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C Gluud

Publications and source records attributed to C Gluud.

At least 19 recordsLinked to original sources
PubMed2007

Multivariable modelling for meta-epidemiological assessment of the association between trial quality and treatment effects estimated in randomized clinical trials.

Methodological deficiencies are known to affect the results of randomized trials. There are several components of trial quality, which, when inadequately attended to, may bias the treatment effect under study. The extent of this bias, so far only vaguely known, is currently being investigated by 'meta-epidemiological' re-analysis of data collected as part of systematic reviews. As inadequate quality components often co-occur, we maintain that the suspected biases must be evaluated simultaneously. Furthermore, the biases cannot safely be assumed to be homogeneous across systematic reviews. Therefore, a stable multivariable method that allows for heterogeneity is needed for assessing the 'bias coefficients'. We present two general statistical models for analysis of a study of 523 randomized trials from 48 meta-analyses in a random sample of Cochrane reviews: a logistic regression model uses the design of the trials as such to give estimates; a weighted regression model incorporates between-trial variation and thus gives wider confidence intervals, but is computationally lighter and can be used with trials of more general design. In both models, heterogeneity in the bias coefficients can be incorporated in two ways. A stratification approach pools the estimates from models estimated on subgroups of the data. We explore stratification by reviews and by broad trial types, the latter of which gives larger subgroups of the data, circumventing instabilities. A multilevel approach also avoids instabilities and addresses the more fundamental problem of interpretation of the pooled multivariable effect in the presence of heterogeneity.

Clinical Trials as Topic↗
PubMed2006

Anabolic-androgenic steroids for alcoholic liver disease.

BACKGROUND: Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease. OBJECTIVES: To assess the beneficial and harmful effects of anabolic-androgenic steroids for patients with alcoholic liver disease based on the results of randomised clinical trials. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register in The Cochrane Library, MEDLINE, EMBASE, LILACS, and Science Citation Index Expanded until June 2006. Electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed anabolic-androgenic steroids at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published, and no language limitations were applied. DATA COLLECTION AND ANALYSIS: Outcomes are assessed at maximal follow-up. All analyses were performed according to the intention-to-treat method. The statistical package RevMan Analyses was used. The methodological quality of the randomised clinical trials was assessed. MAIN RESULTS: Combining the results of five randomised clinical trials randomising 499 patients with alcoholic hepatitis and/or cirrhosis demonstrated no significant effects of anabolic-androgenic steroids on mortality (relative risk (RR) 1.01, 95% confidence interval (CI) 0.79 to 1.29), liver-related mortality (RR 0.83, 95% CI 0.60 to 1.15), complications of liver disease (RR 1.25, 95% CI 0.74 to 2.10), and liver histology. Anabolic-androgenic steroids did not significantly affect a number of other outcome measures, including sexual function and liver biochemistry. Anabolic-androgenic steroids were not associated with a significantly increased risk of non-serious adverse events (RR 1.14, 95% CI 0.50 to 2.59) or with serious adverse events (RR 4.54, 95% CI 0.57 to 36.30). AUTHORS' CONCLUSIONS: This systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes (mortality, liver-related mortality, liver complications, and histology) of patients with alcoholic liver disease.

Anabolic Agents↗
PubMed2006

Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma.

BACKGROUND: Colorectal cancer may be prevented by reducing the development of adenomatous polyps. AIM: To assess the benefits and harms of antioxidant supplements in preventing colorectal adenoma. METHODS: Using the Cochrane Collaboration methodology we reviewed all randomized clinical trials comparing antioxidant supplements with placebo or no intervention. We searched electronic databases and the reference lists until October 2005. Outcome measures were development of colorectal adenoma adverse events. We analysed dichotomous outcomes with fixed- and random-effects model meta-analyses and calculated the relative risk with 95% confidence interval. RESULTS: We identified eight randomized trials (17 620 participants). Neither fixed-effect (relative risk: 0.93, 95% CI: 0.81-1.1) nor random-effect model meta-analyses (0.82, 0.60-1.1) showed statistically significant effects of supplementation with beta-carotene, vitamins A, C, E and selenium alone or in combination. Antioxidant supplements seemed to increase the development of colorectal adenoma in three low-bias risk trials (1.2, 0.99-1.4) and significantly decrease its development in five high-bias risk trials (0.59, 0.47-0.74). The estimates difference is significant (P < 0.0001). There was no significant difference between the intervention groups regarding adverse events, including mortality (0.82, 0.47-1.4). CONCLUSION: We found no convincing evidence that antioxidant supplements have significant beneficial effect on primary or secondary prevention of colorectal adenoma.

