Glucocorticosteroids for people with alcoholic hepatitis
Abstract
Background
Alcoholic hepatitis is a form of alcoholic liver disease, characterised by steatosis, necroinflammation, fibrosis, and potential complications to the liver disease. 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 are used as anti‐inflammatory drugs for people with alcoholic hepatitis. Glucocorticosteroids have been studied extensively in randomised clinical trials in order to assess their benefits and harms. However, the results have been contradictory.
Objectives
To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis.
Search methods
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 We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources.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 20 October 2016.
Selection criteria
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 adult participants 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 co‐interventions in the trial groups, provided they were similar.
Data collection and analysis
We followed Cochrane and CHB methodology, performing the meta‐analyses using Review Manager 5 and Trial Sequential Analysis. We presented the results of dichotomous outcomes as risk ratios (RR) and those of the continuous outcomes as mean difference (MD). We applied both the fixed‐effect model and the random‐effects model 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 due to 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 quality of the evidence using GRADE.
Main results
Sixteen trials fulfilled the inclusion criteria. All trials were at high risk of bias. Fifteen trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). The glucocorticosteroids were administered orally or parenterally for a median of 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. The follow‐up of trial participants, when it was reported, was up to the moment of discharge from the hospital, until they died (a median of 63 days), or for at least a year. There was no evidence of effect of glucocorticosteroids on all‐cause mortality up to three months following randomisation neither with traditional meta‐analysis (random‐effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; I² = 45% (moderate heterogeneity) nor with Trial Sequential Analysis. Meta‐analysis showed no evidence of effect on health‐related quality of life up to three months (MD ‐0.04 points; 95% CI ‐0.11 to 0.03; participants = 377; trial = 1; low‐quality evidence), measured with the European Quality of Life ‐ 5 Dimensions‐3 Levels (EQ‐ 5D‐3L) scale. There was no evidence of effect on the occurrence of serious adverse events during treatment, neither with traditional meta‐analysis (random‐effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; I² = 36% (moderate heterogeneity), 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; I² = 46% (moderate heterogeneity), frequency of any complications up to three months following randomisation (random‐effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; I² = 42% (moderate heterogeneity), and frequency 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; I² = 0% (no heterogeneity) nor with Trial Sequential Analysis. Nine of the trials were industry‐funded.
Authors' conclusions
We found no evidence of a difference between glucocorticosteroids and placebo or no intervention on all‐cause mortality, health‐related quality of life, and serious adverse events during treatment. The risk of bias was high and the quality of evidence was very low or low. Therefore, we are very uncertain about this effect estimate. Due to inadequate reporting, we cannot exclude increases in adverse events. As the confidence intervals were wide, we cannot rule out significant benefits and 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.
PICOs
Plain language summary
Glucocorticosteroids for people with alcoholic hepatitis
Review question
To assess the benefits and harms of glucocorticosteroids administered in 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 60 g to 80 g (for men) or more than 20 g (for women) 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, 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, 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 20 October 2016.
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 (men: 65%) 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 a year. Not all trials reported the follow‐up of participants. The trials were conducted in France, India, UK, and USA. Two trials administered pentoxifylline to both glucocorticosteroids and placebo intervention groups.
Funding
Nine of the trials were industry‐funded.
Quality of evidence
The overall quality of evidence was very low, low, or moderate, and all the trials were at 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 that the trials were conducted and analysed.
Key results
Glucocorticosteroids did not benefit clinical outcomes of importance to people with alcoholic liver disease, such as mortality, no matter the cause, and health‐related quality of life. In addition, glucocorticosteroids may increase the number of adverse events. We cannot exclude benefits and harms of glucocorticosteroids but researchers need to study further their effects in high‐quality, placebo‐controlled, randomised clinical trials. Such trials ought to be registered before they are launched and openly report depersonalised individual participant data so that individual participant data meta‐analysis can be conducted.
