Review question
To assess the benefits and harms of glucocorticosteroids administered at any route, dose, and duration versus placebo or no intervention in people with alcoholic hepatitis in terms of death, health-related quality of life, and complications.
Background
Excessive alcoholic consumption may damage the liver, causing alcoholic hepatitis. The first stage of liver damage in alcoholic hepatitis is usually reversible if people abstain from drinking, but the risk of the disease developing further and getting more complications increases with resumed drinking. A heavy drinker is considered a person who consumes more than 30 g (for men) or more than 20 g (for women) of alcohol per day. Only 10 to 35 people out of 100 heavy drinkers with evidence of excessive fat in the liver would most probably develop alcoholic hepatitis. With time, alcoholic hepatitis will cause liver fibrosis (scarring of the liver) or liver cirrhosis with complications (bleeding, infections, liver cancer, etc.).
Glucocorticosteroids are considered to have anti-inflammatory effects (relieving pain, swelling (oedema), fever). They are administered to people with alcoholic hepatitis in order to repair their liver injury. However, the benefits and harms of glucocorticosteroids are not well studied in randomised clinical trials (studies where people are randomly put into one of two or more treatment groups), and therefore, it is uncertain if they should be used in clinical practice for people with alcoholic liver disease.
Search date
The date of the last search was 18 January 2019.
Study characteristics
Sixteen randomised clinical trials compared glucocorticosteroids with placebo or no intervention in people with alcoholic hepatitis. Fifteen trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). Glucocorticosteroids were administered orally or as an injection for a median of 28 days (range 3 days to 12 weeks). The trial participants were between 25 and 70 years old, 65% were men, and had different stages of alcoholic liver disease. Trial participants were followed up to the moment of discharge from the hospital, or until they died (a median of 63 days), or for at least one year. Not all trials reported the follow-up of participants. The trials were conducted in France, India, the UK, and the USA. Two trials administered pentoxifylline (a medicine used for diseases of the blood vessels) to both glucocorticosteroids and placebo intervention groups.
Funding
Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry.
Reliability of the evidence
The overall reliability of the evidence was low for health-related quality of life and very low for death due to any cause up to three months following entry in the trial; serious side effects during treatment; liver-related death up to three months following entry in the trial; number of participants with any complications up to three months following entry in the trial, and number of participants non-serious side effects up to three months' follow-up after the end of treatment. All trials but one were at overall high risk of bias, which means that there is possibility of drawing wrong conclusions, exaggerating benefits, or underestimating harms of glucocorticosteroids because of the way the trials were conducted and analysed.
Key results
We could not determine whether glucocorticosteroids had a positive or negative effect on people with alcoholic liver disease. Despite available data on outcomes which included mortality, health-related quality of life, and serious complications, we were unable to draw firm conclusions mainly because available data were still insufficient to produce robust results, trials were small, and the included participants differed in severity of disease. Therefore, we have very little confidence in our conclusions.
We are very uncertain about the effect estimate of no difference between glucocorticosteroids and placebo or no intervention on all-cause mortality and serious adverse events during treatment because the certainty of evidence was very low, and low for health-related quality of life. Due to inadequate reporting, we cannot exclude increases in adverse events. As the CIs were wide, we cannot rule out significant benefits or harms of glucocorticosteroids. Therefore, we need placebo-controlled randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.
Alcoholic hepatitis is a form of alcoholic liver disease characterised by steatosis, necroinflammation, fibrosis, and complications to the liver. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids have been studied extensively in randomised clinical trials to assess their benefits and harms. However, the results have been contradictory.
To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis.
We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 18 January 2019.
Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adults diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed cointerventions in the trial groups, provided they were similar.
We followed Cochrane methodology, performing the meta-analyses using Review Manager 5. We presented the results of dichotomous outcomes as risk ratios (RR) and of continuous outcomes as mean difference (MD), with 95% confidence intervals (CI). We used both the fixed-effect and the random-effects models for meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached for our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the certainty of the evidence using GRADE.
Sixteen trials fulfilled our inclusion criteria. All trials but one were at overall high risk of bias. Fifteen trials (one of which was an abstract) provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). Glucocorticosteroids were administered orally or parenterally for a median 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. Follow-up, when reported, was up to the moment of discharge from the hospital, until they died (median of 63 days), or for at least one year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; very low-certainty evidence) or on health-related quality of life up to three months, measured with the European Quality of Life – 5 Dimensions – 3 Levels scale (MD –0.04 points, 95% CI –0.11 to 0.03; participants = 377; trial = 1; low-certainty evidence). There was no evidence of effect on the occurrence of serious adverse events during treatment (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; very low-certainty evidence), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; very low-certainty evidence), number of participants with any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; very low-certainty evidence), and number of participants of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; very low-certainty evidence). Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry.