rifampin and Cholestasis

Pruritus in cholestatic liver diseases can be a major burden and dramatically impair the quality of life of those affected. Here, we provide an update on the latest insights into the molecular pathogenesis of and novel therapeutic approaches for cholestasis-associated itch. Endogenous and exogenous small-molecule pruritogen candidates bind to their receptors on unmyelinated itch C-fibres in the skin. Candidate pruritogens in cholestasis include certain lysophospholipids and sulfated progesterone metabolites, among others, whereas total bile acid or bilirubin conjugates seem unlikely to have a dominant role in the pathogenesis of cholestasis-associated pruritus. Transmission of itch signals via primary, secondary and tertiary itch neurons to the postcentral gyrus and activation of scratch responses offer various targets for therapeutic intervention. At present, evidence-based treatment options for pruritus in fibrosing cholangiopathies, such as primary biliary cholangitis and primary sclerosing cholangitis, are the peroxisome proliferator-associated receptor (PPAR) agonist bezafibrate and the pregnane X receptor (PXR) agonist rifampicin. In pruritus of intrahepatic cholestasis of pregnancy, ursodeoxycholic acid is recommended and might be supported in the third trimester by rifampicin if needed. Alternatively, non-absorbable anion exchange resins, such as cholestyramine, can be administered, albeit with poor trial evidence. Liver transplantation for intolerable refractory pruritus has become an extremely rare therapeutic strategy.

Topics: Cholestasis; Cholestasis, Intrahepatic; Cholestyramine Resin; Female; Humans; Pregnancy; Pruritus; Quality of Life; Rifampin

Hepatic itch remains among the most agonizing symptoms for affected patients and a major clinical challenge for physicians. Pruritus may occur in almost all liver diseases, particularly those with cholestatic features. Hepatic itch arises irrespective of the severity of the underlying liver disease or extent of cholestasis. Antihistamines are ineffective in hepatic itch. Therapeutic recommendations consist of a guideline-based stepwise approach, starting with the anion exchange resin cholestyramine, followed by rifampicin, naltrexone, and sertraline. Bezafibrate and ileal bile acid transporter inhibitors are promising future treatment options. Experimental and invasive procedures should be reserved for refractory pruritus.

Topics: Analgesics, Opioid; Anion Exchange Resins; Antipruritics; Bezafibrate; Carrier Proteins; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Chronic Disease; Cytochrome P-450 Enzyme Inducers; Drainage; Humans; Hypolipidemic Agents; Membrane Glycoproteins; Methylamines; Narcotic Antagonists; Prevalence; Pruritus; Rifampin; Thiazepines; Ursodeoxycholic Acid

Pruritus is a disabling symptom accompanying chronic cholestasis. In some cases, refractory pruritus may require invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway and several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adult patients, there is no consensus in children, given the difficulty in conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of therapy that should always be associated with local cutaneous care and with nonspecific treatment of cholestasis including ursodeoxycholic acid therapy. Pruritus should be assessed as objectively as possible between each therapeutic step. Rifampicin, an enzyme inducer, is the specific first-line treatment of cholestatic pruritus. The second-line therapies require evaluation of the child in an expert center and are discussed on a case-by-case basis depending on the underlying disease, the experience of the center and the will of the child and his family. It could be inhibitors of serotonin reuptake (sertraline) or an opioid antagonist (naloxone). Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases.

Topics: Anion Exchange Resins; Biliary Tract Surgical Procedures; Child; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Chronic Disease; Cytochrome P-450 CYP3A Inducers; Humans; Liver Transplantation; Narcotic Antagonists; Pruritus; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Sorption Detoxification; Ursodeoxycholic Acid

Itch is a global clinical problem and finding effective treatment remains a therapeutic challenge because of the complex pathophysiology of itch. The key component of treating itch should be directed at the underlying etiologies when possible. However, without eradication of the underlying diseases, treatment is often palliative at best. Treatment with systemic therapies can vary according to the etiology of the chronic itch. The aim of this article is to review the major systemic anti-itch agents and give a summary on the possible systemic treatments for different types of itch.

Topics: Amines; Analgesics; Analgesics, Opioid; Anion Exchange Resins; Antidepressive Agents; Aprepitant; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Histamine Antagonists; Humans; Morpholines; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Paraneoplastic Syndromes; Peripheral Nervous System Diseases; Pregabalin; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Rifampin; Thalidomide; Uremia; Ursodeoxycholic Acid

Cholestatic itch is a feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, the inherited form of cholestasis, and intrahepatic cholestasis of pregnancy. Although undervalued by physicians, cholestatic itch can be a source of great discomfort to the patient and significantly affects quality of life. Many pruritogens such as bile salts, opioids, serotonin, and histamine have been implicated in the pathogenesis of cholestatic itch, but no causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may be key elements in its pathogenesis. Treatment options for patients with cholestatic itch include the anion exchange resin cholestyramine, bile acid ursodeoxycholic acid, PXR agonist rifampicin, opioid antagonist naltrexone, and the serotonin inhibitor sertraline. These drugs can be used as a stepwise therapeutic approach. The body of evidence for many of these options, however, is not very robust. Patients who do not respond to medical therapy can be candidates for interventional measures, such as albumin dialysis, plasmapheresis, or nasobiliary drainage, or certain experimental approaches such as UVB phototherapy. Research over the past decade has elucidated many of the receptors and neuropeptides involved in itch sensation and transmission; it is hoped that in the future this will lead to the development of novel antipruritic medication for cholestatic itch.

