What is the aim of this Cochrane Review?
To find out if any form of nutritional supplementation decreases effects of non-alcohol-related fatty liver disease on lifespan, health-related quality of life, chronic liver disease, and its complications, and whether nutritional supplementation causes any harm.
Non-alcoholic fatty liver disease (NAFLD) is an accumulation of fat in the liver of people who have no history of significant alcohol consumption, use of medicines, disease 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 (non-alcohol-related steatohepatitis, or NASH) or liver scarring (liver cirrhosis). Various medical treatments have been tried for treatment of NAFLD. However, no current evidence suggests that any of them work. Nutritional supplementation has the potential to decrease liver damage, but whether this occurs 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. They found 202 randomised clinical trials (studies where participants are randomly assigned to one of two treatment groups). During analysis of data, review authors used standard Cochrane methods, which allow comparison of only two treatments at a time. In addition, review authors used advanced techniques that allow comparison of multiple treatments at the same time (usually referred as 'network (or indirect) meta-analysis').
Date of literature search
Only 19 trials were at low risk of bias, and because of this, uncertainty about the findings of this review is considerable. Studies that reported clinically important liver damage or its complications studied participants for a period of 2 months to 28 months. During this period, clinically important outcomes related to NAFLD such as death, liver-related complications such as liver cirrhosis (scarring of the liver), liver decompensation (complications caused by scarring of the liver), liver transplantation, hepatocellular carcinoma (liver cancer), and death due to liver disease were rare, even without any treatment. No evidence suggests that any nutritional supplementation decreased these. A possible reason for complications of liver disease being rare in trial participants may be the short follow-up period given in these trials (participants were followed only for a period of 2 months to 28 months). Liver-related complications due to NAFLD develop over 8 to 28 years. Therefore, it is unlikely that differences in clinical outcomes can be noted in trials with less than 5 to 10 years of follow-up.
What was studied in the Review?
This Review looked at people of any sex, age, and ethnic origin, with non-alcohol-related liver disease. Review authors excluded studies of people with previous liver transplantation. The average age of participants, when reported, ranged from 7 to 61 years. Participants were given different treatments including various vitamins and other nutritional supplements. Review authors 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 death due to liver damage ('clinical outcomes').
What were the main results of the Review?
The 202 studies included 14,200 participants. Study data were sparse. In all, 115 studies with 7732 participants provided data for analyses. Follow-up of trial participants ranged from 1 month to 28 months (2 months to 28 months for trials that reported clinical outcomes). The Review shows the following.
- The evidence indicates considerable uncertainty about effects of interventions on all clinical outcomes.
- Well-designed trials that collect data over longer follow-up times are needed in the future to find out the best nutritional supplementation (if any) for people with NAFLD.
The evidence indicates considerable uncertainty about effects of nutritional supplementation compared to no additional intervention on all clinical outcomes for people with non-alcohol-related fatty liver disease.
Accordingly, high-quality randomised comparative clinical trials with adequate follow-up are needed. We propose registry-based randomised clinical trials or cohort multiple randomised clinical trials (study design in which multiple interventions are trialed within large longitudinal cohorts of patients to gain efficiencies and align trials more closely to standard clinical practice) comparing interventions such as vitamin E, prebiotics/probiotics/synbiotics, PUFAs, and no nutritional supplementation. The reason for the choice of interventions is the impact of these interventions on indirect outcomes, which may translate to clinical benefit. Outcomes in such trials should be mortality, health-related quality of life, decompensated liver cirrhosis, liver transplantation, and resource utilisation measures including costs of intervention and decreased healthcare utilisation after minimum follow-up of 8 years (to find meaningful differences in clinically important outcomes).
The prevalence of non-alcohol-related fatty liver disease (NAFLD) varies between 19% and 33% in different populations. NAFLD decreases life expectancy and increases risks of liver cirrhosis, hepatocellular carcinoma, and the requirement for liver transplantation. Uncertainty surrounds relative benefits and harms of various nutritional supplements in NAFLD. Currently no nutritional supplement is recommended for people with NAFLD.
• To assess the benefits and harms of different nutritional supplements for treatment of NAFLD through a network meta-analysis
• To generate rankings of different nutritional supplements according to their safety and efficacy
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, the 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) for people with NAFLD, irrespective of 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 performed a network meta-analysis with OpenBUGS using Bayesian methods whenever possible and calculated differences in treatments using hazard ratios (HRs), odds ratios (ORs), and rate ratios with 95% credible intervals (CrIs) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
We included in the review a total of 202 randomised clinical trials (14,200 participants). Nineteen trials were at low risk of bias. A total of 32 different interventions were compared in these trials. A total of 115 trials (7732 participants) were included in one or more comparisons. The remaining trials did not report any of the outcomes of interest for this review.
Follow-up ranged from 1 month to 28 months. The follow-up period in trials that reported clinical outcomes was 2 months to 28 months. During this 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.
We did not calculate effect estimates for mortality because of sparse data (zero events for at least one of the groups in the trial). None of the trials reported that they measured overall health-related quality of life using a validated scale. The evidence is very uncertain about effects of interventions on serious adverse events (number of people or number of events).
We are very uncertain about effects on adverse events of most of the supplements that we investigated, as the evidence is of very low certainty. However, people taking PUFA (polyunsaturated fatty acid) may be more likely to experience an adverse event than those not receiving an active intervention (network meta-analysis results: OR 4.44, 95% CrI 2.40 to 8.48; low-certainty evidence; 4 trials, 203 participants; direct evidence: OR 4.43, 95% CrI 2.43 to 8.42). People who take other supplements (a category that includes nutritional supplements other than vitamins, fatty acids, phospholipids, and antioxidants) had higher numbers of adverse events than those not receiving an active intervention (network meta-analysis: rate ratio 1.73, 95% CrI 1.26 to 2.41; 6 trials, 291 participants; direct evidence: rate ratio 1.72, 95% CrI 1.25 to 2.40; low-certainty evidence).
Data were sparse (zero events in all groups in the trial) for liver transplantation, liver decompensation, and hepatocellular carcinoma. So, we did not perform formal analysis for these outcomes. The evidence is very uncertain about effects of other antioxidants (antioxidants other than vitamins) compared to no active intervention on liver cirrhosis (HR 1.68, 95% CrI 0.23 to 15.10; 1 trial, 99 participants; very low-certainty evidence).
The evidence is very uncertain about effects of interventions in any of the remaining comparisons, or data were sparse (with zero events in at least one of the groups), precluding formal calculations of effect estimates.
Data were probably because of the very short follow-up period (2 months to 28 months). It takes follow-up of 8 to 28 years to detect differences in mortality between people with NAFLD and the general population. Therefore, it is unlikely that differences in clinical outcomes are noted in trials providing less than 5 to 10 years of follow-up.