Pruritus and cholestasis

Introduction
Pruritus is a complication of liver disease, in particular when associated with cholestasis, including:

• syndromes associated with genetic mutations
• progressive familial intrahepatic cholestasis types 1, 2, and 3

• conditions of unknown etiology, such as
• primary biliary cirrhosis (PBC)

• primary sclerosing cholangitis

• acquired conditions, such as
• drug-induced cholestasis transient or associated with ductopenia

• Intra- and extrahepatic obstruction from any cause
• (eg, stones, tumors, postsurgical strictures, and nodes)

The magnitude of the problem

• It ranges in severity from mild, to moderate in which sleep is disturbed, to extreme in which the lifestyle of the patient is completely disrupted.

• The prevalence of pruritus in liver disease in general varies from 5 % in patients with chronic hepatitis C to 70% in patients with PBC.
  • Many patients with liver disease and pruritus do not report the symptom to their physicians because they do not make a connection between itch and liver disease.

In one study interesting features found are:

• Thirty-five percent of the subjects who described their sensation of itch reported it as ‘‘bugs crawling,’’ and 6 respondents (3.6%) stated they scratched until they bled.
  • Indeed, bloody sheets are often reported by the parents of children with cholestasis and pruritus, a distressing situation.
• Sixty-five percent of the subjects reported that the itch was worse at night, consistent with what is reported by patients who suffer from any type of pruritus.
  • This worsening at night may be due to the decrease of external stimuli at night with sensory input taking over cognition.
• Twenty-five percent of respondents addressing the question reported that the itch increased in the premenstrual state.
  • This observation may relate to the hormonal milieu associated with menstruation. In this context, intrahepatic cholestasis of pregnancy, which is characterized by pruritus usually in the last trimester, may be triggered by increased availability of estrogens and by alterations in progesterone metabolites.
• Fourteen percent of 112 respondents reported that their itch was worse after meal.
  • This report may support the idea that the pruritogen or pruritogens are excreted in bile, poured into the duodenum, and subsequently reabsorbed into the systemic circulation.
• Sixty-four percent of 88 respondents reported that something cool relieved their itch.
• Forty-six percent of 52 respondents reported that they itched more in the summer than in the winter

Pathogenesis

The pathogenesis of pruritus in cholestasis is unknown but several hypotheses have been proposed, including bile acid accumulation and increased opiodergic tone.

It is inferred that the pruritus of cholestasis results in part from substances normally excreted in bile that, as a result of cholestasis, accumulate in plasma and other tissues. The liver is considered to be the source of the pruritogen or pruritogens. The fact that pruritus disappears after liver transplantation and after the resolution of extrahepatic obstruction seems to support this idea.

Bile acids — One theory proposed that elevated levels of bile acid in the skin of patients with cholestatic diseases act as pruritogens. Observations in favor of this theory include the recovery of bile acids from the skin surface of affected patients in relation to the intensity of pruritus , although the reliability of the methods used is uncertain.

However, a strong line of evidence suggests that bile acids are not the pruritogens in cholestasis.

• In patients with cholestasis and pruritus, the pruritus tends to cease as the liver fails.
• At this stage, bile acids tend to be very high in plasma and other tissues. This observation suggests that some mechanism other than bile acids alone mediates the pruritus of cholestasis.
• In addition, it suggests that some degree of synthetic function is necessary for pruritus to be experienced, and that the pruritogen, pruritogens, or cofactors to pruritogens are made in the liver.
• It is conceivable that a certain proportion of bile acids in the bile acid pool of cholestatic patients is required for the pruritus to be experienced, but this is highly speculative at present.

Increased central neurotransmission via the endogenous opioid system can result in pruritus.

• This situation is best exemplified by the pruritus that results from the central (eg, intrathecal) administration of morphine.
• Morphine is an alkaloid that exerts its effect by stimulating opioid receptors, in particular, the mu opioid receptor.
• Naloxone and other opiate antagonists can effectively relieve and prevent morphine-induced pruritus, which supports the hypothesis that the pruritus is mediated by the opioid receptor.

Pproposal that serotonin neurotransmission may mediate pruritus is plausible. Serotonin can cause itch in experimental conditions.

• For example, the intracutaneous administration of serotonin can cause pruritus in humans; however, this is not a model of pruritus in cholestasis.
  
• It has not been documented that central serotoninergic neurotransmission is altered in cholestasis is altered.

Treatment of the pruritus of cholestasis

The lack of understanding of the pathogenesis of the pruritus of cholestasis has led to a large body of literature on therapeutic interventions based on empiricism.

On the other hand, clinical observations are the pillars for understanding pathophysiology and have provided some insight into the pathogenesis of the pruritus of cholestasis. Therefore, it seems reasonable that relevant observations be followed by controlled studies that apply behavioral methodology.

The treatment of choice for pruritus associated with cholestasis is correction of the underlying hepatobiliary disease.

o In cases of extrahepatic biliary obstruction in which definitive therapy is not possible, biliary drainage is usually effective in eliminating pruritus.

o In cases of intrahepatic cholestasis in which definitive therapy is not possible, several measures can be attempted to relieve bothersome pruritus.

It has been difficult to evaluate the efficacy of medical therapy for pruritus in controlled trials since pruritus is a subjective symptom that can wax and wane spontaneously.

In mild cases, pruritus can often be controlled by nonspecific measures such as warm baths and emollients. However, these measures often fail when the pruritus is moderate to severe and often accompanied by excoriations. In such cases, the following options are available.

Bile acid resins — The bile acid resins cholestyramine and colestipol are effective first-line agents in the management of moderate or severe cholestatic pruritus based upon their favorable safety profile and clinical experience.

• These drugs are nonabsorbable, basic polystyrenes which bind anions in the gut lumen, including bile acids.
  
• They lower bile acid levels by inhibiting the reabsorption of bile acids by approximately 90 percent.
  
• They also decrease pruritus in noncholestatic disorders, such as uremia and polycythemia vera. Hence, these resins bind other pruritogens.

The effective dose of cholestyramine ranges from 4 to 16 grams per day. Efficacy may be increased by administering a dose before and after breakfast in patients with an intact gallbladder to enhance the excretion of the pruritogens, which presumably accumulate in the gallbladder during the overnight fast. However, compliance is a major problem with the use of bile acid resins. These drugs are relatively unpalatable, induce constipation, and can interfere with the absorption of a number of medications including digoxin, warfarin, propranolol, and thiazide diuretics.

The administration of metronidazole, another antibiotic, at doses of 250 mg orally three times a day for one week has been reported to control refractory pruritus in patients with PBC.

• In patients with primary sclerosing cholangitis and pruritus, which can be triggered by infection in the biliary tree, metronidazole has been associated with relief of pruritus; however, long-term use of this drug is discouraged because of side effects (eg, neuropathy).

A report of relief of pruritus after smoking marihuana in a patient with pruritus and liver disease refractory to other therapies was followed by the experience on the use of dronabinol, an agonist at the cannabinoid B1 receptor, which was reported to be associated with relief of intractable pruritus and improvement in sleep. The experience on the use of dronabinol has not been followed by controlled studies.

The original reports on ligocaine, propofol, and lidocaine as providing amelioration of pruritus in cholestasis have not been followed by controlled studies since the initial reported experience.

Pruritus secondary to histamine release is associated with erythema and edema, which are absent in the skin of patients with the pruritus of cholestasis.

• In contrast, the skin of patients with cholestasis may reveal excoriations, thickening, and prurigo nodularis from chronic scratching.
• Antihistamine drugs do not appear to have a specific antipruritic effect in patients with cholestasis.
• However, they are associated with sedation and, in this context, may help patients sleep, which is often a major problem in patients with chronic pruritus.

UDCA, a choleretic agent, may decrease the degree of cholestasis in many instances. However, UDCA is not consistently associated with relief in pruritus. Furthermore, UDCA has not been studied specifically as an antipruritic agent in cholestasis.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, usually in the third trimester.

• Serum levels of bile acids of 40 micromoles/L or more have been was associated with a four-fold increase in spontaneous premature births and meconium passage into the amniotic fluid; however, a diagnosis of ICP cannot be excluded if the serum concentration of bile acids is normal.
• UDCA is reported to be associated with relief of pruritus and decreased intrauterine fetal death, although recommendations for the systematic use of UDCA in ICP are not available because the data to support this treatment have not been considered robust.
• The use of cholestyramine in ICP can contribute to vitamin K deficiency and to increased risk of hemorrhagic consequences in the peripartum period. Therefore, everyone involved in the care of these mothers must be made aware of potential hemorrhagic complications.

Treatments aimed at removing pruritogens from the body

Plasma separation, anion adsorption, and two recently developed extracorporeal liver support systems (Molecular Adsorbent Recirculating System [MARS] and Prometheus) have been used to treat patients with intractable pruritus and have been reported to be associated with relief. Some investigators have commented on the need for clinical trials on the use of this intervention.

Antibiotics

In a study of the effect of rifampicin as an enzyme inducer in patients with cholestasis, it was reported that the drug ‘‘strikingly improved’’ their pruritus.

• In reports of two meta-analyses, rifampicin was found to relieve pruritus.
  
• However, the hepatotoxicity of this drug is well documented, indicating that the liver profile has to be followed when this medication is prescribed.
  
• Rifampicin is a ligand of the pregnane X receptor, whose stimulation induces drug-metabolizing enzymes and transporters.
  
• Rifampin may induce microsomal enzymes that promote 6- alpha-hydroxylation and subsequent glucuronidation of toxic bile salts.

Changes in neurotransmission

Opiate antagonists

The publication of a meta-analysis that explored the efficacy and safety of opiate antagonists in the treatment of the pruritus of cholestasis reported that this type of drug significantly reduced the pruritus of cholestasis.

• The opioid-withdrawal–like reaction seems to be the limiting factor to accepting this type of drug to treat the pruritus of cholestasis. Not all patients experience this reaction and most of those who do experience a mild reaction. However, because those who will experience the reaction or will have a severe reaction cannot be identified a priori, treatment with opiate antagonists can be started at a dose lower than what is provided in the naltrexone tablet, the opiate antagonist available for oral use.
• The naltrexone tablet can be divided in four to provide 12.5 mg per dose, instead of the 50 mg provided by the whole preparation. Alternatively, patients can be admitted for intravenous naloxone infusions to be followed by oral naltrexone.
• If admission to the hospital is not an alternative, infusions in a well equipped outpatient unit can be considered.
• The point of intravenous infusions of naloxone is to introduce an opiate antagonist slowly to prevent the withdrawal reaction.
• As done in two controlled studies, an intravenous bolus of naloxone (0.4 mg) can be given slowly, immediately followed by an infusion of naloxone at doses of 0.2 mg/kg/min in 250 or 500 mL of a suitable intravenous solution.
• Ultra-low doses of naloxone (0.002 mg/kg/min) have also been used at the start of the infusion to prevent an opiate-withdrawal–like syndrome.
• The rate can be increased gradually every 2 to 4 hours, if tolerated, until approximately 0.8 mg/kg/min or until the patient reports relief. After 24 or 48 hours of infusion, naltrexone at a dose of 12.5 mg/d can be introduced and the infusion stopped.
• The dose of naltrexone can be increased by 12.5 mg every week or two until the patient’s pruritus decreases. The dose should not be increased if signs of an opiate withdrawal–like syndrome arise.
• In general, the drug can be held or maintained at the same dose, as the reaction tends to subside spontaneously. One hundred milligrams of naltrexone per day can be required. There are cases in which 250 mg of naltrexone per day have been prescribed. This dose is high and is not required by the majority of patients. When such high doses are required, alternative treatments should be considered. The treatment with naltrexone should be followed with a comprehensive panel to detect any toxicity, which is not common, but which has been reported. Thus, following up the liver profile and a complete blood count after starting patients seems prudent. In decompensated liver disease, naltrexone metabolites can accumulate, which requires dose reduction. However, it is not common for patients with liver failure to experience pruritus. Thus, the need to use this drug in advanced disease does not often arise.

Serotonin antagonists

Nociception is mediated in part by serotonin neurotransmission. Ondansetron was reported to decrease the pruritus associated with cholestasis in studies that applied subjective methodology, including a case of cholestasis of pregnancy. Intravenous ondansetron (4 and 8 mg) and not placebo was reported to be associated with a decrease in pruritus in a small number of patients. Studies that have incorporated behavioral methodology (ie, measurement of scratching activity) have not confirmed an antipruritic effect of ondansetron in cholestasis.

Changes in threshold to experience nociception

• The drug gabapentin has been studied as a therapeutic alternative in the treatment of pruritus.
  
• The rationale for the research is that such a drug might raise the nociception threshold. In this context, a double-blind randomized placebo-controlled study was conducted to observe the effect of gabapentin on the perception of pruritus and on its behavioral manifestation, scratching activity. In this study, the administration of gabapentin was associated with an increase in hourly scratching activity, in contrast to the placebo administration, which was associated with a decrease in this behavior.

• Gabapentin was used at doses of 300 mg/d in divided doses, to a maximum of 2400 mg/d. This study underscores the importance of behavioral studies in pruritus and the antipruritic effect of a placebo intervention.
  
• Furthermore, these results confirm existing doubts on the reliability of data in studies of pruritus that apply subjective methodology only.
  
• In addition, provocative ideas on the neurotransmission of the placebo effect as potentially antipruritic have emerged from this study.

Antidepressants

• Data from a retrospective analysis of subjective reports on pruritus in patients with PBC who participated in a clinical study of UDCA and methotrexate and who were on sertraline suggested that this drug was associated with relief in pruritus.
  
• It was reported from a randomized, placebo controlled crossover study of sertraline, at doses associated with relief of pruritus (75 to 100 mg) in the dose-finding open-label phase of the study, that this medication was associated with relief of pruritus, as assessed by the visual analog scale, and its cutaneous consequences (ie, scratch marks), as evaluated by physical examination.
  
• Eight of 21 subjects associated the use of sertraline with mood stability, and the subjects who met criteria for depression at baseline improved on sertraline. However, it was reported that the decrease in the visual analog score for pruritus was independent from the improvement in depression.
  

• Selective serotonin reuptake inhibitors have been reported to decrease pruritus in polycythaemia vera and in patients with malignancy whose pruritus was multifactorial.
  
• Mirtazapine, a noradrenergic and serotonergic antidepressant, has also been reported to relieve pruritus in a small heterogeneous group of patients with malignancy and uremia, and in patients with nocturnal itch from skin diseases.
  
• Taken together, these data may suggest that not only the serotonin system, but also other neurotransmitters, including noradrenaline, may contribute to the pruritus of cholestasis and other forms of pruritus.

Approach to the patient with liver disease and pruritus

• A thorough medical history should provide information about the presence of pruritus in patients with liver disease.
  
• Other causes of pruritus (eg, skin lesions) need to be excluded because the treatment in those cases may be completely different.
  
• As cholestyramine tends to be well tolerated by most patients, treatment can be started with this resin. Doses of more than 16 g/d are not recommended. The method for taking cholestyramine takes into account the presumed storage of pruritogenic substance (or substances) in the gallbladder during the overnight fast. Thus, one dose (ie, 4 g) immediately before and after breakfast can be prescribed to start the treatment. This method allows for the resin to decrease the absorption of the pruritogen or pruritogens presumably excreted in bile as this substance is poured into the duodenum after breaking the overnight fast.
  
• If this dose does not suffice, increasing to 4 g at lunch and/or dinnertime can follow.
• If the treatment with resins is not associated with relief of pruritus, naltrexone or rifampicin can be prescribed.
  
• The American Association for the Study of Liver Disease practice guidelines for the management of pruritus in PBC suggest to proceed to rifampicin. If that recommendation is followed, hepatic panel has to be followed carefully over time to detect any early signs of hepatotoxicity. The drug should be stopped immediately if alterations from the baseline are noted in the liver panel. Naltrexone can also be started if cholestyramine fails or is not sufficient.
  
• A combination of cholestyramine and naltrexone can be used, provided that the naltrexone (and other drugs) is taken at least 2 hours before or after the cholestyramine.
• If the patient does not experience relief of the pruritus, sertraline can be prescribed at doses of 75 to 100 mg, as reported in the controlled study. Prudence suggests starting at low doses, as would be done for depression (eg, 25 mg/d).
  
• For care of the skin, which is important, moisturizers can be useful.
• Patients should avoid as much as possible environmental factors that worsen pruritus (eg, extreme temperatures).
  
• Medications known to cause pruritus should be discontinued or replaced with substitutes.

Patients who fail the regimen described above pose a problem.

• In those patients, such interventions as dronabinol, ondansetron, and short-term metronidazole can be tried.
  
• Butorphanol, available in spray form, can be used. However, this drug has addiction potential and caution must be exercised when prescribing it. Doses of up to 2 mg per day (1 mg per puff) have been used in a patient with chronic hepatitis C and intractable pruritus and in patients who have primary biliary cirrhosis.
  
• Filtration procedures, including those provided by extracorporeal liver support systems (MARS and Prometheus) can be explored.
  • These procedures tend to be available, sometimes for research purposes, at institutions where liver transplantations are performed.
    
• Surgical procedures that divert the flow of bile are reported to relieve pruritus. These procedures cannot be recommended at this point because specific expertise is necessary and insufficient information on the long-term effect on the pruritus in adult subjects is not available.
  
• Intractable pruritus can be an indication for liver transplantation.