Topics: Anion Exchange Resins; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Naltrexone; Narcotic Antagonists; Plasmapheresis; Pregnane X Receptor; Pruritus; Receptors, Steroid; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Ultraviolet Therapy; Ursodeoxycholic Acid

The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritus.

Topics: Animals; Anion Exchange Resins; Antibiotics, Antitubercular; Bile Acids and Salts; Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Narcotic Antagonists; Pregnane X Receptor; Pruritus; Receptors, Steroid; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Signal Transduction

Pruritus can be the dominant symptom of cholestatic liver disease but is difficult to treat since unraveling its pathophysiology is a great challenge. Serum autotaxin activity correlates with pruritus intensity, but its causal relationship, expression pattern and exact mode of action during cholestasis remain to be established. The anion exchange resin cholestyramine, the PXR agonist rifampicin, the opioid antagonist naltrexone and the serotonine reuptake inhibitor sertraline are recommended by evidence-based guidelines as stepwise therapeutic approaches to treat itch in cholestasis. Rifampicin, the most effective antipruritic agent in cholestatic itch, has been shown to reduce autotaxin transcription in vitro. Experimental approaches include UVB phototherapy, extracorporeal albumin dialysis, nasobiliary drainage and in desperate cases even liver transplantation. Relevant clinical observations along with the different metabolic, neurologic and endocrine targets of available therapies in cholestatic pruritus are reviewed here.

Topics: Anion Exchange Resins; Antipruritics; Cholestasis; Cholestyramine Resin; Combined Modality Therapy; Dialysis; Disease Management; Enzyme Inhibitors; Humans; Narcotic Antagonists; Phosphoric Diester Hydrolases; Phototherapy; Prognosis; Pruritus; Rifampin; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Treatment Outcome

Pruritus can occur as a severe complication of cholestasis. Several hypotheses suggest an important role for the accumulation of bile acids, endogenous opioids and - mire recently - lysophosphatidic acid. Bile acid sequestrants are the first-line therapeutic agents. In refractory cases, a stepwise approach using rifampicin, oral opiate antagonists and the selective serotonin reuptake inhibitor sertraline should be tested. Recent case series reported effective relief of pruritus using extracorporal liver support systems and plasmapheresis.

Topics: Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Opioid Peptides; Plasmapheresis; Pruritus; Renal Dialysis; Rifampin; Sertraline; Sorption Detoxification; Ursodeoxycholic Acid

Pruritus is commonly associated with cholestatic disorders and shows wide interindividual variability. The presence of skin lesions due to scratching and the application of a visual analogue scale are useful for clinical evaluation. Although the pathophysiology of this entity is not well understood, advances have recently been made in understanding of the pruritoceptive neural pathway, which shares certain similarities with the nociceptive pathway, although there are other distinguishing characteristics such as the action of a specific neurotransmitter, GPR, on the first synapsis at the posterior horn of the spinal cord. Amongst the modulator systems of the pruritoceptive pathway is the action of the endogenous opioids. An increase of these opioids in cholestatic situations is the most widely accepted hypothesis for pruritus in these patients. Some treatments have proven efficacy in randomized clinical trials in patients with cholestatic disorders, such as anion exchange resins, rifampicin, opioid antagonists and ursodeoxycholic acid; the latter is especially useful in intrahepatic cholestasis of pregnancy.

Topics: Animals; Anion Exchange Resins; Cholestasis; Evidence-Based Medicine; Female; Gastrin-Releasing Peptide; Haplorhini; Humans; Male; Models, Neurological; Narcotic Antagonists; Neural Pathways; Opioid Peptides; Posterior Horn Cells; Pregnancy; Pregnancy Complications; Pruritus; Randomized Controlled Trials as Topic; Rifampin; Ursodeoxycholic Acid

