Pathogenesis and treatment of pruritus in patients with cholestasis

The pathogenesis of initiating the pruritus in patients with cholestasis is still not completely understood. One hypothesis is, that the cause for initiating the pruritus in patients with cholestasis is the activation of nerves in the skin. The activating substances are unknown, probably they are substances who accumulate in patients with cholestasis. Therefore one of the conventional approaches to treat pruritus is to remove pruritogenic substances from the body. Examples of this approach include the administration of anion exchange resins as cholestyramine or the administration of hepatic enzyme-inducing drugs such as rifampicin or phenobarbital. None of these drugs has been conclusively shown to be efficacious. A new hypothesis is the association of pruritus with altered central neurotransmission. Altered opioid concentrations probably play a central role in the pathogenesis of pruritus. This hypothesis is corroborate by the possibility of treating pruritus in patients with cholestasis with opiate antagonists such as naloxone or nalmefene. The treatment with ondansetron may also have effects on the pruritus of patients with cholestasis. A completely new treatment strategy is the application of dronabinol (r-9-tetrahydrocannabinol).     

Pruritus in cholestasis: No direct causative role for bile acid retention

Discrepancies have existed regarding the correlation between raised bile acid levels in cholestasis and the presence of pruritus. Nevertheless, the prevalent view is that bile acids have a direct etiologic role. To resolve the issue, we quantified separately all naturallyoccurring bile acid species detectable in serum and skin, and on the skin surface of 13 patients with pruritus associated with cholestasis, 10 patients with cholestasis who did not have pruritus, three patients with uremia and generalized pruritus and in 10 controls. We were unable to find any correlations between the presence of pruritus and bile acid levels from the various sources. We did find great overlap in these same values with data from the group with cholestasis but without pruritus. As expected, the symptomatic (uremic) and asymptomatic control groups showed comparable levels. The results of the present study together with those of a similar recent study provide strong evidence against the hypothesis of a direct causative role for retained bile acids in pruritus associated with cholestasis.     

An approach to the management of the pruritus of cholestasis

The cause of the pruritus of cholestasis is unknown. It is inferred that pruritus results from the accumulation in plasma of substances that are made in the liver and excreted in bile under physiologic conditions. The idea of neurotransmitters as important mediators in the pruritus of cholestasis has evolved over the past several years. There is evidence to suggest that endogenous opioids contribute to the pruritus of cholestasis and, for the first time, specific treatment for the pruritus has been instituted. The deficiency of studying pruritus with subjective methodology alone has been overcome with the development of objective methodology to study the behavioral manifestation of pruritus, scratching behavior. The use of this tool allows the definition of clear objective end-points, scratching activity, for inclusion in clinical trials.     

Pathophysiology and current management of pruritus in liver disease

Pruritus is frequently reported by patients with cholestatic hepatobiliary diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy and hereditary cholestatic syndromes, but may accompany almost any other liver disease. Increased concentrations of bile salts, histamine, progesterone metabolites or endogenous opioids have been controversially discussed as potential pruritogens in cholestasis in the past. Most recently, novel insights unravelled lysophosphatidic acid (LPA), a potent neuronal activator, as a potential pruritogen in pruritus of cholestasis. Nevertheless, the pathogenesis of pruritus in cholestasis is still not clearly defined and current antipruritic treatment strategies provide relief only in a part of the affected patients. Based on recent experimental and clinical findings, this review outlines the actual insight in pathogenesis of pruritus in cholestasis and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients suffering from itch.     

Central mu-opioid receptors are down-regulated in a rat model of cholestasis.

Ameliorations of the pruritus of cholestasis by opioid antagonists are consistent with this form of pruritus being centrally mediated by the opioid system. To determine whether the central opioid system is altered in cholestasis, the specific binding of a selective mu-opioid receptor ligand, 3H-DAMGO, to mu-opioid receptors was studied in rats with acute cholestasis due to bile duct resection. Using whole brain membranes and subcellular mitochondrial-synaptosomal fractions the density of mu-receptor sites was 30% (p less than 0.01) and 22% (p = 0.03) less in bile-duct-resected rats than in sham-resected rats. Using membranes from individual brain regions specific binding of 3H-DAMGO was reduced by 43-53% in the cerebral cortex, hippocampus and caudate nucleus of bile-duct-resected rats. Thus mu-opioid receptors in the brain are down-regulated in a classical model of cholestasis. This alteration of the central opioid system could be a consequence of increased exposure of opioid receptors to endogenous opioids in cholestasis and may reflect an important mechanism in the pathogenesis of the pruritus of cholestasis.     

