients decrease in VAS – mean decrease in SA 50%P < 0.001.

  • ** 

    See text.

  • †† 

    Significant changes with respect to baseline only in the treatment group; daytime itching P = 0.001; night-time itching P = 0.002.

StudyOpen-labelSB PCTDB RCTDB RCTOpen-label
 cross-over cross-over  
No. of patients (T/C)11 (9 PBC)8 PBC29 (16 PBC)16 (13 PBC)14 (3 PBC)
     (8/8) 
DrugNalmefeneNaloxone ivNaloxone ivNaltrexoneNalmefene
Dose (per day)10 mg*0.2 µg.min/kg0.2 µg.min/kg50 mg4 mg§
Study period6 months1 day4 days4 weeks2–26 months
Pruritus scoreVASVAS & SAVAS & SAVASVAS & SA
Improvement9SignificantSignificant**Significant††13
Withdrawal-like reaction11None445
BreakthroughNRNRNR15
ToleranceNRNRNRNR3
image

Figure 1. Improvement of pruritus in studies of opiate antagonists. SA, scratching activity; VAS, visual analogue scale.

Download figure to PowerPoint

All three opioid antagonists used in these trials (nalmefene, naloxone and naltrexone) have been associated, to various extents, with an opioid withdrawal-like reaction when administered to cholestatic patients, but not to normal subjects. The reaction may begin within 1 h from the administration of the drug,20 and is always temporary, often becoming minimal after 2 or 3 days, despite continued administration of the drug. Amongst other symptoms, its features may include anorexia, nausea, colicky abdominal pain, pallor, cool skin and increase in blood pressure. Its severity varies and, when severe, may lead to the discontinuation of treatment. To avoid or minimize the occurrence of this reaction, three approaches have been adopted: (i) co-administration of clonidine during the first week of treatment, with a starting dose of 100 µg t.d.s. and gradual reduction to zero;20 (ii) low starting dose of the opioid antagonist and subsequent gradual stepwise increases in dose (nalmefene, initially 2 mg b.d., then doubled every 2 days until subjective reduction in pruritus);69 and (iii) starting therapy with an intravenous infusion of naloxone at a slow sub-therapeutic rate (0.002 µg.min/kg), with a slow increase to the therapeutic range (0.2 µg.min/kg), and then switching to small oral doses of an orally bio-available opioid antagonist (naltrexone, 12.5 mg b.d. or t.d.s., increased as necessary over the next few days).70, 71

The ‘breakthrough’ phenomenon, which is the sustained exacerbation of the perception of pruritus in the early weeks of treatment after an initial decrease, has been observed during naltrexone and nalmefene therapy.68, 69 It has been suggested that the down-regulation of opiate receptors in the brain in cholestatic patients is reversed during therapy with opiate antagonists. The ensuing up-regulation leads to an increased sensitivity to endogenous opioids.23 The ‘breakthroughs’ are managed by upward adjustment of the dose,69 or prevented by interrupting treatment for 2 days every week.72

The opiate antagonists used in the trials do not completely abolish pruritus in cholestatic patients. The reason for this could be that the dose administered is insufficient, as it has not been standardized for the different drugs, or there may be a carryover effect of the chronic scratching habit into periods of treatment. Finally, the opioid system may not be the sole pathogenetic mediator of pruritus. However, there is a definite role for opiate antagonists in the treatment of pruritus in cholestasis; parenterally administered naloxone can be used for the emergency treatment of severe exacerbation of pruritus in patients with PBC, and the orally bio-available naltrexone and nalmefene can be employed in the long-term management of this symptom. An adequate trial of opiate antagonist therapy should also be considered before liver transplantation for intractable pruritus.71

Nalmefene, compared with naloxone, has a greater bio-availability, more potent action and longer plasma half-life. The value of naltrexone needs to be further assessed in longer and larger studies. As it has been associated with hepatotoxicity in a dose-related manner in studies in the treatment of obesity,73 its side-effects, together with the development of tolerance to treatment, need to be further evaluated.