The objective of this review was to evaluate the efficacy and safety of rifampin, opioid antagonists, or bile acid binding agents in the treatment of cholestasis-related pruritus (CAP) from available randomized controlled trial evidence.. In addition to a comprehensive gray literature search, the Cochrane Library, MEDLINE, EMBASE, PubMed, and Web of Science were searched. Only full-text RCTs in participants (>75% adult) with CAP on at least one of the three medications were included. The primary outcome was change in pruritus score, recorded as a continuous or dichotomous outcome. Two independent reviewers performed trial selection and quality assessment.. From 487 citations, 12 RCTs were included. Rifampin (standardized mean difference [SMD]-1.62, 95% CI -3.05 to -0.18) and opioid antagonists (SMD -0.68, 95% CI -1.19 to -0.17) significantly reduced CAP. The two cholestyramine studies were too heterogeneous to pool. Although cholestyramine (P= 0.35) and rifampin (P= 0.96) were not associated with greater side effects compared with placebo, opioid antagonists were (number needed to harm = 2.6, 95% CI 1.4-25).. The available RCTs are small, few in number, and use varying scales for measuring pruritus. Although both opioid antagonists and rifampin demonstrated a reduction in pruritus, there were insufficient data to judge the efficacy of cholestyramine. Opioid antagonists were associated with transient side effects in a significant proportion of patients. A longer well-designed randomized controlled trial is needed to confirm the efficacy of bile acid binding agents and accurately assess adverse events.

Topics: Anticholesteremic Agents; Cholestasis; Cholestyramine Resin; Humans; Leprostatic Agents; Narcotic Antagonists; Pruritus; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome

To determine the safety and efficacy of rifampin for treatment of pruritus associated with cholestasis due to chronic liver disease.. 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.. 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).. 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.

Topics: Cholestasis; Chronic Disease; Cross-Over Studies; Humans; Prospective Studies; Pruritus; Rifampin

Pruritus is a frequent, distressing and sometimes disabling symptom of liver and biliary tract disorders. Results of treatment are sometimes disappointing and the pathophysiology is still largely unknown. It was recently discovered that endogenous opioids contribute to the perception of itching and that opiate receptor antagonists can reduce the overstimulation of these receptors and thereby attenuate the itching. A stepwise treatment strategy focusing successively on ion exchange resins, rifampicin and opiate receptor antagonists leads to effective alleviation of itching in most patients.

Topics: Cholestasis; Histamine H1 Antagonists; Humans; Ion Exchange Resins; Narcotic Antagonists; Pruritus; Receptors, Opioid; Rifampin; Serotonin Antagonists; Ultraviolet Therapy

Topics: Androgens; Antipruritics; Bile Acids and Salts; Cholestasis; Cholestyramine Resin; Female; Humans; Narcotic Antagonists; Plasmapheresis; Pregnancy; Pregnancy Complications; Propofol; Pruritus; Rifampin; Ultraviolet Therapy; Ursodeoxycholic Acid

Topics: Butyrophenones; Chemical and Drug Induced Liver Injury; Cholestasis; Contraceptives, Oral, Hormonal; Humans; Novobiocin; Prognosis; Rifampin; Salicylates; Steroids

Topics: Adenosine Triphosphate; Age Factors; Animals; Bilirubin; Biotransformation; Carbon Isotopes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chlordiazepoxide; Chlorpromazine; Cholestasis; Dogs; Humans; Infant, Newborn; Liver; Liver Diseases; Mice; Microsomes, Liver; Phenylbutazone; Rats; Rifampin; RNA

Pruritus is one of the most common and disabling symptoms of liver disease such as Primary Sclerosing Cholangitis and Primary Biliary Cholangitis. Cholestyramine, rifampin, opioid antagonists, antihistaminic agents and SSRIs are used for the management of pruritus. Due to rifampin drug interactions as well as its serious side effects such as hepatotoxicity, clinicians are endeavoruing to find a safer and a more effective substitution.. The purpose of this study was to compare the efficacy and safety of sertraline with rifampin in the management of cholestatic pruritus.. In a single-blinded randomized clinical trial a total of 36 patients of PSC and PBC were divided into two equal groups, one group received 100 mg/day sertraline and the other group received rifampin 300 mg/day for 4 weeks. Visual analog scale was used to record pruritus severity at baseline and 4 weeks after drug intervention, also, ALT, AST, ALP and total bilirubin of all patients were measured at three different time points.. Over the follow-up period, pruritus had relieved in both groups, but there was no significant differences between sertraline and rifampin in pruritus management (pvalue=0.740), also there was no significant difference between the two intervention strategies (A versus B) in total bilirubin level (pvalue=0.106). Moreover, the ALT, AST and ALP levels were found to be significantly different between the two groups (Pvalue˂0.01).. There is no difference between sertraline and rifampin in pruritus improvement, but sertraline has less adverse effects on hepatobiliary enzyme levels, so it seems to be safer than rifampin.

Topics: Adult; Anti-Bacterial Agents; Cholestasis; Female; Humans; Male; Middle Aged; Pruritus; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Single-Blind Method; Treatment Outcome

To determine the safety and efficacy of rifampin for treatment of pruritus associated with cholestasis due to chronic liver disease.. 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.. 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).. 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.

