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.     

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).     

The pruritus of cholestasis: evolving pathogenic concepts suggest new therapeutic options

Pruritis is a distressing symptom experienced by a large proportion of patients with cholestasis. The cause of this form of pruritus is unknown, and therapy tends to be empirical and unsatisfactory. This article discusses the emerging role of the brain and neurotransmitter systems in the pathogenesis of the pruritus of cholestasis and emphasizes the importance of the application of quantitative methodology in clinical trials of therapies for the pruritus of cholestasis.     

胆汁淤积性肝病并发皮肤瘙痒的发病机制及治疗进展

瘙痒是胆汁淤积性肝病如原发性胆汁性肝硬化、原发性硬化性胆管炎和妊娠期肝内胆汁淤积症的一个常见症状。既往研究的胆汁淤积性瘙痒的潜在致痒因子有胆盐、组胺、孕酮代谢产物、内源性阿片样物质和溶血性磷脂酸等。然而,胆汁淤积性瘙痒的确切发病机制尚不清楚,现有的止痒方法仅可使部分患者症状得到缓解,新的止痒方法已被提出和(或)正在研究中。在回顾近期关于胆汁淤积型肝病并发皮肤瘙痒的发病机制和治疗的实验和临床试验,以便提高对胆汁淤积性瘙痒的认识和治疗。     

Pruritus and fatigue in primary biliary cirrhosis.

Pruritus is experienced by about 80% of patients with primary biliary cirrhosis. It can have a marked negative impact on the quality of life of patients, and it can be an indication for liver transplantation. There is evidence to suggest that the pruritus of cholestasis is mediated, at least in part, by endogenous opioids. A central component has been proposed. Behavioural data have shed light on the pathogenesis of this form of pruritus. Fatigue affects the majority of patients with primary biliary cirrhosis. It interferes with work performance and family life. An idea is emerging that suggests that fatigue in primary biliary cirrhosis also may be mediated centrally. Research tools need to be developed to study fatigue objectively in patients with primary biliary cirrhosis.     

LIVER DISEASE IN PREGNANCY,WITH PARTICULAR EMPHASIS ON THE CHOLESTATIC SYNDROMES

This review is primarily concerned with the ætiology, pathology, clinical features, differential diagnosis, pathogenesis and treatment of obstetric cholestasis and pruritus of pregnancy. The exact mechanism of the pruritus, jaundice and deranged biochemical state in these disorders is discussed in the light of advances in our understanding of bile salt metabolism and a recent and more acceptable concept of the pathogenesis of cholestasis. The incidence, ætiology and clinical features of cholestasis following oral contraceptives are outlined in detail, and the relationship of these changes to the cholestatic syndrome in the third trimester is discussed. Other hepatic disorders which appear to be related to pregnancy are also briefly reviewed. Biochemical derangements of hepatic function in pregnant women without underlying hepatic disease are considered in detail.     

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.     

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.     

The pathogenesis and treatment of pruritus and fatigue in patients with PBC.

The pathogenesis of the pruritus that complicates cholestasis in patients with primary biliary cirrhosis (PBC) is uncertain. The limited and inconsistent efficacy of conventional empiric therapies, such as anion exchange resins and rifampicin, has led to inconclusive trials of invasive experimental therapies, such as plasmapheresis, charcoal haemoperfusion and partial external diversion of bile. However, some double-blind, placebo-controlled trials that used a subjective primary efficacy end-point (the perception of pruritus) have suggested that certain drugs that affect the metabolism of many compounds, for example rifampicin, may be efficacious. The potential mechanisms by which such drugs may mediate a beneficial effect have not been determined. There is a paucity of data to indicate whether peripheral events, such as the accumulation of bile acids in interstitial fluid of the skin, initiate the neural events which mediate this form of pruritus. Recent findings suggest that central events in the brain, specifically an increase in neurotransmission/ neuromodulation mediated by endogenous opioid agonists (increased opioidergic tone), may be implicated. This hypothesis is supported by three lines of evidence. (1) Opioid receptor ligands with agonist properties (e.g. morphine) mediate pruritus. (2) Endogenous opioid-mediated neurotransmission/neuromodulation in the central nervous system (CNS) is increased in cholestasis. (3) Controlled trials have shown that opiate antagonists induce ameliorations of the behavioural consequence of the pruritus of cholestasis (scratching activity). In such trials, measurements of scratching activity independent of limb movements constituted an objective quantitative primary efficacy end-point. Potent opiate antagonists, that are bioavailable when given by mouth, such as nalmefene and naltrexone, may have a place in the long-term management of pruritus in patients with PBC. Evidence that increased serotoninergic neurotransmission also contributes to the pruritus is at present less strong than that implicating an involvement of the opioid system, and further investigation is needed to determine whether specific serotonin receptor subtype ligands have a place in the treatment of pruritus in patients with PBC. There is some evidence which suggests that increased serotoninergic neurotransmission in the CNS contributes to fatigue of central origin, but whether there is a causal relationship between altered serotoninergic neurotransmission and the profound fatigue that occurs in many patients with PBC is currently uncertain.     

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.     

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.     

Pruritus and fatigue in primary biliary cirrhosis

Pruritus and fatigue are the most common symptoms of patients with PBC, and both have marked negative impact on quality of life. Over the past decade, evidence has emerged supporting a role of the central nervous system in the pathogenesis of these two common manifestations of PBC. There is no evidence that the pruritus of cholestasis is mediated in the skin. Clinical and laboratory data do support a role of the opioid neurotransmitter system in the mediation of the pruritus of cholestasis; a central mechanism has been proposed. Treatment with opiate antagonist is thus a specific alternative. Studies of the behavioral consequence of the pruritus of cholestasis, scratching activity, allow for the design of clinical trials with objective end-points. The etiology of fatigue is unknown. A central component is being considered. The identification of objective alterations in fatigue and the adoption of a definition that incorporates the perception and the behavioral consequences of fatigue should facilitate the development of objective methodology. The potential role of various neurotransmitter systems, including the serotonin system and the opioid system, in the mediation of the fatigue of PBC seems to merit further investigation.     

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.     

Pruritus in primary biliary cirrhosis: pathogenesis and therapy

Pruritus is a symptom experienced by patients who have primary biliary cirrhosis. It seems to result from pruritogens that (as a result of cholestasis) accumulate in plasma and other tissues, and which lead to altered neurotrasnmission. Administration of medications that change opioid neurotransmission (ie, opiate antagonists) results in relief of pruritus and its behavioral manifestation, scratching. Through unknown mechanisms, other centrally acting medications, including antidepressants, may have ameliorating effects on the pruritus of cholestasis. Stimulating endogenous detoxification pathways in the liver may also lead to the amelioration of pruritus. The removal of pruritogens through administration of nonabsorbable resins, nasobiliary drainage, biliary diversion, plasmapheresis, and various dialysis procedures is reported to decrease pruritus in liver disease, although the substances that are presumably removed are unknown.     

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.     

Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.

A woman with stage III (pre-cirrhotic) primary biliary cirrhosis was referred for liver transplantation because of intractable pruritus. Oral administration of 50 mg naltrexone precipitated a severe opioid withdrawal-like reaction. Subsequently, when oral naltrexone therapy was reintroduced following a cautious infusion of naloxone, no reaction occurred and the pruritus resolved completely. Liver transplantation should not be considered for apparently intractable pruritus of cholestasis before an adequate trial of opiate antagonist therapy.     

Intrahepatic cholestatic syndromes: pathogenesis, clinical features and management.

Intrahepatic cholestasis is characterized by a decrease in bile flow in the absence of overt bile duct obstruction, resulting in the accumulation of bile constituents in the liver and blood. Various etiological factors have been incriminated including drugs, total parenteral nutrition, sepsis, pregnancy, graft-versus-host disease and systemic disorders such as sarcoidosis, amyloidosis and Hodgkin's disease. The pathogenesis of cholestasis is unclear and several mechanisms have been hypothesized, without convincing evidence that any of these play a role in clinical cholestasis. Despite the uncertainty about the pathophysiology of intrahepatic cholestasis, several forms of therapy have been employed. Ursodeoxycholic acid may relieve pruritus and lethargy, and in some cases may modify disease progression. If cholestasis persists, supportive therapy is important to maintain optimal physical and nutritional well-being. In patients with advanced liver disease associated with hepatocellular failure, liver transplantation is the only viable option.     

REVIEW: Intrahepatic cholestasis. A puzzling disorder of pregnancy

Intrahepatic cholestasis of pregnancy is characterized by skin pruritus and a biochemical cholestasis of mild to moderate severity appearing during pregnancy (mainly in the third trimester) and disappearing after delivery. It recurs in 40–60% of future pregnancies. The intensity of pruritus and the laboratory alterations (increased serum bile salts and transaminases in almost all patients, hyperbilirubinaemia in 20% of patients) fluctuate during one pregnancy and also vary in subsequent affected pregnancies. This disease has no meaningful consequences for the mother; in contrast, it is associated with an increased risk of foetal distress, causing premature deliveries and stillbirths. Cholestasis of pregnancy has been recognized in most countries and ethnic groups but its prevalence is higher in Chile (14% of deliveries in 1975 and approximately 4% in 1995) and in Sweden than in other countries. The cause is unknown. Sex hormones, mainly oestrogens and progesterone, appear to be involved in its pathogenesis. An interplay between a genetic metabolic predisposition and some environmental factor(s) is apparently relevant. Clinical and experimental studies suggest that a marginal selenium deficiency could be a dietary pathogenic factor. Some drugs attenuate pruritus and improve maternal cholestasis, but not the foetal prognosis. Ursodeoxycholic acid (UDCA) administration provides a significant improvement in maternal pruritus and in the biochemical abnormalities, with no adverse effects in the mother or child. Recent clinical and experimental studies show that UDCA administration improves maternal disease and foetal prognosis without any detectable adverse effects.     

Treatment of cholestatic hepatic diseases: more than the substitution of fat soluble vitamins?

The clinical-biochemical syndrome of cholestasis is characterized by an alteration in bile constituents. As a consequence, the concentrations of bilirubin, bile acids, phospholipids and cholesterol are elevated. The main clinical symptoms of cholestasis are icterus and pruritus, and in severe cases xanthelasma and xanthoma. Primary intrahepatic cholestasis, caused by impaired bile secretion in the liver, should be separated from the extrahepatic secondary cholestasis which is a consequence of a biliary obstruction. This paper evaluates the therapy of liver diseases which developed as consequence of a primary disturbance in bile secretion.     

Therapie cholestatischer Lebererkrankungen

The clinical-biochemical syndrome of cholestasis is characterized by an alteration in bile constituents. As a consequence, the concentrations of bilirubin, bile acids, phospholipids and cholesterol are elevated. The main clinical symptoms of cholestasis are icterus and pruritus, and in severe cases xanthelasma and xanthoma. Primary intrahepatic cholestasis, caused by impaired bile secretion in the liver, should be separated from the extrahepatic secondary cholestasis which is a consequence of a biliary obstruction. This paper evaluates the therapy of liver diseases which developed as consequence of a primary disturbance in bile secretion.