rifampin and Liver-Cirrhosis--Biliary

Chronic pruritus is a classic symptom in patients with primary biliary cholangitis. It affects up to two-thirds of patients in the course of the disease. Efficient therapy consists of topical treatment combined with systemic options such as anion exchangers, rifampicin, bezafibrate, μ-opioid receptor antagonists, selective-serotonin receptor uptake inhibitors, and gabapentinoids. Future therapeutic approaches may contain the selective blockade of the enterohepatic cycle by inhibiting the ileal bile acid transporter, the agonism at κ-opioid receptors, and antagonism of the mas-related G protein-coupled receptor X4. As nondrug treatment, ultraviolet B therapy, albumin dialysis, and biliary drainage are available at specialized centers.

Topics: Albumins; Bezafibrate; Humans; Liver Cirrhosis, Biliary; Narcotic Antagonists; Pruritus; Receptors, Opioid; Receptors, Serotonin; Rifampin; Selective Serotonin Reuptake Inhibitors

Pruritus is a common symptom with primary biliary cholangitis. Research has focused on refining understanding of the neurohumoral pathways involved in transduction of pruritus from peripheral cutaneous receptors to the central nervous system, and identifying modulating drugs. Current treatments have variable efficacy and safety. Because of the deleterious effects on quality of life or debilitation, many patients necessitate individualized therapeutic approaches; clinicians may need to consider invasive treatment options. This article highlights various therapeutic interventions, from general measures to invasive strategies, and novel agents under investigation, providing clinicians with the management tricks of the trade.

Topics: Anion Exchange Resins; Bile Acids and Salts; Cholestyramine Resin; Drainage; Filtration; Humans; Liver Cirrhosis, Biliary; Lysophospholipids; Narcotic Antagonists; Opioid Peptides; Phosphoric Diester Hydrolases; Plasmapheresis; Pruritus; Receptors, Opioid; Rifampin; Selective Serotonin Reuptake Inhibitors; Serotonin; Sertraline; Substance P

Primary biliary cirrhosis (PBC) is a chronic cholestatic autoimmune liver disease that predominantly affects middle-aged women. It is characterized by slowly progressive destruction of the small intrahepatic bile ducts together with portal inflammation, and this initially leads to fibrosis and later to cirrhosis. It is currently accepted that the pathogenesis of PBC is multifactorial with genetic and environmental factors interplaying to determine the disease onset and progression. In addition to antimitochondrial antibody (AMA), which is the hallmark of PBC and is detected in at least 90% of the patients, other autoantibodies (antinuclear antibody, anti-smooth muscle antibody and rheumatoid factor, etc.) may also be found in the patients. There is no correlation between the titer of AMAs and the disease severity. Most patients are diagnosed either during the asymptomatic phase of PBC or after presenting with non-specific symptoms. Pruritus and fatigue are the most common symptoms of PBC. The prognosis of PBC has improved significantly during the last few decades. Patients are now diagnosed earlier in its clinical course, they are more likely to be asymptomatic at diagnosis and they are more likely to receive medical treatment. A wide variety of drugs have been assessed for the treatment of this condition: such immunosuppressive agents as corticosteroids, cyclosporine and azathioprine have a weak effect on the disease's natural history. Ursodeoxycholic acid (UDCA) is the only currently approved medical treatment. For PBC patients with end-stage liver disease or an unacceptable quality of life, liver transplantation is the only accepted therapeutic option. Early diagnosis and treatment of PBC are important because effective treatment with UDCA has been shown to delay disease progression and improve rate survival in the early stage.

Topics: Autoimmune Diseases; Cholagogues and Choleretics; Cholestadienes; Cholic Acids; Female; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Prevalence; Rifampin

Topics: Anti-Inflammatory Agents; Azathioprine; Biopsy, Needle; Cholagogues and Choleretics; Female; Gastroscopy; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Liver Transplantation; Middle Aged; Patient Selection; Prednisolone; Rifampin; Ursodeoxycholic Acid

The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.

Topics: Adult; Alkaline Phosphatase; Antipruritics; Aspartate Aminotransferases; Bilirubin; Biomarkers; Cholagogues and Choleretics; Cholestyramine Resin; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Minnesota; Multivariate Analysis; Predictive Value of Tests; Pruritus; Rifampin; Risk Factors; Serum Albumin; Severity of Illness Index; Treatment Outcome; Ursodeoxycholic Acid

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

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P less than 0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.