Adult↗
PubMed2006

S-adenosyl-L-methionine for alcoholic liver diseases.

BACKGROUND: Alcohol is a major cause of liver disease and disrupts methionine and oxidative balances. S-adenosyl-L-methionine (SAMe) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione, the main cellular antioxidant. Randomised clinical trials have addressed the question whether SAMe may benefit patients with alcoholic liver diseases. OBJECTIVES: To evaluate the beneficial and harmful effects of SAMe for patients with alcoholic liver diseases. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and Science Citation Index Expanded (searched May 2005). SELECTION CRITERIA: We included randomised clinical trials studying patients with alcoholic liver diseases. Interventions encompassed per oral or parenteral administration of SAMe at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: We performed all analyses according to the intention-to-treat method using RevMan Analyses provided by the Cochrane Collaboration. We evaluated the methodological quality of the randomised clinical trials by quality components. MAIN RESULTS: We identified nine randomised clinical trials including a heterogeneous sample of 434 patients with alcoholic liver diseases. The methodological quality regarding randomisation was generally low, but 8 out of 9 trials were placebo controlled. Only one trial including 123 patients with alcoholic cirrhosis used adequate methodology and reported clearly on all-cause mortality and liver transplantation. We found no significant effects of SAMe on all-cause mortality (relative risks (RR) 0.62, 95% confidence interval (CI) 0.30 to 1.26), liver-related mortality (RR 0.68, 95% CI 0.31 to 1.48), all-cause mortality or liver transplantation (RR 0.55; 95% CI 0.27 to 1.09), or complications (RR 1.35, 95% CI 0.84 to 2.16), but the analysis is based mostly on one trial only. SAMe was not significantly associated with non-serious adverse events (RR 4.92; 95% CI 0.59 to 40.89) and no serious adverse events were reported. AUTHORS' CONCLUSIONS: We could not find evidence supporting or refuting the use of SAMe for patients with alcoholic liver diseases. We need more long-term, high-quality randomised trials on SAMe for these patients before SAMe may be recommended for clinical practice.

Humans↗
PubMed2006

Interventions for paracetamol (acetaminophen) overdose.

BACKGROUND: Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdose. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until December 2005. SELECTION CRITERIA: Randomised clinical trials and observational studies were included. DATA COLLECTION AND ANALYSIS: The primary outcome measure was all-cause mortality plus liver transplantation. Secondary outcome measures were clinical symptoms, (eg, hepatic encephalopathy, fulminant hepatic failure), hepatotoxicity, adverse events, and plasma paracetamol concentration. We used Peto odds ratios and odds ratios with 95% confidence intervals (CI) for analysis of outcomes. Random- and fixed-effects meta-analyses were performed. MAIN RESULTS: Ten small and low-methodological quality randomised trials, one quasi-randomised study, and 48 observational studies were identified. It was not possible to perform relevant meta-analyses of randomised trials that have addressed our outcome measures. Activated charcoal, gastric lavage, and ipecacuanha are able to reduce the absorption of paracetamol, but the clinical benefit is unclear. Of these, activated charcoal seems to have the best risk-benefit ratio. N-acetylcysteine seems preferable to placebo/supportive treatment, dimercaprol, and cysteamine, but N-acetylcysteine's superiority to methionine is unproven. It is not clear which N-acetylcysteine treatment protocol offers the best efficacy. No strong evidence supports other interventions for paracetamol overdose. N-acetylcysteine may reduce mortality in patients with fulminant hepatic failure (Peto OR 0.26, 95% CI 0.09 to 0.94, one trial). Liver transplantation has the potential to be life saving in fulminant hepatic failure, but refinement of selection criteria for transplantation and long-term outcome reporting are required. AUTHORS' CONCLUSIONS: Our results highlight a paucity of randomised trials on interventions for paracetamol overdose. Activated charcoal seems the best choice to reduce absorption. N-acetylcysteine should be given to patients with overdose but the selection criteria are not clear. No N-acetylcysteine regime has been shown to be more effective than any other. It is a delicate balance when to proceed to liver transplantation, which may be life-saving for patients with poor prognosis.