Topics: Cholestasis; Chronic Disease; Cross-Over Studies; Humans; Prospective Studies; Pruritus; Rifampin

Rifampin has been proposed to reduce pruritus in children and adults with chronic cholestasis; however, there is a paucity of published data regarding the use of rifampin in children.. In an open trial, 24 children were evaluated during a 6-year period. Diagnoses included 13 patients with extrahepatic biliary atresia (54%), six with Alagille's syndrome, three with Byler's disease, and one each with primary sclerosing cholangitis and alpha1-antitrypsin deficiency. All patients had severe pruritus that had not responded adequately to at least 2 months of therapy with ursodeoxycholic acid, diphenhydramine, or phenobarbital and local skin care measures. Treatment was initiated with rifampin, 10 mg/kg per day in two divided doses for 18+/-20 months, and the effect on the severity of pruritus was assessed by a clinical scoring system.. Ten patients showed a complete response, 12 a partial response, and 2 no response. Complete response was more common in extrahepatic cholestasis (64% vs. 10%), whereas partial response was more common in intrahepatic cholestasis (80% vs. 29%). Treatment was associated with reduction of gamma-glutamyl transpeptidase. No clinical or biochemical toxicity of rifampin was observed.. We conclude that for more than 90% of children with chronic cholestasis and severe pruritus unresponsive to other treatments, rifampin appears to be a safe and effective therapy.

Topics: Adolescent; Child; Child, Preschool; Cholestasis; Chronic Disease; Female; Humans; Infant; Male; Pruritus; Rifampin; Treatment Outcome

The effects of rifampicin treatment (10 mg.kg-1.day-1) on pruritus and cholestasis were evaluated in 16 patients with primary biliary cirrhosis and pruritus followed up for 2-24 months. Assessment of pruritus severity, liver tests, aminopyrine breath test, and bile acids was done at 2 weeks and every 3 months after the beginning of the study. Two patients (12.5%) were withdrawn after 2 months of treatment because they had hepatitis caused by rifampicin. Four patients were withdrawn after 4 months because of liver transplantation (3 cases) and the development of leg edema associated with administration of rifampicin. The remaining 10 patients received therapy for 14.4 +/- 0.7 months and did not experience side effects. Pruritus improved in all patients and disappeared in 11 patients (79%) after 3 months of treatment. Moreover, all patients followed up for more than 1 year were free of pruritus. The alkaline phosphatase level decreased significantly, and the aminopyrine breath test results increased significantly after 2 weeks of treatment (P less than 0.001) and did not change thereafter. In the 9 patients treated for 15 months, alkaline phosphatase levels decreased to 63% of the basal levels and aminopyrine breath test results increased to 153% of baseline values. Transaminases, gamma-glutamyltransferase, and total bile salt levels decreased significantly after 2 weeks of treatment but returned to baseline after 3 months. No changes in bilirubin and cholesterol levels were observed. It is concluded that long-term rifampicin treatment is effective for relieving pruritus in primary biliary cirrhosis, but liver enzymes should be monitored to detect drug-induced hepatitis.

Topics: Bile Acids and Salts; Cholestasis; Female; Humans; Liver; Liver Cirrhosis, Biliary; Middle Aged; Pruritus; Rifampin

The anti-pruritic effects of rifampicin (10 mg/kg) and phenobarbitone (3 mg/kg) were assessed in 22 patients with primary biliary cirrhosis in a crossover randomised clinical trial. Each agent was given for 14 days, with a 30-day washout period between treatments. 21 patients completed the course of rifampicin and 18 that of phenobarbitone; rifampicin was withdrawn from 1 patient when anaemia and renal failure developed, whereas 3 patients stopped taking phenobarbitone because of a rash and the 4th merely refused the drug. Rifampicin had a greater anti-pruritic effect than phenobarbitone. The symptom improved in 19 patients taking rifampicin and in 8 taking phenobarbitone, the degree of improvement being greater with rifampicin than with phenobarbitone. Pruritus disappeared in 9 patients receiving rifampicin, and three of them were free of itch when switching over to phenobarbitone. Both drugs were equally effective in inducing hepatic microsomal function but rifampicin has the additional effect of reducing cholestasis. Its anti-pruritic effect should be tested in long-term clinical trials.

Topics: Adult; Cholestasis; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Liver Cirrhosis, Biliary; Microsomes, Liver; Middle Aged; Phenobarbital; Pruritus; Random Allocation; Rifampin; Severity of Illness Index

Biallelic variants in the USP53 gene have recently been reported to segregate with normal gamma glutamyltransferase (GGT) cholestasis. Using whole-exome sequencing (WES), we detected two USP53 homozygous variants (c.951delT; p. Phe317fs and c.1744C>T; p. Arg582*) in five additional cases, including an unpublished cousin of a previously described family with intractable itching and normal GGT cholestasis. Three patients, a child and two adults, presented with recurrent episodes of normal GGT cholestasis, consistent with a diagnosis of benign recurrent intrahepatic cholestasis (BRIC). Cholangiopathic changes, possibly autoimmune in origin, were recognized in some patients. Additional phenotypic details in one patient included an enlarged left kidney, and speech/developmental delay. Notably, two patients exhibited a complete response to rifampicin, and one responded to ursodeoxycholic acid (UDCA). Two adult patients were suspected to have autoimmune liver disease and treated with steroids. This report describes new cases of USP53 disease presenting with normal GGT cholestasis or BRIC in three children and two adults. We also describe the novel finding of a dramatic response to rifampicin. The association of cholangiopathy with normal GGT cholestasis provides a diagnostic challenge and remains poorly understood.