Ondansetron. Based on the putative implication of the serotonin neurotransmitter system in the pathogenesis of pruritus in cholestasis, some data, in the form of case reports,74 series of cases75, 76 and two placebo-controlled trials,77, 78 support the use of ondansetron as therapy. The pitfalls of the trials are the small sample sizes and the inclusion of patients with various liver pathologies (metastatic liver disease, cholangiocarcinoma, alcoholic cirrhosis, chronic hepatitis, PBC and primary sclerosing cholangitis) (Table 3). Schwöreret al. concluded that the collective visual analogue scale scores of placebo and ondansetron treatment were significantly different (P < 0.05), in favour of ondansetron, during the observation period. The anti-pruritic effect of the drug seemed to be dose dependent and was reproducible in the same patient.77 The trial by Mülleret al. showed a small, but significant, reduction of the composite peak visual analogue scale score of 1.34 points during treatment with ondansetron (P = 0.033) when compared with placebo. In addition, a period effect was observed, that is a further reduction in the peak visual analogue scale score in the second treatment period, irrespective of the kind of treatment the patient was receiving (P = 0.044).78 No adverse effects of ondansetron were observed in both studies.

Table 3.  Controlled trials of ondansetron treatment in patients with cholestasis
ReferenceStudyNo. of patientsDose (mg/day)Pruritus scoreStudy periodTreatment efficacy
  • DB RCT, double-blind, randomized controlled trial; iv, intravenous; PBC, primary biliary cirrhosis; PC, placebo-controlled trial; po, per os; VAS, visual analogue scale.

  • *

    P < 0.05.

  • P = 0.033 (95% CI, 0.12–2.56).

Schwörer et al.77PC cross-over10 (2 PBC)4–8 mg ivRating scale 0–1024 hSignificant reduction*
Müller et al.78DB RCT cross-over18 (6 PBC)24 mg poVAS 0–105 weeks[DOWNWARDS ARROW] composite peak VAS  score: 1.34 points

Non-specific therapies. A considerable number of non-specific therapies may alleviate itching in cholestatic patients. The commonly prescribed antihistamines (non-sedative) do not appear to be efficacious, as there are no histamine-mediated effects in the pruritus of cholestasis. Antihistamines with a sedative effect, e.g. chlorpheniramine (chlorphenamine), and sedatives, such as benzodiazepines, may facilitate sleep at night, and therefore carry a non-specific efficacious effect.

Experimental therapies — surgery. Propofol has been used for the relief of pruritus secondary to spinal morphine administration, and Borgeat et al. have reported the efficacy of the drug in sub-hypnotic doses (15 mg) for the short-term symptomatic relief of pruritus associated with liver disease.79 In two randomized controlled trials with 10 and 20 patients, treatment success was achieved in 85% and 80% of patients, respectively. It has been suggested that propofol exerts its anti-pruritic action by inhibiting the afferent signals by the spinal root nerves that are mediated, in part, by endogenous opioids.80, 81

Based on the observation that pruritus disappeared in a patient whilst sunbathing, an early pilot study (published as correspondence) showed a remarkable relief of itching (in five of six patients with PBC) after exposure to ultraviolet (UV) light.82 The authors suggested that phototherapy might alter the skin sensitivity to the putative pruritic agent which may be a photosensitive compound. The combination of UV phototherapy and cholestyramine relieved severe cholestatic pruritus in a case report.83 In a recently published pilot study, Bergasa et al. administered bright light therapy in eight patients with chronic liver disease of different aetiologies. They concluded that the pruritus of cholestasis is responsive in some patients to bright light therapy reflected towards the eyes.84

S-Adenosyl-methionine (SAMe) is a physiological compound formed from the metabolism of methionine, and is involved in metabolic processes in the hepatocyte that are important in the detoxification of BA. SAMe has been used most extensively for pruritus in intrahepatic cholestasis of pregnancy.85–87 Reports on benign recurrent intrahepatic cholestasis treated with SAMe failed to show an effect, and suggested the possible hepatotoxicity of the drug.88

Given the potential role of oxidative stress in cholestasis-related liver damage,89, 90 the Newcastle group, in an open-label, randomized, pilot study of 24 patients, examined the therapeutic effects of antioxidant medication on the symptoms of PBC.91 Patients who received 3 months of treatment with a combination of two antioxidant preparations (Bio-Antox and Bio-Quinone Q 10) reported significant improvement in pruritus in the visual analogue scale (P < 0.005) and night itch severity (P < 0.005) scores. Fatigue was also improved. Interestingly, no change in biochemical parameters was seen in the treatment groups.