Acetaminophen↗
PubMed2006

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers.

BACKGROUND: Hepatitis B vaccine and hepatitis B immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis B infection. OBJECTIVES: To assess the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of HBsAg-positive mothers. SEARCH STRATEGY: Trials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, and EMBASE (until February 2004), authors of trials, and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing: plasma-derived vaccine (PDV) or recombinant vaccine (RV) versus no intervention, placebo, or other active vaccines; hepatitis B immunoglobulin versus no intervention, placebo, or other control immunoglobulin; as well as PDV or RV plus hepatitis B immunoglobulin versus no intervention, placebo, or other control vaccines or immunoglobulin. DATA COLLECTION AND ANALYSIS: Outcomes are assessed at maximal follow-up. The primary outcome measure was hepatitis B occurrence, based on a blood specimen positive for HBsAg, HBeAg, or antibody to hepatitis B core antigen (anti-HBc). Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality of the trial, mother's HBe-Ag status, and time of immunisation after birth. MAIN RESULTS: We identified 29 randomised clinical trials, five of which were considered high quality. Only three trials reported inclusion of hepatitis B e-antigen negative mothers. Compared with placebo/no intervention, vaccine reduced hepatitis B occurrence (RR 0.28, 95% confidence interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine (RV) versus plasma-derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high-dose versus low-dose vaccine (PDV: RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention, hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17, 3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events. AUTHORS' CONCLUSIONS: Vaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants of HBsAg positive mothers.

Female↗
PubMed2006

Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis--Cochrane Hepato-Biliary Group.

BACKGROUND: D-Penicillamine is used for patients with primary biliary cirrhosis due to its ability to decrease hepatic copper and modulate the immune response. The results on effects of D--penicillamine in randomized-clinical trials of primary biliary cirrhosis patients are inconsistent. AIM: To systematically evaluate the benefits and harms of D-penicillamine for patients with primary biliary cirrhosis. METHODS: We have performed a systematic review with meta-analyses of randomized-clinical trials to evaluate the effects of D-penicillamine for primary biliary cirrhosis. The primary outcomes are mortality and mortality or liver transplantation. We analysed the data by fixed-effect and random-effect models. RESULTS: Seven randomized trials including 706 patients were analysed. d-Penicillamine was without significant effects on mortality (RR 1.08, 95% CI: 0.82-1.43, P = 0.56), mortality or liver transplantation (RR 1.11, 95% CI: 0.74-1.68, P = 0.62), pruritus, liver complications, progression of liver histological stage and liver biochemical variables. D--Penicillamine significantly decreased serum alanine aminotransferase activity (weighted mean difference -45 IU/L, 95% CI: -75 to -15, P < 0.05) and led to significantly more adverse events (RR 4.18, 95% CI: 1.38-12.69, P = 0.01). CONCLUSION: D-Penicillamine did not appear to reduce the risk of mortality or morbidity, and led to more adverse events in patients with primary biliary cirrhosis.

Chelating Agents↗
PubMed2005

Vaccines for preventing hepatitis B in health-care workers.