Topics: Adolescent; Adult; Child; Cholangitis; Cholestasis; Exome Sequencing; Female; gamma-Glutamyltransferase; Homozygote; Humans; Infant; Male; Mutation; Nucleic Acid Synthesis Inhibitors; Pedigree; Prognosis; Rifampin; Ubiquitin-Specific Proteases

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Topics: Animals; Anticoagulants; Biological Transport; Cholestasis; Disease Models, Animal; Humans; Male; Organic Anion Transporters, Sodium-Dependent; Rats; Rats, Sprague-Dawley; Rifampin

Persistent hepatocellular secretory failure (PHSF) is a rare condition of severe cholestasis caused by drugs, toxins, infection, or temporary biliary obstruction. Real-world data on rifampicin in cholestasis, particularly among patients with deep jaundice, are scarce. We aimed to expand the knowledge on the efficacy and safety of rifampicin treatment in PHSF patients.. Sixteen patients with PHSF who had received rifampicin treatment (150-300 mg/d) at our institution from September 2016 to July 2020 were included. Treatment efficacy was assessed by 20% improvement in serum total bilirubin (TBIL) concentration at 4 weeks. Follow-up was continued until the concentration of TBIL returned to normal.. Among the 16 enrolled patients, 12 had predisposing factors (drugs, infection, or transient biliary obstruction). ATP8B1 or ABCB11 mutations were detected in the other four patients without trigger events. UGT1A1 mutations were found in 7/10 patients. Before rifampicin treatment, the median TBIL level was 352 μmol/L (range 171-591 μmol/L). TBIL > 20% improvement was observed in 14 patients at 4 weeks. TBIL levels of 14 patients eventually returned to normal after 6-12 weeks of rifampicin treatment. The remaining two patients who did not respond to rifampicin finally recovered after nasobiliary drainage. Except for one patient with transient drug-induced hepatitis, no other serious adverse events were observed.. Rifampicin could be a promising option for most PHSF patients. Most PHSF patients have UGT1A1 deficiency, which may be the target of rifampicin.

Topics: Cholestasis; Humans; Rifampin; Treatment Outcome

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study drug-induced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Ketoconazole; Liver; Male; Mice; Rifampin

The use of rifampicin for cholestatic pruritus is accompanied by concerns over safety, but the availability of real-world prescribing data is relatively limited.. We sought to describe the rate and characteristics of rifampicin-induced hepatitis in a mixed aetiology cohort of patients with established liver disease and cholestatic pruritus.. Retrospective review of records for out-patients commenced on rifampicin for pruritus 2012-2016 inclusive. Rifampicin-induced hepatitis was recorded where alanine aminotransferase activity (ALT) increased to both ≥5 × baseline and ≥5 × upper limit of normal (ULN), or to both ≥3 × baseline and ≥3 × ULN with concurrent elevation in serum bilirubin to ≥2 × baseline and ≥2 × ULN, in addition to a Roussel-Uclaf Causality Assessment Method score of "probable" or "highly probable" for rifampicin causality.. After exclusions, we reviewed 105 patients who took rifampicin for a median of 131 days. Most had primary biliary cholangitis or primary sclerosing cholangitis; 40 (38.1%) were men and median age was 44 years (IQR: 32-57). 44 (41.9%) patients had baseline serum bilirubin ≥2 × ULN and 28 (26.7%) ALT ≥3 × ULN. 5 (4.8%) developed rifampicin-induced hepatitis at a median of 70(range 27-130) days after drug initiation. No individual or laboratory baseline characteristics were significantly associated with subsequent development of hepatitis. All cases of hepatitis recovered after drug cessation, although one patient was hospitalised and received corticosteroids.. Given the efficacy of rifampicin for an important sub-group of those with cholestatic pruritus, adult patients, including those with jaundice, can be counselled that 95% of prescriptions are safe, and where hepatitis occurs, including at long latency, drug cessation appears effective.

Topics: Adult; Cholestasis; Cohort Studies; Female; Humans; Liver Diseases; Male; Middle Aged; Pruritus; Rifampin; Risk Factors

Topics: Chemical and Drug Induced Liver Injury; Cholestasis; Cohort Studies; Humans; Pruritus; Rifampin

Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.. Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).. Serum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.. Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.

