What is the aim of this Cochrane Review?
To find out if any lifestyle modifications decrease the effect of nonalcohol-related fatty liver disease on lifespan, health-related quality of life, chronic liver disease and its complications, and whether they cause any harms.
Nonalcoholic fatty liver disease (NAFLD) is an accumulation of fat in the liver in people who have no history of significant alcohol consumption, use of medicines, diseases such as hepatitis C virus infection, or other conditions such as starvation that can damage the liver. Fatty liver can lead to liver damage resulting in inflammation (nonalcohol-related steatohepatitis (NASH)) or liver scarring (liver cirrhosis). Various medical treatments have been tried for the treatment of NAFLD. However, there is currently no evidence that any of them work. Lifestyle modifications have the potential to decrease the liver damage, but whether they achieve this is currently unclear. The authors of this review collected and analysed all relevant randomised clinical trials with the aim of finding out what is the best treatment.
We found 59 randomised clinical trials (studies where participants are randomly assigned to one of two treatment groups). During analysis of data, the review authors used standard Cochrane methods, which allow comparison of only two treatments at a time. We also planned to use advanced techniques that allow comparison of multiple treatments at the same time, usually referred as 'network (or indirect) meta-analysis'.
Date of literature search
What we studied in the review?
This review looked at people of any sex, age (including children), and ethnic origin, with NAFLD. We excluded studies in people who had previously had liver transplantation. The average age of participants, when reported, ranged from 13 years to 65 years. Participants were given different treatments, ranging from advice to supervised exercise and special diets, or a combination of these and no intervention, in addition to the public health advice. We wanted to gather and analyse data on death, quality of life, serious and non-serious adverse events, severe liver damage, complications resulting from severe liver damage, liver cancer, and deaths due to liver damage ('clinical outcomes').
What were the main results of the review?
The 59 studies included a small number of participants (3631 participants). Study data were sparse. Twenty-eight studies with 1942 participants provided data for analyses. The follow-up of the trial participants ranged from 1 month to 24 months. For trials that reported clinical outcomes, follow-up was 2 months to 24 months. Only two small trials did not raise major concerns for bias (deviation from truth because of the way the trials were conducted), and because of this, there is considerable uncertainty about the findings of this review.
The review shows that:
- During a follow-up period of 2 to 24 months, clinically important outcomes related to NAFLD such as deaths were rare and none of the participants developed liver-related complications such as liver cirrhosis (scarring of the liver), liver decompensation (complications because of scarring of the liver), liver transplantation, liver cancer, or deaths due to liver disease. This is probably because the trial participants were followed for too short a time.
- The evidence indicates considerable uncertainty about the effect of the interventions on any of the clinical outcomes.
- Future well-designed randomised clinical trials are needed to find out the best lifestyle modifications for people with NAFLD. Liver-related complications develop over 8 to 28 years. It is therefore unlikely that differences in clinical outcomes will become apparent in trials with less than 5 years to 10 years of follow-up. Sample sizes also need to be much larger.
The evidence indicates considerable uncertainty about the effects of the lifestyle interventions compared with no additional intervention (to general public health advice) on any of the clinical outcomes after a short follow-up period of 2 months to 24 months in people with nonalcohol-related fatty liver disease.
Accordingly, high-quality randomised clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (a study design in which multiple interventions are trialed within large longitudinal cohorts of participants to gain efficiencies and align trials more closely to standard clinical practice), comparing aerobic exercise and dietary advice versus standard of care (exercise and dietary advice received as part of national health promotion). The reason for the choice of aerobic exercise and dietary advice is the impact of these interventions on indirect outcomes which may translate to clinical benefit. The outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource use measures including costs of intervention and decreased healthcare use after a minimum follow-up of eight years, to find meaningful differences in the clinically important outcomes.
The prevalence of nonalcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases the risks of liver cirrhosis, hepatocellular carcinoma, and requirement for liver transplantation. There is uncertainty surrounding the relative benefits and harms of various lifestyle interventions for people with NAFLD.
To assess the comparative benefits and harms of different lifestyle interventions in the treatment of NAFLD through a network meta-analysis, and to generate rankings of the different lifestyle interventions according to their safety and efficacy.
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, World Health Organization International Clinical Trials Registry Platform, and trials registers until February 2021 to identify randomised clinical trials in people with NAFLD.
We included only randomised clinical trials (irrespective of language, blinding, or status) in people with NAFLD, whatever the method of diagnosis, age, and diabetic status of participants, or presence of non-alcoholic steatohepatitis (NASH). We excluded randomised clinical trials in which participants had previously undergone liver transplantation.
We planned to perform a network meta-analysis with OpenBUGS using Bayesian methods and to calculate the differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios (RaRs) with 95% credible intervals (CrIs) based on an available-participant analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. However, the data were too sparse for the clinical outcomes. We therefore performed only direct comparisons (head-to-head comparisons) with OpenBUGS using Bayesian methods.
We included a total of 59 randomised clinical trials (3631 participants) in the review. All but two trials were at high risk of bias. A total of 33 different interventions, ranging from advice to supervised exercise and special diets, or a combination of these and no additional intervention were compared in these trials. The reference treatment was no active intervention. Twenty-eight trials (1942 participants) were included in one or more comparisons. The follow-up ranged from 1 month to 24 months. The remaining trials did not report any of the outcomes of interest for this review.
The follow-up period in the trials that reported clinical outcomes was 2 months to 24 months. During this short follow-up period, clinical events related to NAFLD such as mortality, liver cirrhosis, liver decompensation, liver transplantation, hepatocellular carcinoma, and liver-related mortality were sparse. This is probably because of the very short follow-up periods. It takes a follow-up of 8 years to 28 years to detect differences in mortality between people with NAFLD and the general population. It is therefore unlikely that differences by clinical outcomes will be noted in trials with less than 5 years to 10 years of follow-up.
In one trial, one participant developed an adverse event. There were no adverse events in any of the remaining participants in this trial, or in any of the remaining trials, which seemed to be directly related to the intervention.