BACKGROUND: Hepatitis B virus (HBV) causes acute and chronic liver diseases. Hepatitis B vaccination is recommended for health-care workers. OBJECTIVES: To assess the beneficial and harmful effects of hepatitis B vaccination in health-care workers. SEARCH STRATEGY: We searched the trial registers of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, and EMBASE to February 2003. SELECTION CRITERIA: Randomised trials comparing any dose, injection route, injection site, or schedule of hepatitis B plasma-derived vaccines (PDV) or recombinant vaccines (RV) versus placebo, no intervention, or another hepatitis B vaccine in health-care workers. DATA COLLECTION AND ANALYSIS: Two reviewers extracted the data independently. The reviewers assessed the methodological quality of the trials regarding generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The results were presented as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: We identified 21 randomised trials, all with one or more methodological weaknesses. Four trials demonstrated that PDV versus placebo significantly decreased hepatitis B events at maximum follow-up (RR 0.51, 95% CI 0.35 to 0.73). RV did not differ significantly from PDV in eliciting a protective hepatitis B surface antibody (anti-HBs) level in two trials. Both vaccines were well tolerated. Low-dose vaccine (1 or 2 microg) by the intradermal route resulted in significantly more participants without protective anti-HBs level compared with high-dose (10 or 20 microg) by the intramuscular route (RR 1.41, 95% CI 1.13 to 1.76). The intradermal route caused significantly more local adverse events, while the intramuscular route caused significantly more systemic adverse events. The gluteal injection produced significantly more participants without protective anti-HBs level than the deltoid injection. The prevalence of anti-HBs seroconversion by rapid vaccination (0, 1, and 2 months) was significantly lower than that by standard vaccination (0, 1, and 6 months). Booster vaccinations with different RV doses (2.5, 5, 10, 20, or 40 microg) produced similar prevalence of anti-HBs seroconversion in three trials assessing participants who did not respond to previous HBV vaccination. AUTHORS' CONCLUSIONS: PDV significantly prevents hepatitis B events. RV seems to be able to elicit similar protective anti-HBs levels. The intramuscular route with 20 microg RV was significantly more effective compared with the intradermal route with 2 microg RV as was the standard schedule compared with a rapid schedule and deltoid intramuscular injection compared with the gluteal intramuscular injection. It is unclear if booster vaccination of non-responders offers higher anti-HBs seroconversion and hepatitis B vaccine prevents the infection of hepatitis B mutants in health-care workers.

Health Personnel↗
PubMed2005

Propylthiouracil for alcoholic liver disease.

BACKGROUND: Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease. OBJECTIVES: To assess the beneficial and harmful of propylthiouracil for patients with alcoholic liver disease. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and The Web of Science (May 2005) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method in RevMan Analyses. The methodological quality of the randomised clinical trials was evaluated by components (generation of the allocation sequence; allocation concealment; double blinding; follow-up). MAIN RESULTS: Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (relative risks (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.80, 95% CI 0.50 to 1.29), complications of the liver disease, or liver histology. Propylthiouracil was associated with a non-significant increased risk of non-serious adverse events and with the seldom occurrence of serious adverse events (leukopenia). AUTHORS' CONCLUSIONS: We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, and liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

Antimetabolites↗
PubMed2005

Ribavirin monotherapy for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades. Ribavirin monotherapy may represent a treatment for some patients. OBJECTIVES: To assess the beneficial and harmful effect of ribavirin monotherapy for patients with chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until May 2005. SELECTION CRITERIA: We included all randomised trials irrespective of blinding, language, or publication status comparing ribavirin versus no intervention, placebo, or interferon for chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the six months sustained loss of hepatitis C virus RNA in blood after end of treatment and liver-related morbidity plus all-cause mortality. Secondary outcome measures were end of treatment virological response, biochemical response, histological response, and adverse events. Random- and fixed-effects meta-analyses with 95% confidence intervals (CI) were performed for all outcomes. We used Peto odds ratios (OR) for analysis of morbidity plus mortality and relative risks (RR) for the remaining outcomes. MAIN RESULTS: We identified 13 randomised trials including 594 patients with chronic hepatitis C. Most trials had low methodological quality. Compared with placebo/no intervention, ribavirin had no significant effect on sustained (RR 1.01, 95% CI 0.96 to 1.07, five trials) or end of treatment virological response (RR 1.00, 95% CI 0.94 to 1.07, ten trials). Ribavirin had no significant effect on liver-related morbidity plus mortality (Peto OR 1.96, 95% CI 0.20 to 19.0, eleven trials). Ribavirin significantly improved end of treatment biochemical and histological response but not sustained biochemical response. Further, ribavirin significantly increased the risk of anaemia. Ribavirin was significantly inferior to interferon regarding virological and biochemical response (four trials). AUTHORS' CONCLUSIONS: We found that ribavirin versus placebo/no intervention had no significant beneficial effect on virological response and liver morbidity, but may improve biochemical and histological response transiently. Ribavirin increased the risk of anaemia. Therefore, we cannot recommend ribavirin monotherapy for patients with chronic hepatitis C outside randomised trials.