Topics: Adenosine Triphosphatases; Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Female; Genetic Predisposition to Disease; Glucuronosyltransferase; Hep G2 Cells; HT29 Cells; Humans; Liver; Liver Failure; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation; Pregnane X Receptor; Receptors, Steroid; Rifampin; Risk Factors; Severity of Illness Index; Treatment Outcome; Up-Regulation; Young Adult

Topics: Alkaline Phosphatase; Anticholesteremic Agents; Cholestasis; Cholestyramine Resin; Female; Humans; Liver; Liver Diseases; Liver Function Tests; Male; Practice Guidelines as Topic; Primary Health Care; Pruritus; Rifampin

Alagille syndrome (AGS) is an autosomal dominant disorder of chronic cholestasis characterized by paucity of interlobular bile ducts. The condition has been described only as isolated case reports in India. We describe clinical profile and outcome of nine subjects (six infants and three older children) with AGS. Cholestasis and characteristic facies were present in all, followed by congenital heart disease, vertebral anomalies, and posterior embryotoxon in seven, five, and four cases, respectively. Pruritus was the commonest symptom which was refractory to medical treatment in one third of cases. Two cases developed decompensated liver disease on follow up. High index of suspicion for this multisystemic condition is essential for correct diagnosis and management.

Topics: Alagille Syndrome; Calcium, Dietary; Child; Child, Preschool; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Energy Intake; Female; Humans; India; Infant; Male; Prognosis; Pruritus; Recommended Dietary Allowances; Rifampin; Tertiary Care Centers; Triglycerides; Ursodeoxycholic Acid; Vitamins

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkin's disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values.. Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR-dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis.

Topics: Allylamine; Analysis of Variance; Antipruritics; Biomarkers; Blotting, Western; Carcinoma, Hepatocellular; Case-Control Studies; Cholestasis; Cohort Studies; Colesevelam Hydrochloride; Electrophoresis, Polyacrylamide Gel; Female; Fibroblast Growth Factors; Hep G2 Cells; Humans; Liver Neoplasms; Lysophospholipase; Male; Multivariate Analysis; Phosphoric Diester Hydrolases; Polymerase Chain Reaction; Pruritus; Rifampin; ROC Curve; Treatment Outcome

Benign recurrent intrahepatic cholestasis type 1 (BRIC-1), a rare autosomal recessive disorder characterized by recurrent episodes of jaundice and pruritus, is caused by mutations in the ATP8B1 gene. Rifampicin has been reported to be an effective treatment of jaundice and pruritus in patients with BRIC. Proposed mechanisms of effect for rifampicin include enhancement of multidrug-resistance protein 2 expression, activation of the enzymes of uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 3A4, and stimulation of 6α-hydroxylation of bile acids.. To confirm the diagnosis of BRIC-1 and demonstrate the effect of rifampicin treatment on bile acid metabolism, we analyzed the patient's ATP8B1 gene and bile acids in urine.. We detected 2 heterozygous mutations in the ATP8B1 gene, and increasing amounts of unusual bile acids such as 1β-hydroxylated cholic acid, 2β-hydroxylated cholic acid, 4β-hydroxylated cholic acid, 6α-hydroxylated cholic acid, and hyocholic acid in urine during rifampicin treatment.. We diagnosed a jaundiced pediatric patient with BRIC-1 caused by 2 novel mutations (1226delA/2210delA) in the ATP8B1 gene. Rifampicin was effective in treating cholestasis. Results of urinary bile acid analyses during rifampicin treatment in this patient, suggested that rifampicin might stimulate 1β-, 2β-, and 4β-hydroxylation of bile acids in addition to 6α-hydroxylation.

Topics: Adenosine Triphosphatases; Bile Acids and Salts; Child; Cholestasis; Cholestasis, Intrahepatic; Cholic Acid; Cholic Acids; Female; Humans; Hydroxylation; Mutation; Rifampin

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.

Topics: Cholestasis; Humans; Narcotic Antagonists; Pruritus; Rifampin; Serotonin Antagonists

Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.. Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.. The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.. The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.

Topics: Animals; Apoptosis; Bile Acids and Salts; Carrier Proteins; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cholestasis; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation; Glycochenodeoxycholic Acid; Hepatectomy; Hepatocytes; Humans; Male; Membrane Glycoproteins; Middle Aged; Polymerase Chain Reaction; Rats; Rats, Wistar; Rifampin; RNA, Messenger

The present study aimed at verifying the safety and efficacy of rifampicin in ameliorating pruritus in cholestatic children.. Twenty-three Egyptian children (14 boys and 9 girls), suffering from intractable pruritus of cholestasis, were included. Rifampicin was started at a dose of 10 mg/Kg/day in two divided doses and increased gradually to a maximum of 20 mg/Kg/day if there was no response. Liver function tests were followed up weekly.. Seventeen patients (74%) showed improvement of pruritus with rifampicin. None of the patients showed any deterioration in liver functions.. Rifampicin in a dose of 10-20 mg/Kg/day is safe and effective in ameliorating uncontrollable pruritus in children with persistent cholestasis.