Topics: Adult; Aged; Alkaline Phosphatase; Bilirubin; Female; Humans; Liver Cirrhosis, Biliary; Male; 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

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

Topics: Antipyrine; Bile Acids and Salts; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Liver Cirrhosis, Biliary; Middle Aged; Placebos; Pruritus; Random Allocation; Rifampin

Topics: Antitubercular Agents; Drug Therapy, Combination; Female; Fever; Glucocorticoids; Humans; Immunocompromised Host; Isoniazid; Liver Cirrhosis, Biliary; Liver Transplantation; Middle Aged; Mycobacterium tuberculosis; Pericardiocentesis; Pericarditis, Tuberculous; Prednisolone; Pyrazinamide; Rifampin; Treatment Outcome

Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain.. To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy.. We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating).. The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented.. Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Cholagogues and Choleretics; Drug Administration Schedule; Enzyme Inhibitors; Fatigue; Female; gamma-Glutamyltransferase; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Methotrexate; Middle Aged; Pruritus; Rifampin; Treatment Outcome; Ursodeoxycholic Acid

Topics: Alkaline Phosphatase; Antipruritics; Aspartate Aminotransferases; Bilirubin; Biomarkers; Cholagogues and Choleretics; Cholestyramine Resin; Dose-Response Relationship, Drug; Enzyme Inhibitors; History, 21st Century; Humans; Liver Cirrhosis, Biliary; Pruritus; Rifampin; Serum Albumin; Ursodeoxycholic Acid

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.

Topics: Adult; Antipruritics; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Cirrhosis, Biliary; Middle Aged; Pruritus; Rifampin

Topics: Aged; Female; Humans; Liver Cirrhosis, Biliary; Prurigo; Pruritus; Rifampin

A patient with primary biliary cirrhosis (PBC) developed marked hypoprothrombinemia with decreased concentrations of the vitamin K-dependent coagulation factors VII, IX, and X during treatment with rifampicin. The coagulation abnormalities were easily corrected by administration of vitamin K. Different mechanisms may be involved, such as a decreased production of menaquinones by intestinal bacteria, a warfarin-like effect by inhibition of the vitamin K epoxide reductase, or an increased oxidative degradation of vitamin K as a result of hepatic microsomal enzyme stimulation. Whatever the mechanism involved, the appearance of this complication in a patient with PBC probably points to the importance of a pre-existing poor vitamin K status. Patients with PBC, treated with rifampicin, should have a regular monitoring of their vitamin K status. Adequate vitamin substitution should be administered, if necessary.

Topics: Female; Humans; Hypoprothrombinemias; Liver Cirrhosis, Biliary; Middle Aged; Prothrombin Time; Rifampin; Vitamin K; Vitamin K Deficiency

Seven patients with primary biliary cirrhosis were treated with rifampicin administered for 2 weeks in a daily dose 450-600 mg. Due to the treatment the itch disappeared completely in 4 and decreased significantly in 3 patients. As shown by the antipyrine test, half-life and clearance of antipyrine returned to normal suggesting cytochrome P-450 induction as a result of hydroxylation activity. There was a tendency to lowering of bilirubin, cholesterol, alkaline phosphatase, asparagine--and alanine aminotransferase against an increase in gammaglobulins. The differences were, however, insignificant. Rifampicin tolerance was satisfactory.

Topics: Adult; Drug Evaluation; Drug Tolerance; Female; Humans; Liver Cirrhosis, Biliary; Middle Aged; Pruritus; Rifampin; Time Factors

Six patients with primary biliary cirrhosis (PBC) were treated with a daily oral dose of 600 mg rifampicin for 2 weeks to induce the hepatic metabolism of drugs and bile acids. On rifampicin 5 of 6 patients experienced a pronounced decrease of their pruritus. In all patients the oxidative cytochrome P-450 dependent drug metabolism was induced as shown by an increase of antipyrine-clearance from 36.3 +/- 8.8 to 80.6 +/- 20.1 ml/min and an enhanced urinary excretion of 6-beta-hydroxycortisol from 454 +/- 1.99 to 1607 +/- 362 micrograms/24 h. Furthermore, in all 6 patients the serum alkaline phosphatase declined. In the 3 cholestatic patients (bilirubin greater than 1.0 mg/dl) the serum concentration of total and conjugated bile acids was strikingly reduced. Thus, rifampicin is an inducer of hepatic metabolism in PBC-patients, ameliorates the pruritus and can lower serum concentrations of alkaline phosphatase and bile acids.

Topics: Adult; Alkaline Phosphatase; Antipyrine; Bile Acids and Salts; Humans; Liver; Liver Cirrhosis, Biliary; Middle Aged; Rifampin