Antiviral Agents↗
PubMed2005

Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B.

BACKGROUND: Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon. OBJECTIVES: The objectives were to assess the effects of the sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone in hepatitis B 'e' antigen positive chronic hepatitis B on mortality, virological response, biochemical response, liver histology, quality of life, and adverse events. SEARCH STRATEGY: Eligible trials were identified through searches of The Cochrane Hepato-Biliary Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (Excerpta Medica Database) (1980 to May 2005), BIOSIS (1969 to May 2005), and reference lists of relevant articles. Further trials were sought through correspondence with authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing identical alfa interferon treatment regimens with and without glucocorticosteroid pretreatment for hepatitis B 'e' antigen positive chronic hepatitis. We included trials irrespective blinding, publication status, or language. DATA COLLECTION AND ANALYSIS: Three authors selected the trials independently and one extracted the data, which were then validated. We performed assessments of the outcome measures at the end of treatment and at six months and at maximal follow-up after the end of treatment with alfa interferon. MAIN RESULTS: We included a total of 13 randomised trials with 790 patients. Loss of hepatitis B 'e' antigen (OR 1.41, 95% confidence interval 1.03 to 1.92, P = 0.03) and hepatitis B virus DNA (OR = 1.51, 95% confidence interval 1.12 to 2.05, P = 0.008) were significantly more frequent among patients treated with the sequential combination of glucocorticosteroids and alfa interferon than among patients treated with alfa interferon alone. Glucocorticosteroid pretreatment did not significantly influence seroconversion from hepatitis B 'e' antigen to antibodies to hepatitis B 'e' antigen, loss of hepatitis B surface antigen, normalisation of alanine aminotransferase/aspartate aminotransferase activities, and severity of adverse events. Glucocorticosteroid pretreatment did not significantly affect mortality and adverse events. The effect of glucocorticosteroid pretreatment on liver histology and quality of life could not be assessed due to insufficient data. AUTHORS' CONCLUSIONS: Pretreatment with glucocorticosteroids before treatment with alfa interferon in patients with hepatitis B 'e' antigen positive chronic hepatitis B may be more effective than treatment with alfa interferon alone with regard to loss of hepatitis B 'e' antigen and hepatitis B virus DNA, but evidence for effect on clinical outcomes is lacking.

Antiviral Agents↗
PubMed2005

Methotrexate for primary biliary cirrhosis.

BACKGROUND: Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS: Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.

Folic Acid Antagonists↗
PubMed2005

Bile acids for liver-transplanted patients.

BACKGROUND: Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease the degree of allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein endothelium. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for liver-transplanted patients. SEARCH STRATEGY: We performed searches of the Cochrane Hepato-Biliary Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to April 2003. We also searched The Chinese Biomedical Database to May 2002. SELECTION CRITERIA: Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo, no intervention, or another intervention. We included randomised clinical trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: W Chen extracted the data and C Gluud validated them. We evaluated the methodological quality of the trials from the method for generation of the allocation sequence, allocation concealment, double blinding, and follow-up. We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risk (RR) or weighted mean difference (WMD), both with 95% confidence intervals (CI). MAIN RESULTS: We identified seven randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention and one evaluating tauro-ursodeoxycholic acid versus no intervention) with a total of 335 liver-transplanted patients. The administration of bile acids began one day or more after liver transplantation. All patients received the standard triple-drug immunosuppressive regimen (steroids, azathioprine, and cyclosporine or tacrolimus) to suppress the allograft rejection response after liver transplantation. Bile acids did not significantly reduce all-cause mortality, mortality related to allograft rejection, retransplantation, acute cellular rejection, or number of patients with steroid-resistant rejection. Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in a random-effects model. Bile acids were safe and well tolerated by liver-transplanted patients. AUTHORS' CONCLUSIONS: Bile acids do not seem to have significant beneficial effects in liver-transplanted patients.