Pilot study of bright-light therapy reflected toward the eyes for the pruritus of chronic liver disease

OBJECTIVE: It is proposed that the pruritus of cholestasis is, in part, centrally mediated by endogenous opioid peptides. The expression of these peptides and their receptors on neurons displays a circadian rhythm, as does the scratching activity in patients with cholestasis and pruritus. Because light has regulatory effects on circadian rhythms via retinothalamic pathways, we hypothesized that bright-light therapy (BLT) reflected toward the eyes might alter the pruritus of cholestasis. To test this hypothesis, we studied the effect of BLT on this form of pruritus. METHODS: Eight patients with chronic liver disease of different etiologies and pruritus were studied in an open-label, pilot study of 8-wk duration. BLT (10,000 lux) was administered for up to 60 min twice a day. Pruritus was assessed subjectively by a visual analog scale from which a visual analog score (VAS) was derived, and objectively, by a scratching activity monitoring system that recorded hourly scratching activity (HSA). RESULTS: In seven of the eight patients studied, the mean HSA was lower during BLT. BLT was associated with a mean decrease in HSA of 32.2% (p = 0.123). The mean VAS for pruritus was lower in six patients during BLT; the mean VAS score derived from the eight patients studied decreased by 42% (p = 0.05) during treatment. CONCLUSIONS: The results of this short-term study suggest that the pruritus of cholestasis is responsive to bright light reflected toward the eyes and that in some patients, BLT may ameliorate this form of pruritus.     

Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis

Findings consistent with the hypothesis that increased central opioidergic tone contributes to the pruritus of cholestasis provide a rationale for treating this form of pruritus with opiate antagonists. However, initiation of therapy with an opiate antagonist in a cholestatic patient may precipitate a transient opioid withdrawal-like reaction. A woman with chronic cholestasis and disabling pruritus experienced severe transient opioid withdrawal-like reactions after oral administration of 12.5 and 2 mg naltrexone. Subsequently, naloxone was administered by intravenous infusion. Initially, the infusion rate was low and subtherapeutic. It was gradually increased to a rate known to be effective in inducing opioid antagonism. Oral naltrexone was then reintroduced without any reaction occurring. During the ensuing 12 months, while taking naltrexone, 25 mg daily, the patient has been completely free from pruritus. These observations strongly support the hypothesis that increased central opioidergic tone is a component of the pathophysiology of cholestasis.     

A case of severe benign intrahepatic cholestasis treated with liver transplantation

A male patient with benign recurrent cholestasis since age 2.5 yr developed unremitting cholestasis with incapacitating pruritus and hepatic fibrosis by age 21. He was tried on numerous medical therapies for pruritus with transient or no relief. He responded only temporarily to biweekly plasmapheresis, which was carried out for 4 yr. He underwent orthotopic liver transplantation at age 25 with immediate resolution of his pruritus. At age 30 he is a happy, asymptomatic, fully employed professional.     

A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterized by recurrent episodes of cholestasis and pruritus without anatomical obstruction. Generally, medical therapy is not effective in benign recurrent intrahepatic cholestasis. Here, we report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented with cholestatic jaundice and pruritus, refractory to standard therapies. He improved on treatment with temporary endoscopic nasobiliary drainage. We propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. A 36-year-old male patient admitted to our outpatient clinic with the complaint of pruritus. His anamnesis revealed that he experienced the same symptoms and signs in 2006. He was hospitalized in a hepatology clinic and was thoroughly examined. Liver biopsy was performed, and he was finally diagnosed as having benign recurrent intrahepatic cholestasis. Medical therapy options all proved to be ineffective and we were able to achieve remission in this patient only with the help of nasobiliary drainage. For this patient, we tried nasobiliary drainage in addition to the standard medical therapies. He improved on nasobiliary drainage. In conclusion, we propose that temporary endoscopic biliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. We hope that this case report contributes to the topic, since only a few nasobiliary drainage case experiences have been reported to date.     

Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

Progressive familial intrahepatic cholestasis type 3 （PFIC3） is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System （MARS） has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.     

Pruritus in chronic cholestatic liver disease

Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed.     

Prolonged cholestasis after troleandomycin-induced acute hepatitis

We report the case of a patient in whom troleandomycin-induced hepatitis was followed by prolonged anicteric cholestasis. Jaundice occurred after administration of troleandomycin for 7 days and was associated with hypereosinophilia. Jaundice disappeared within 3 months but was followed by prolonged anicteric cholestasis marked by pruritus and high levels of alkaline phosphatase and gammaglutamyltransferase activities. Finally, pruritus disappeared within 19 months, and liver tests returned to normal 27 months after the onset of hepatitis. This observation demonstrates that prolonged cholestasis can follow troleandomycin-induced acute hepatitis.     

Diagnosis and therapy of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 ( BSEP) and ATP8B1 ( FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.     