Δ-9-Tetrahydrocannabinol is a chemical compound included in the smoke of cannabis. Recently, Neff et al. administered dronabinol (the per os form of Δ-9-tetrahydrocannabinol) to three patients with intractable pruritus secondary to cholestatic liver disease; itching was resolved, together with insomnia and depression, in all three patients. No withdrawal symptoms or addiction was developed.92

The role of macrolide antibiotics has mainly been investigated in the context of skin disorders. As described in case reports and open trials, patients suffering from psoriasis vulgaris, atopic dermatitis, prurigo chronica or pruritus pigmentosa found relief from itching after treatment with clarithromycin or roxythromycin.93–95 The mechanism of the anti-pruritic effect is unclear; macrolide antibiotics may inhibit the production of certain cytokines or neuropeptides that cause pruritus.93

More invasive modalities of therapy have also been used when conventional therapeutic approaches have not proven to be efficacious. Plasmapheresis, which aims to remove from the body any putative pruritogens, appears from a series of cases to offer relief of pruritus, even transient.96–98 Recently, albumin dialysis, using the molecular adsorbents recycling system, has been shown to achieve high clearance of albumin-bound substances, such as BA and bilirubin, and to diminish cholestatic pruritus.99 Nonetheless, this treatment is expensive and time consuming and should be considered only in cases of severe, intractable pruritus. Partial external diversion of the bile has been reported to offer relief of pruritus in a series of children with intrahepatic cholestasis.10, 100 Reports in the adult PBC population or those with other liver diseases are not available. Finally, pruritus that causes sleep deprivation, leads to suicidal ideation and generally confers poor quality of life is an indication for liver transplantation, irrespective of the evidence of hepatic decompensation or indices of prognosis.

Conclusions

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

The pruritus of cholestasis remains a challenging medical problem. There are few definitive data on the mechanisms involved and therefore its management remains empirical. Guidelines on treatment have been published, but are only supported by evidence from clinical experience, descriptive studies or reports of expert committees, with very few randomized studies.101 We recommend that, before embarking on the use of treatment modalities with a higher cost and, most importantly, a wider range of side-effects, the use of cholestyramine, which is a safe, low-cost drug (60-sachet pack of cholestyramine costs £21.06), should be optimized. This includes the dosing used (low dose initially with a stepwise increase), the timing of administration (30 min before meals), the need for daily intake and the occasionally long time, up to several weeks, before any effect takes place. In the majority of the above-mentioned trials, pruritus was recorded as cholestyramine-resistant after an inadequate dose of the drug had been used. In addition, there was no record of the other issues relating to its administration or whether the treating clinician had checked these. True non-responders should always be managed with a different drug, as pruritus is a very distressing symptom which affects the quality of life. The ‘stepwise’ approach used in our unit for the treatment of pruritus in cholestatic liver disease is shown in Figure 2.

image

Figure 2. Treatment strategy for pruritus in chronic liver disease. *See text for incremental dosage. †Alternatives (all experimental) are: molecular adsorbents recycling system, antioxidant treatment or bright light therapy. Transition to the next step of therapy is performed in patients with inadequate response or intolerance.

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Pruritus in non-cholestatic liver disease

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

The majority of the literature on pruritus in chronic liver disease refers to cholestatic pathologies, namely PBC. However, non-cholestatic liver diseases have also been linked with pruritus. In case reports, autoimmune hepatitis has manifested with pruritus and, in liver biopsy specimens, a histological variant associated with prominent centrilobular necrosis was identified.102, 103 Patients with alcoholic cirrhosis and non-A, non-B hepatitis have been included in studies of pruritus.78, 84, 104 Liver involvement in alpha(1)-antitrypsin deficiency may show manifestations of cholestatic injury, including pruritus. Hepatitis A may present with a cholestatic picture and hence pruritus.