Cholagogues and Choleretics↗
PubMed2005

Ribavirin plus interferon versus interferon for chronic hepatitis C.

BACKGROUND: Hepatitis C is a major cause of liver-related morbidity and mortality. The disease progresses without symptoms for several decades and most patients are diagnosed based on the presence of hepatitis C virus ribonucleic acid and elevated transaminases. OBJECTIVES: To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C. SEARCH STRATEGY: We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials and pharmaceutical companies, until May 2004. SELECTION CRITERIA: We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon alone for treatment of chronic hepatitis C. DATA COLLECTION AND ANALYSIS: The primary outcome measures were the sustained loss of hepatitis C virus and liver-related morbidity plus all-cause mortality. We separately analysed patients who were naive, relapsers, or non-responders to previous antiviral treatment. Random-effects and fixed-effect model meta-analyses were performed for all outcomes. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). MAIN RESULTS: We included 72 randomised trials with 9991 patients. Most trials had low methodological quality but we did not find any significant influence of quality on our results. Compared with interferon, combination therapy had a significant beneficial effect on sustained virological response (RR 0.73, 95% CI 0.71 to 0.75) and in subgroups of naive patients (RR 0.72, 95% CI 0.68 to 0.76), relapsers (RR 0.63, 95% CI 0.54 to 0.73), and non-responders (RR 0.89, 95% CI 0.84 to 0.94) individually. Combination therapy significantly reduced morbidity plus mortality (Peto OR 0.46, 95% CI 0.22 to 0.96), but not in naive, relapsers, or non-responders individually. Combination therapy also had a significant beneficial effect on the histological response. Combination therapy significantly increased the risk of anaemia (RR 10.48, 95% CI 5.34 to 20.55), which occurred in 22% of patients on combination therapy. Combination therapy also significantly increased the risk of dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnea, fatigue) adverse events. Accordingly, combination therapy significantly increased the risk of treatment discontinuation (RR 1.19, 95% CI 1.01 to 1.39). AUTHORS' CONCLUSIONS: Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus and improving liver histology. This may lead to reduced morbidity and mortality. However, combination therapy significantly increased the risk of several adverse events.

Antiviral Agents↗
PubMed2005

Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis.

BACKGROUND: Alcohol and hepatotropic viruses cause the majority of liver cirrhosis cases in the Western World. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic or non-alcoholic fibrosis and cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of colchicine in patients with alcoholic or non-alcoholic fibrosis or cirrhosis, excluding primary biliary cirrhosis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE, EMBASE, Web of Science, and full text searches were combined (September 2004). Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: We included randomised trials irrespective of blinding, language, or publication status comparing per oral colchicine with placebo or no intervention for patients with fibrosis or cirrhosis induced by either alcohol, virus, or unknown factors (cryptogenic). DATA COLLECTION AND ANALYSIS: The statistical package (RevMan Analyses) provided by The Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated. MAIN RESULTS: We could include fifteen randomised clinical trials in which 1714 patients were randomised. We found no significant effects of colchicine on mortality (relative risks (RR) 1.00, 95% confidence interval (CI) 0.87 to 1.16), liver-related mortality (RR 1.08, 95% CI 0.88 to 1.33), complications (RR 1.01, 95% CI 0.74 to 1.38), liver biochemistry, liver histology, and alcohol consumption (RR 1.03, 95% CI 0.77 to 1.39). Colchicine was associated with a significantly increased risk of adverse events (RR 4.35, 95% CI 2.16 to 8.77). AUTHORS' CONCLUSIONS: Colchicine should not be used for alcoholic, viral, or cryptogenic liver fibrosis or liver cirrhosis outside randomised clinical trials.

Anti-Inflammatory Agents↗
PubMed2005

Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases.