Topics: Adolescent; Child; Child, Preschool; Cholestasis; Female; Humans; Infant; Male; Pruritus; Rifampin

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Enzyme Inhibitors; Homeostasis; Humans; Mice; Pregnane X Receptor; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; Transcription Factors

Vectorial transport of bile acids across hepatocytes is a major driving force for bile flow, and bile acid retention in the liver causes hepatotoxicity. The basolateral and apical transporters for bile acids are thought to be targets of drugs that induce cholestasis. Previously, we constructed polarized LLC-PK1 cells that express both a major bile acid uptake transporter human Na+/taurocholate cotransporting polypeptide (SLC10A1) (NTCP) and the bile acid efflux transporter human bile salt export pump (ABCB 11) (BSEP) and showed that monolayers of such cells can be used to characterize vectorial transcellular transport of bile acids. In the present study, we investigated whether cholestasis-inducing drugs could inhibit bile acid transport in such cells. Because fluorescent substrates allow the development of a high-throughput screening method, we examined the transport by NTCP and BSEP of fluorescent bile acids as well as taurocholate. The aminofluorescein-tagged bile acids, chenodeoxycholylglycylamidofluorescein and cholylglycylamidofluorescein, were substrates of both NTCP and BSEP, and their basal-to-apical transport rates across coexpressing cell monolayers were 4.3 to 4.5 times those of the vector control, although smaller than for taurocholate. The well known cholestatic drugs, rifampicin, rifamycin SV, glibenclamide, and cyclosporin A, reduced the basal-to-apical transport and the apical efflux clearance of taurocholate across NTCP- and BSEP-coexpressing cell monolayers. Further analysis indicated that the drugs inhibited both NTCP and BSEP. Our study suggests that such coexpressing cells can provide a useful system for the identification of inhibitors of these two transport systems, including potential drug candidates.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Biological Transport; Cholestasis; Cyclosporine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fluoresceins; Kinetics; LLC-PK1 Cells; Organic Anion Transporters, Sodium-Dependent; Oxadiazoles; Rifampin; Rifamycins; Swine; Symporters; Taurocholic Acid; Transfection

Bile acids, steroids, and drugs activate steroid and xenobiotic receptor pregnane X receptor (PXR; NR1I2), which induces human cytochrome P4503A4 (CYP3A4) in drug metabolism and cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been used to treat cholestatic diseases. The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene were assayed in human primary hepatocytes by quantitative real-time PCR (Q-PCR). Rifampicin reduced CYP7A1 and small heterodimer partner (SHP; NR02B) mRNA expression suggesting that SHP was not involved in PXR inhibition of CYP7A1. Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to the bile acid response element-I. Mammalian two-hybrid assays revealed that PXR interacted with hepatic nuclear factor 4 alpha (HNF4 alpha, NR2A1) and rifampicin was required. Coimmunoprecipitation assay confirmed PXR interaction with HNF4 alpha. PXR also interacted with peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha), which interacted with HNF4 alpha and induced CYP7A1 gene transcription. Rifampicin enhanced PXR interaction with HNF4 alpha and reduced PGC-1 alpha interaction with HNF4 alpha. Chromatin immunoprecipitation assay showed that PXR, HNF4 alpha, and PGC-1 alpha bound to CYP7A1 chromatin, and rifampicin dissociated PGC-1 alpha from chromatin. These results suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4 alpha and blocks PGC-1 alpha activation with HNF4 alpha and results in inhibition of CYP7A1 gene transcription. Rifampicin inhibition of bile acid synthesis may be a protective mechanism against drug and bile acid-induced cholestasis.

Topics: Bile Acids and Salts; Cholestasis; Cholesterol 7-alpha-Hydroxylase; DNA-Binding Proteins; Enzyme Inhibitors; Hepatoblastoma; Hepatocyte Nuclear Factor 4; Humans; Liver Neoplasms; Phosphoproteins; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; Receptors, Steroid; Rifampin; RNA, Messenger; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured; Up-Regulation

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).

Topics: Brain; Cholestasis; Cholestyramine Resin; Dronabinol; Enzyme Induction; Humans; Liver; Narcotic Antagonists; Ondansetron; Opioid Peptides; Phenobarbital; Pruritus; Rifampin; Skin; Synaptic Transmission; Treatment Outcome

Topics: Allylamine; Anti-Bacterial Agents; Bile Acids and Salts; Cholagogues and Choleretics; Cholestasis; Colesevelam Hydrochloride; Humans; Pruritus; Rifampin

Topics: Antibiotics, Antitubercular; Cholestasis; Drug Resistance, Microbial; Humans; Immunocompromised Host; Neoplasms; Pruritus; Rifampin

Topics: Antibiotics, Antitubercular; Child; Cholestasis; Contraindications; Drug Resistance, Microbial; Humans; Pruritus; Rifampin; Tuberculosis

The efficacy and safety of using rifampicin to treat the pruritus associated with malignant cholestasis was evaluated. The outcomes of eight patients who received 150 mg rifampicin twice daily were reviewed. All responded, with six having complete resolution of the itch. Two patients were able to discontinue rifampicin following resolution of their cholestatic jaundice by surgery and chemotherapy respectively. No side effects were reported. Rifampicin is a safe effective treatment for the pruritus associated with cholestasis secondary to cancer.

