Pharmacological interventions for alcoholic liver disease (alcohol‐related liver disease)
Abstract
Background
Alcohol‐related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol‐related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol‐related liver disease remains controversial.
Objectives
To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol‐related liver disease through a network meta‐analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta‐analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol‐related liver diseases.
Selection criteria
Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol‐related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co‐existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.
Data collection and analysis
Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed‐effect and random‐effects models based on available‐participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
Main results
We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes.
Alcoholic hepatitis
Fifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow‐up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta‐analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health‐related quality of life or incidence of hepatocellular carcinoma.
Severe alcoholic hepatitis
Of the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow‐up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis.
Source of funding: Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials.
Other alcohol‐related liver diseases
Thirty‐one randomised clinical trials included 3695 participants with other alcohol‐related liver diseases (with a wide spectrum of alcohol‐related liver diseases). The period of follow‐up ranged from one to 48 months. The mortality at maximal follow‐up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low‐quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol‐related liver diseases. The mortality at maximal follow‐up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low‐quality evidence).
Source of funding: Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials.
Authors' conclusions
Because of very low‐quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low‐quality evidence, propylthiouracil may decrease mortality in people with other alcohol‐related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.
Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow‐up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health‐related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.
PICOs
Plain language summary
Medical treatment of alcohol‐related liver disease
Background
Alcohol‐related liver disease or alcoholic liver disease is liver disease related to excessive alcohol consumption. It includes a spectrum of liver diseases that includes alcoholic steatosis (simple fatty liver or simple steatosis or accumulation of fat in liver cells), alcoholic hepatitis (inflammation of liver cells), and alcoholic cirrhosis (destruction of liver cells and replacement with scar tissue). This can cause major health problems such as excessive tiredness, and liver failure leading to vomiting blood, confusion, and death. A number of medical treatments have been used to treat alcohol‐related liver disease. The best way to treat alcohol‐related liver disease is not clear. We sought to resolve this issue by searching for existing studies on the topic. We included all randomised clinical trials whose results were reported until February 2017. We included only studies in which participants had not undergone liver transplantation previously and those who did not have liver disease due to other causes such as viral infections. Apart from using standard Cochrane methods which allow comparison of only two treatments at a time (direct comparison), we planned to use an advanced method which allows comparison of the many different treatments that are individually compared in the trials (network meta‐analysis). However, because of the nature of the information available, we could not determine whether the network meta‐analysis results were reliable. Therefore, we used standard Cochrane methodology.
Study characteristics
We identified 81 trials which were eligible for our review. We have presented the results for people with differing spectrum of alcohol‐related liver disease separately.
Key results
Alcoholic hepatitis
Fifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow‐up ranged from one to 12 months. Because of the nature of the information available, we used methods similar to Cochrane methodology. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes deaths (at various time points), cirrhosis, liver failure or liver transplantation. None of the trials reported health‐related quality of life or incidence of primary liver cancer.
Severe alcoholic hepatitis
Of the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis. The period of follow‐up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis.
Source of funding: Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials.
Other alcohol‐related liver diseases
Thirty‐one randomised clinical trials included 3695 participants with other alcohol‐related liver diseases (with a wide spectrum of alcohol‐related liver diseases). The period of follow‐up ranged from one to 48 months. The risk of deaths was lower in the propylthiouracil group than in the no intervention group and higher in the ursodeoxycholic acid group than in the no intervention group. However, these results are based on trials with methodological deficiencies that make the results unreliable. As a result, trials of low risk of bias of sufficient sample size are required before propylthiouracil can be recommended routinely. There was no evidence of improvement in any of the remaining clinical outcomes by any of the interventions compared with no intervention.
Source of funding: Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials.
Quality of the evidence
The overall quality of the evidence was very low and all the trials were at unclear or high risk of bias, which means that there is possibility of making wrong conclusions overestimating benefits or underestimating harms of one treatment or the other because of the way that the studies were conducted. Further high‐quality randomised clinical trials are necessary.