BACKGROUND: Alcohol and hepatotoxic viruses cause the majority of liver diseases. Randomised clinical trials have assessed whether extracts of milk thistle, Silybum marianum (L) Gaertneri, have any effect in patients with alcoholic and/or hepatitis B or C virus liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of milk thistle or milk thistle constituents versus placebo or no intervention in patients with alcoholic liver disease and/or viral liver diseases (hepatitis B and hepatitis C). SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and full text searches were combined (December 2003). Manufacturers and researchers in the field were contacted. SELECTION CRITERIA: Only randomised clinical trials in patients with alcoholic and/or hepatitis B or C virus liver diseases (acute and chronic) were included. Interventions encompassed milk thistle at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published and no language limitations were applied. DATA COLLECTION AND ANALYSIS: The primary outcome measure was mortality. Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality. MAIN RESULTS: Thirteen randomised clinical trials assessed milk thistle in 915 patients with alcoholic and/or hepatitis B or C virus liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered adequately double-blinded. Milk thistle versus placebo or no intervention had no significant effect on mortality (RR 0.78, 95% CI 0.53 to 1.15), complications of liver disease (RR 0.95, 95% CI 0.83 to 1.09), or liver histology. Liver-related mortality was significantly reduced by milk thistle in all trials (RR 0.50, 95% CI 0.29 to 0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28 to 1.19). Milk thistle was not associated with a significantly increased risk of adverse events (RR 0.83, 95% CI 0.46 to 1.50). AUTHORS' CONCLUSIONS: Our results question the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases and highlight the lack of high-quality evidence to support this intervention. Adequately conducted and reported randomised clinical trials on milk thistle versus placebo are needed.

Hepatitis B↗
PubMed2005

Glucocorticosteroids for primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis is a chronic progressive cholestatic liver disease of presumed autoimmune etiology, characterised by the destruction of small intrahepatic bile ducts and the eventual development of cirrhosis and liver failure. Its progression may be influenced by immunosuppression. Glucocorticosteroids are potent immunosuppressive agents, but they are associated with significant adverse effects, including osteoporosis. OBJECTIVES: To systematically evaluate the beneficial and harmful effects of glucocorticosteroids versus placebo or no intervention for patients with primary biliary cirrhosis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Controlled Trials Register,The Cochrane Library, MEDLINE, EMBASE, and the full text of the identified studies were searched until June 2004. The search strategy included terms for primary biliary cirrhosis and glucocorticosteroids (including the names of frequently used preparations). Previous research groups and manufacturers were contacted for additional references. No language restrictions were applied. SELECTION CRITERIA: Double-blind, single-blind, or unblinded randomised clinical trials evaluating any preparation of glucocorticosteroids versus placebo or no intervention in patients with primary biliary cirrhosis diagnosed by abnormal liver function tests and either anti-mitochondrial antibodies or histology were included. Additional agents were allowed if they were administered to both groups equally. DATA COLLECTION AND ANALYSIS: The quality of the randomised clinical trials was evaluated by methodology components (generation of allocation sequence; allocation concealment; blinding; follow up). Analyses were performed according to the intention-to-treat method with missing data being accounted for by imputation. MAIN RESULTS: Only two underpowered trials (reporting 36 and 40 patients) were identified. These differed markedly in their inclusion criteria and treatment protocols. Both stated that they used placebo. However, allocation concealment was unclear. Only one trial reported any patient deaths. No significant improvement in mortality was identified (odds ratio (OR) 0.42, 95% confidence interval (CI) 0.10 to 1.76). Improvements in serum markers of liver inflammation and liver histology were identified. Potentially prognostically linked markers such as bilirubin and albumin were incompletely reported. Bone mineral density (weighted mean difference -2.84%, 95% CI -4.16 to -1.53) and the number of patients with any adverse event (OR 8.99, 95% CI 2.15 to 37.58) were significantly increased in the glucocorticosteroid group. AUTHORS' CONCLUSIONS: There is insufficient data to support or reject the use of glucocorticosteroids for patients with primary biliary cirrhosis. It may be appropriate to consider a large prospective randomised clinical trial on this topic.

Budesonide↗