Topics: Adult; Aged; Antipruritics; Cholestasis; Female; Humans; Male; Middle Aged; Palliative Care; Pruritus; Rifampin; Treatment Outcome

Topics: Antipruritics; Cholestasis; Female; Humans; Infant; Male; Pruritus; Rifampin; Sampling Studies

Pruritus in hepatic cholestasis has been suggested to be secondary to a high concentration of serum bile acids. Rifampicin, which inhibits the uptake of bile acids by hepatocytes, has been used to treat pruritus. To determine the efficacy of rifampicin as a treatment for refractory pruritus, the medical records of 33 children (median age 25 months, range 4-135; 19 boys) with chronic cholestasis liver disease (21 with Alagille's syndrome, eight with progressive intrahepatic cholestasis, one with extrahepatic biliary atresia, one with an inborn error of bile acid metabolism, and one with cryptogenic cirrhosis) were reviewed retrospectively. The median dose of rifampicin was 5(4-10) mg/kg/day. The median duration of intake was 36(4-120) weeks. Complete relief of pruritus was noted in five (15%) patients and a partial response in 12 (36%). Overall, no significant difference was noted in the laboratory parameters before and after treatment with rifampicin. In the 21 patients with Alagille's syndrome, however, a significant decrease in alkaline phosphatase was seen before and after one and six months of starting treatment. No adverse side effects were seen. Rifampicin appears to be effective in the treatment of refractory pruritus. A prospective study is warranted to assess further the effect of rifampicin treatment in children with hepatic cholestasis.

Topics: Child; Child, Preschool; Cholestasis; Female; Humans; Infant; Liver Diseases; Male; Pruritus; Retrospective Studies; Rifampin; Treatment Outcome

Topics: Aged; Cholestasis; Humans; Male; Rifampin; Troleandomycin

It is generally accepted that hepatitis occurring during treatment with INH and rifampicine results from the hepatotoxicity of INH metabolites. A case is reported of cholestatic hepatitis occurring during such treatment, in which there was a previous history of an isolated hepatic affection. The administration of INH and rifampicin caused cholestasis alone, which reoccurred after rifampicin administration only. No immuno-allergic phenomenon has been shown to be involved in rifampicin toxicity. This observation suggests that rifampicin may be hepatotoxic itself, especially in patients with previous hepatic affections.

Topics: Aged; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver; Liver Diseases; Peritonitis, Tuberculous; Rifampin

Eleven patients with hepatic cirrhosis or cholestasis were treated with rifampicin for 7 to 132 days. Ten patients received hexobarbital (7.32 mg/kg) and five received tolbutamide (20 mg/kg) by i.v. infusion prior to and after rifampicin treatment; plasma concentrations of the two test compounds were determined during and after infusion. The average elimination half-life of hexobarbital had decreased from 624 to 262 min and that of tolbutamide from 292 to 160 min following rifampicin treatment. It was calculated that the metabolic clearance of hexobarbital had increased more than two-fold and that of tolbutamide almost two-fold. The results suggests that rifampicin is able to stimulate hepatic drug metabolism in patients with liver disease. It was apparent in general that the induction did not lead to improvement of hepatocellular function during disease as judged by laboratory findings.

Topics: Adult; Aged; Cholestasis; Female; Hexobarbital; Humans; Kinetics; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Rifampin; Stimulation, Chemical; Time Factors; Tolbutamide

Topics: Bone Marrow; Bone Marrow Examination; Cholestasis; Erythema; Ethambutol; Humans; Isoniazid; Leukopenia; Male; Middle Aged; Neutropenia; Peritonitis, Tuberculous; Rifampin; Streptomycin; Thrombocytopenia; Tuberculosis; Tuberculosis, Hepatic; Tuberculosis, Osteoarticular; Tuberculosis, Splenic; Vitamin B Complex

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Clinical Enzyme Tests; Drug Therapy, Combination; Ethambutol; Fatty Liver; Female; Humans; Isoniazid; Liver Diseases; Liver Function Tests; Male; Middle Aged; Necrosis; Rifampin; Sulfobromophthalein; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Cholestasis; Humans; Isoniazid; Jaundice; Liver; Male; Rifampin; Tuberculosis, Miliary

Topics: Bile; Bile Duct Neoplasms; Cholangitis; Cholelithiasis; Cholestasis; Colitis, Ulcerative; Humans; Rifampin