More data exist on the association between chronic hepatitis C and cholestasis/pruritus. When Lebovics et al. reviewed the records of 175 chronic hepatitis C patients, they identified nine patients with pruritus. The clinical course of the symptom was relapsing, and the response to a variety of interventions was incomplete and inconsistent. The histology in these nine patients revealed advanced pathology and bile duct abnormalities.105 Chia et al. confirmed these findings in eight patients with chronic hepatitis C and severe pruritus.106 In addition, Kumar et al. found histological evidence of bile duct injury in six patients with chronic hepatitis C and biochemical or clinical cholestatic features.107 In an attempt to determine the prevalence of pruritus in viral hepatitis, Bonacini studied, prospectively, 310 patients with hepatitis C virus (HCV), human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection, alone or in combination (119 HCV, 91 HCV + HIV, 51 HIV, 31 HBV + HIV, 18 hepatitis B surface antigen carriers). He found that 20% of patients with chronic hepatitis C and 8% of hepatitis B patients complained of pruritus. In contrast with previous reports, patients with pruritus had laboratory and histological parameters comparable to those without.108

Whether the pathogenesis of pruritus in chronic hepatitis C and other non-cholestatic liver diseases varies from that in cholestatic diseases remains to be studied. The approach to management, though, should be the same as described for pruritus in chronic cholestasis.

Pruritus in intrahepatic cholestasis of pregnancy

  1. Top of page
  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References

Intrahepatic cholestasis of pregnancy is part of the spectrum of cholestatic diseases that present with pruritus. It affects 0.5–1% of pregnant women, predominantly in the third trimester, and carries a high risk of adverse foetal outcome. Intrahepatic cholestasis of pregnancy affects maternal well-being and is associated with pruritus (pruritus gravidarum) that may lead to a lack of sleep, anorexia and malnutrition. In addition, miscarriage and premature labour occur more frequently. However, the overall maternal morbidity and mortality are low. On the other hand, foetal morbidity and mortality are significant, with increased risks of meconium-stained amniotic fluid, foetal distress, spontaneous pre-term delivery and sudden foetal death. Early identification of the condition, careful interdisciplinary monitoring and prompt delivery at foetal maturity can improve the outcomes in mother and child.

Pruritus in intrahepatic cholestasis of pregnancy has been treated with antihistamines or cholestyramine, but they are usually not well tolerated and are commonly ineffective.109 As both intrahepatic cholestasis of pregnancy and cholestyramine may independently lead to vitamin K deficiency, it is important that patients receive parenteral substitution of the vitamin and, to prevent postpartum haemorrhage, it should be administered before delivery. Studies on the efficacy of SAMe in the treatment of pruritus in intrahepatic cholestasis of pregnancy have shown conflicting results. Although it significantly decreased pruritus, as well as liver enzymes, in two randomized controlled trials with 18 and 30 patients (800 mg/day intravenously and 1600 mg/day per os, respectively),85, 86 SAMe treatment (900 mg/day intravenously) had no effect in a double-blind randomized controlled trial of 18 patients.87 The foetal/neonatal outcomes were not significantly different or were not recorded. Therefore, the role of SAMe in the treatment of intrahepatic cholestasis of pregnancy is debatable. Dexamethasone, which inhibits foeto-placental hormone synthesis, has been shown to improve pruritus in intrahepatic cholestasis of pregnancy in a study of 10 patients, when given at a dose of 12 mg/day for 7 days with tapering over 3 days.110