Serum concentrations of substance P in cholestasis

Substance P (SP) is an excitatory neuropeptide that acts via the neurokinin-I receptor (NK-1) in the nervous system. Pruritus, a complication of cholestasis, is a nociceptive stimulus; thus, we hypothesized that cholestasis would be associated with increased neurotransmission via SP as evidenced, in part, by increased serum concentrations of this neuropeptide. Accordingly, the aim of this study was to determine the serum concentration of SP in patients with pruritus secondary to cholestasis and in the serum of rats with cholestasis secondary to bile duct resection (BDR). The mean serum SP concentration of patients with chronic liver disease (CLD) and pruritus was 9.09 pg/mL SD ± 6.5, significantly higher than 0.74 pg/mL SD ± 0.77, the mean serum concentration of SP from patients with CLD without pruritus (p = 0.0001), and from that of the control group, which was 0.65 pg/mL SD ± 0.37 (p = 0.0001). The mean serum SP concentration from six rats with cholestasis secondary to BDR six and fourteen days after surgery was 57.9 pg/mL, SD ± 17.3, and 56.3 pg/mL, SD ± 21.4, respectively, as compared to the concentration from the sham resected control group, which was 3.5 pg/mL SD ± 0.59 (p = 0.002) at six days post surgery. In conclusion, in choles-tasis, there is increased availability of SP. These data provide a rationale for the study of SP release and metabolism in cholestasis, and in the mediation of the pruritus.     

Danazol-Induced Cholestasis

A 39-yr-old female on high-dose Danazol presented with jaundice and pruritus. Danazol-induced cholestasis was suspected, and the drug was discontinued. A liver biopsy revealed panlobular cholestasis with portal and periportal inflammation. The cholestasis resolved completely in 8 wk. This is a rare case of Danazol-induced cholestasis and should be considered in the differential diagnosis of drug-induced liver injury.     

Successfully treated intractable pruritus with rifampin in a case of benign recurrent intrahepatic cholestasis

A 56-year-old gentleman with benign recurrent intrahepatic cholestasis (BRIC) suffered from recurrent episodes of pruritus for over 40 years. The treatment prescribed, namely cholestyramine, was minimally effective. However, rifampin 150 mg b.i.d promptly and completely relieved his severe pruritus. The diagnosis of BRIC, being a rare condition, may go unrecognized. The severity of the lifelong episodes of intermittent cholestasis with pruritus in BRIC may be extremely distressing to the affected patient. Administration of rifampin during the acute episode of severe pruritus led to a marked improvement in his quality of life.     

Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare autosomal recessive disorder characterized by repeated episodes of intense pruritus, profound elevations in serum alkaline phosphatase and bilirubin, with normal or nearly normal values for serum gamma-glutamyl transferase. Attack lasts from several weeks to months and resolve spontaneously. Between attacks patients remain asymptomatic for months to years. The disorder does not lead to progressive liver injury and is not fatal. Genetic studies have demonstrated that the disorder is the result of a mutation in ATP8BI, a gene that codes for the FIC1 (familial intrahepatic cholestasis) protein, which is also affected in other forms of familial intrahepatic cholestasis. It is believed this protein plays a role in bile acid secretion, in aminophospholid transport, and in maintaining fluidity of the cell membrane. Therapy is supportive and aimed at relieving pruritus and other complications of severe cholestasis until the episode resolves spontaneously.     

Rifampin relieves pruritus in children with cholestatic liver disease

Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.     

Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials.

OBJECTIVES: To determine the safety and efficacy of rifampin for treatment of pruritus associated with cholestasis due to chronic liver disease. METHODS: Medical literature was searched systematically using keywords as rifampicin, rifampin, rifamycin, cholestasis, pruritus, itching, and liver disease. Trials that compared the efficacy of rifampin with placebo/alternative for treatment of pruritus due to chronic cholestasis were selected for analysis. Primary outcomes were resolution of pruritus and development of side effects. Association was measured with the odds ratio (OR). Breslow-Day method was used to treat for homogeneity under null hypothesis that OR was consistent across all the trials. Corrected Mantel-Haenszel chi(2) test was used to test if OR differed systematically from value of 1. RESULTS: Five prospective randomized-controlled cross-over trials with 61 patients were identified. Treatment with rifampin led to complete or partial resolution of pruritus in 47 (77%) patients as compared with 12(20%) treated with placebo or alternative (OR 15.2, 95% confidence interval 5.2-45.6, P=0.001). Four (7%) patients treated with rifampin suffered side effects, which resolved after its discontinuation. There was no incidence of hepatotoxicity. Test of heterogeneity for primary end points among the trials was not significant (P=0.16). CONCLUSION: This meta-analysis suggests that rifampin is safe and effective for treatment of pruritus due to chronic cholestasis. This analysis also suggests that use of rifampin for short duration is associated with a low risk of hepatotoxicity.