Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis

OBJECTIVES: Generalized pruritus is a common complication of cholestatic liver diseases, although its pathogenesis remains elusive. Current treatments are often inadequate and may be poorly tolerated, so the clinician is sometimes faced with a patient in misery and no good therapeutic options. Because, in our experience, several patients with primary biliary cirrhosis (PBC) claimed that sertraline had improved their pruritus, we sought to determine whether sertraline use was associated with changes in pruritus medications or self-reported severity of pruritus in a large cohort of patients with PBC. METHODS: The self-reported severity of pruritus was followed prospectively in 40 patients with PBC for a mean of 7.5 +/- 1.3 yr. These data were then retrospectively examined to determine the effect of sertraline on pruritus in all subjects who had received sertraline at some time during the study. RESULTS: For 28 of 32 patients with pruritus, itching was stable or fluctuated slightly over the follow-up period. No patient experienced rapid progression of pruritus, and four patients experienced a sustained resolution of their pruritus. Ten subjects started sertraline and continued it long enough (>6 months) to determine its lasting effect on pruritus. Three of these individuals did not have significant pruritus before or after sertraline. Of the seven patients with pruritus, six (86%) recorded a significant reduction or resolution of pruritus in their weekly diaries and also decreased or completely stopped other medications for pruritus. CONCLUSIONS: Sertraline use is associated with an improvement in cholestatic pruritus. This novel observation implies that serotonergic fibers are important in regulating the perception of itch.     

The aminopyrine breath test does not correlate with histologic disease severity in patients with cholestasis

To determine whether the aminopyrine breath test can be used to document the presence of cirrhosis in patients with cholestatic liver disease, 19 patients (13 primary biliary cirrhosis, 4 sclerosing cholangitis and 2 chronic extrahepatic bile duct obstruction) underwent clinical and biochemical evaluations, liver biopsies and an aminopyrine breath test. Results were compared with those in 10 patients with biopsy-proven chronic active hepatitis with bridging and/or cirrhosis and in 22 healthy subjects. The aminopyrine breath test results in the 10 cholestatic patients with cirrhosis were not significantly different from the results in precirrhotic cholestatic patients (mean +/- S.D., 11.2 +/- 5.0 vs. 11.6 +/- 2.8% dose per 2 hr, p greater than 0.05) or healthy subjects (11.5 +/- 2.9% dose per 2 hr). In contrast, the results in the patients with chronic hepatitis were markedly depressed (3.2 +/- 1.9% dose per 2 hr, p less than 0.05). The aminopyrine breath test results did not correlate with results of conventional liver function tests in the cholestatic patients. These results demonstrate that the aminopyrine breath test is not clinically useful in identifying the presence of cirrhosis in patients with cholestatic liver disease, and provide further evidence that decreased microsomal enzyme function is a late feature of cholestatic liver disease.     

C ASE R EPORT: Oral antioxidant therapy for the treatment of primary biliary cirrhosis: A pilot study

BACKGROUND: The symptoms of the chronic cholestatic liver disease primary biliary cirrhosis (PBC), in particular fatigue and chronic pruritus, adversely affect quality of life and respond only poorly to treatment. Recent studies have suggested that oxidative stress may play a role in tissue damage in cholestatic liver disease and may contribute to symptoms, such as fatigue. We have, therefore, examined, in an open-label pilot study, the therapeutic effects of antioxidant medication on the biochemistry and symptomatology of PBC. METHODS: Patients were randomized to 3 months treatment with a compound antioxidant vitamin preparation (Bio-Antox), four tablets daily (n = 11, group 1), or the combination of Bio-Quinone Q10 (100 mg) with Bio-Antox (n = 13, group 2). Biochemical and symptomatic responses were assessed at 3 months. RESULTS: Significant improvement in both pruritus and fatigue was seen in the patients in group 2. Mean itch visual analogue score improved from 2.4 +/- 3.0 to 0.4 +/- 0.7 post therapy (P < 0.05) while mean night itch severity score improved from 2.6 +/- 1.9 to 1.3 +/- 0.7 (P < 0.05). Nine of 13 of these patients reported less fatigue, while 10/13 showed an improvement in at least one domain of their Fisk Fatigue Severity Score. No significant improvement in itch and only limited improvement in fatigue were seen in the patients in group 1. No change in biochemical parameters was seen in either group. CONCLUSIONS: Antioxidant therapy, as a combination of Bio-Antox and Bio-Quinone Q10, may improve the pruritus and fatigue of PBC. This combination of therapy should be investigated further in a double-blind, placebo-controlled trial.     