UDCA, although not licensed for use in pregnancy, is the only therapy that has been proven to be effective, albeit in small studies, in the alleviation of pruritus, and it seems to have no obvious adverse effects on the foetus. This hydrophilic BA protects against injury to the bile ducts by hydrophobic BA and potentiates the excretion of these and other potentially hepatotoxic compounds.111 It also stimulates the excretion of the sulphated metabolites of progesterone that are known to be elevated in intrahepatic cholestasis of pregnancy. This effect seems to be independent of the effect on BA excretion.112 The studies on UDCA vs. placebo in intrahepatic cholestasis of pregnancy are shown in Table 4.113–117 In all studies, patients on UDCA treatment experienced subjective improvement and, not uncommonly, complete resolution of pruritus (significant reduction in four of the five studies), as assessed by five-point scales. The levels of BA and transaminases were also significantly reduced. Of note, in three patients who received UDCA treatment for two periods, separated by a washout/drug-free period, pruritus and laboratory alterations relapsed and improved again with the re-administration of UDCA.113 UDCA has also been shown to be superior to SAMe in controlling pruritus and reducing total BA in a randomized controlled trial of 20 patients. Indeed, all women in the UDCA group reported the disappearance of itching within 3 days of treatment. No adverse side-effects were observed in mothers or babies.118 Nicastri et al. compared SAMe, UDCA and SAMe + UDCA with placebo in a randomized controlled trial of 32 patients with intrahepatic cholestasis of pregnancy. The severity of pruritus diminished in all treatment and placebo groups. However, SAMe resulted in a greater reduction of pruritus scores from baseline than UDCA (P = 0.004), and the women given the combination SAMe + UDCA achieved significantly greater reduction in pruritus than women given placebo (P < 0.001) or UDCA (P < 0.001), but not SAMe (P = 0.1), alone.116

Table 4.  Trials of ursodeoxycholic acid (UDCA) treatment vs. placebo in maternal pruritus in patients with intrahepatic cholestasis of pregnancy
ReferenceStudy No. of patients (T/C)UDCA dose (mg/day)Duration of treatment (days)Improvement
  • C, control; RCT, randomized controlled trial; T, UDCA.

  • *

    P < 0.01.

  • P < 0.02. In three patients, complete resolution.

  • ‡ 

    In both T and C groups; P < 0.01.

Palma et al.113Open pilot 81000207*
Diaferia et al.114RCT16 (8/8) 60020Significant
Palma et al.115RCT15 (8/7)100021T: 7, C: 2
Nicastri et al.116RCT32 (8/8) 60020Significant
Laifer et al.117Retrospective  2.5 years 8 600–1200 8

With regard to the effect of UDCA on the foetus, it has been shown that UDCA corrects the maternal serum BA profile and decreases the delivery of BA to the foetus.119 In addition, it restores the ability of the placenta to carry out vectorial BA travel.111 Consequently, relevant aspects of foetal outcome (deliveries at or near term, adequate birth weight) are also improved.115, 120

With the aim to evaluate the effectiveness and safety of therapeutic interventions in pregnant women with a clinical diagnosis of intrahepatic cholestasis of pregnancy, a systematic review of nine randomized controlled trials (227 patients) was conducted. Randomized controlled trials on the use of SAMe and UDCA,85–87, 114–116, 118 as well as guar gum and activated charcoal, were included. In contrast with the encouraging results of UDCA treatment on pruritus and foetal outcome in the individual studies, the reviewer concluded that none of the interventions studied was consistently effective or superior in resolving maternal pruritus. The above discrepancy could be explained by the fact that small sample sizes, methodological problems and inadequate and inconsistent reporting of results precluded the pooling of the results of small studies.121

As UDCA appears to be a safe drug with no adverse effects on the foetus and only mild diarrhoea as a side-effect, it seems reasonable to consider or recommend its use in obstetric cholestasis.122 However, as it is unlicensed for use in pregnancy, this should be discussed with the patient so that she can make an informed decision. In contrast with pruritus in PBC and non-cholestatic liver disease, itching in intrahepatic cholestasis of pregnancy seems to respond or even disappear with UDCA treatment, raising the issue of a different pathogenesis. Nevertheless, larger randomized controlled trials will further establish its role in the treatment of pruritus in patients with intrahepatic cholestasis of pregnancy.

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  2. Summary
  3. Pruritus in cholestatic liver disease
  4. Introduction
  5. Pathogenesis
  6. Treatment
  7. Conclusions
  8. Pruritus in non-cholestatic liver disease
  9. Pruritus in intrahepatic cholestasis of pregnancy
  10. Acknowledgement
  11. References
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