Evaluation of the role of bile acids and serotonin as markers of pruritus in children with chronic cholestatic liver disease

Background and study aimsPruritus is an annoying symptom with an unclear pathogenesis accompanied by chronic cholestasis. This cross-sectional study was conducted to define the relationship between serum levels of presumed pruritogens (bile acids (BAs) and serotonin) and severity of pruritus in pediatric patients with chronic cholestatic liver disease.Patients and methodsA total of 28 children suffering from pruritus due to chronic cholestatic liver disease and 29 age- and sex-matched healthy control subjects were examined. Scores obtained used the 5-D itch scale were evaluated among patients. Serum levels of BAs and serotonin were determined using enzymatic assays and high-performance liquid chromatography, respectively.ResultsPatients had higher serum BA levels and lower serotonin levels than control subjects. Serum BA levels were significantly elevated in 61% of patients. The 5-D itch scale scores were significantly higher in cholestatic individuals with normal γ-glutamyl transpeptidase levels. Neither BA nor serotonin levels correlated with the severity of the 5-Ditch scale score.ConclusionNeither BA nor serotonin levels correlated with the severity of pruritus, indicating that they may not be good laboratory markers for the intensity of itch in children with cholestasis. Our findings suggest that it is necessary to identify another potential pruritogenic mediator, most probably of a biliary origin.     

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.     

Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial

Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients.     

Prevalence of pruritus in patients with chronic liver disease: A multicenter study

Aim

Pruritus is a common comorbidity in chronic liver disease. The aim of this study was to clarify the prevalence of pruritus and its characteristics in patients with chronic liver disease.

Methods

A total of 1631 patients with chronic liver disease who attended one of nine joint‐research facilities from January to June 2016 were enrolled. We investigated the prevalence of pruritus, itch location, itch duration, daily itch fluctuation, seasonal itch exacerbation, treatment drugs, and therapeutic effects using a medical interview questionnaire.

Results

The median age was 66 years and 890 (54.6%) patients were women. The prevalence of pruritus was 40.3% (658/1631), and it differed according to the underlying liver disease. The most frequent body location for pruritus was on the back (63.1%). Pruritus duration was more than 6 months in 252 (38.3%) patients. The severity of pruritus, assessed using a visual analog scale, was higher during the day than at night (median, 4 vs. 3, P < 0.001). Seasonal exacerbation was observed in 296 (45.0%) patients. Although 301 (45.7%) patients were treated with antipruritic agents, 57.8% (174/301) patients reported an insufficient effect. Active hepatitis B virus infection (odds ratio [OR], 2.51; P = 0.043), primary biliary cholangitis (OR, 3.69; P = 0.018), diabetes (OR, 1.57; P = 0.010), and aspartate aminotransferase ≥60 U/L (OR, 2.06; P = 0.011) were independent factors associated with pruritus.

Conclusion

The prevalence of pruritus varies according to the chronic liver disease etiology. Underlying liver disease, aspartate aminotransferase ≥60 U/L, and comorbid diabetes are factors associated with pruritus in patients with chronic liver disease.     

Recent advances in the management of pruritus in chronic liver diseases

Pruritus is a symptom found in patients with chronic liver diseases,especially cholestatic liver diseases such as primary biliary cholangitis.This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation.Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems,leading to the development of various therapeutic options.Little evidence for the efficacy of most of these treatments is currently available,indicating a need for further investigations.     

Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis

There is evidence to suggest that rifampicin is an effective second line therapy for controlling pruritus in patients with chronic cholestatic liver disease. It is most widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). Rifampicin has been reported as causing hepatitis in patients being treated for tuberculosis. Most reports of this have been confounded however by the concurrent use of other hepatotoxic antitubercular therapy. Here we report a single centre experience of the use of rifampicin in PBC, and describe three cases of significant hepatitis associated with rifampicin therapy. Two of these patients had significant impairment of liver synthetic function (necessitating liver transplantation in one case). These are the first reports of impaired hepatic synthetic function due to rifampicin monotherapy. Rifampicin caused significant hepatitis in 7.3% (95% confidence interval 2.5-19.4%) of patients treated for cholestatic liver disease in our centre.     

Raised histamine concentrations in chronic cholestatic liver disease.

Pruritus is a frequent symptom in chronic cholestatic liver disease. To date, no single causative mechanism has been identified. We examined venous plasma concentrations of the known pruritogen, histamine, using a highly sensitive radioenzymatic assay in 42 patients with chronic cholestatic liver disease, and in normal controls. The mean plasma histamine level was significantly greater in chronic cholestatic liver disease patients (275 (117) pg/ml; X (SD) than in controls (140 (72) pg/ml, n = 20) (p less than 0.0001). No significant differences were found between histamine concentrations in the two chronic cholestatic liver disease subgroups: primary biliary cirrhosis and sclerosing cholangitis. Histamine concentrations were significantly greater (p less than 0.01) in the pruritic (319 (132) pg/ml) as compared with the non-pruritic (227 (75) pg/ml) chronic cholestatic liver disease patients. The histaminase activity was equivalent in patients and controls. The finding of raised histamine concentrations in chronic cholestatic liver disease suggests in vivo mast cell activation and a potential role for its mediators in the pruritus characteristic of these disorders.     

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.     

A Pilot Study of Etanercept in the Treatment of Primary Sclerosing Cholangitis

There is no effective medical treatment for primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease that usually progresses to cirrhosis and liver failure. The aim of this study was to determine the safety and efficacy of etanercept, an inhibitor of tumor necrosis factor, in the treatment of PSC. Ten patients with clinically active PSC were studied. All had elevated serum alkaline phosphatase levels, cholangiograms that were diagnostic of PSC, and liver histology consistent with PSC. Five patients had elevated serum bilirubin levels, five had pruritus, eight had failed to respond to ursodiol and/or methotrexate, and six had rapidly recurring dominant bile duct strictures. Patients were to receive etanercept, 25 mg subcutaneously twice weekly, for 6 months if there were no side effects and for 1 year if there was evidence of efficacy after 6 months. Biochemical tests of liver function did not improve in any patient. Mean serum bilirubin levels increased significantly, from 2.0 to 3.6 mg/dl (P = 0.026). Two of the five patients with pruritus had resolution of pruritus during treatment with etanercept, recurrence when etanercept was stopped, and resolution when it was restarted, although there was little change in liver enzymes or bilirubin levels. There was no decrease in the rate of stricture formation and there were no side effects. Etanercept, at the dosage used, was well tolerated but not effective in the treatment of PSC. It may be helpful in treating pruritus due to 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。     

A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.

To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary biliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous (24-hour) IV infusions of naloxone (0.2 micrograms.kg-1.min-1) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed subjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P less than 0.001). These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients.     

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.     

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with end-stage liver disease and yields excellent long-term survival in both groups.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with endstage liver disease and yields excellent long-term survival in both groups.     

Evolving concepts of the pathogenesis and treatment of the pruritus of cholestasis.

The site of the pathogenic events responsible for initiating the pruritus of cholestasis has been assumed to be the skin. This assumption cannot be excluded but is not supported by convincing data. Empirical therapies such as anion exchange resins and rifampicin often appear to be partially efficacious. Recent evidence suggests that altered neurotransmission in the brain may contribute to this form of pruritus. In particular, the hypothesis that increased central opioidergic tone is involved is supported by three observations: opiate agonists induce opioid receptor-mediated scratching activity of central origin, central opioidergic tone is increased in cholestasis and opiate antagonists reduce scratching activity in cholestatic patients. Apparent subjective ameliorations of pruritus following intravenous administration of ondansetron to cholestatic patients suggest that altered serotoninergic neurotransmission may also contribute to this form of pruritus.