Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis

Oluyemi Komolafe, Elena Buzzetti, Audrey Linden, Lawrence M.J. Best, Angela M. Madden, Danielle Roberts, Thomas J.G. Chase, Dominic Fritche, Suzanne C. Freeman, Nicola J. Cooper, Alex J. Sutton, Elisabeth Jane Milne, Kathy Wright, Chavdar S. Pavlov, Brian R. Davidson, Emmanuel Tsochatzis, Kurinchi Selvan Gurusamy

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    1 Citation (Scopus)

    Abstract

    Background: 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. Objectives: • 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. Search methods: 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. Selection criteria: 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. Data collection and analysis: 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. Main results: 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. Authors' conclusions: 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).

    Original languageEnglish
    Article numberCD013157
    JournalCochrane Database of Systematic Reviews
    Volume2021
    Issue number7
    DOIs
    Publication statusPublished - 19 Jul 2021

    Bibliographical note

    Funding Information:
    Source of funding (q uote): "funding : this study was funded by BASF AS. Conflicts of Interest: D.T. and Y.Q. are employees of BASF AS; M.B.A. is a former employee of BASF AS; P.C.C. is an advisor to BASF AS" Trial name/Trial reg istry number: NCT02923804 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "MRB was supported by Alberta Innovates Health Solutions (AIHS)" Trial name/Trial reg istry number: NCT03184376 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was financially supported by a Grant (No. RDC-9105) from Vice-Chancellor for Research Affairs of Jundishapur University of Medical Sciences and approved by the Research Institute for Infectious Diseases of the Dig estive System, Jundishapur University of Medical Sciences,Ahvaz, Iran" Trial name/Trial registry number: IRCT2012071810333N1 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this research was supported by Hallym University ResearchFund, the Korea Society of Ginseng funded by Korea Ginseng Corporation (Korea Red Ginseng ; 2016), the Basic Science ResearchProg ram throug h the National Research Foundation of Korea (NRF)funded by the Ministry of Education, Science and Technolog y (NRF-2018M3A9F3020956 and NRF-2019R1I1A3A01060447) and Hallym University Research Fund 2018 (HURF-2018-67)" Trial name/Trial reg istry number: NCT03945123 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "the work described in this paper was partially supported by the direct g rant of The Chinese University of Hong Kong (Ref 2010.1.042)" Trial name/Trial reg istry number: NCT00870012 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "kindly provided by Abbott Laboratories. This study was supported by National Institutes of Health Grants DK 37948, DK 56341 (to Clinical Nutrition Research Unit), RR024992 (to Clinical and Translational Science Award), and RR-00954 (to Biomedical Mass Spectrometry Resource)" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was financially supported by Alimentary Tract Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Grant Number: RDC-9612)" Trial name/Trial registry number: IRCT20180513039634N Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this research was supported by a g rant from the Korea Society of Ginseng funded by Korea Ginseng Corporation (Korean Red Ginseng ; 2011)" Trial name/Trial reg istry number: NCT02331589 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the authors would like to thank Chang Gung Memorial Hospital for its financial support (CMRP 841)" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the study was financially supported by the Nutrition Research Center of Tabriz University of Medical Sciences, and Iran National Science Foundation (INSF)" Trial name/Trial registry number: IRCT20110530006652N2 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "the study was funded by AstraZeneca" Trial name/Trial reg istry number: NCT02279407 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the study was supported by Shahid Beheshti University of Medical Science" Trial name/Trial registry number: IRCT20100524004010N23 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this work was financially supported by a g rant from the Baq iyatallah University of Medical Sciences (Tehran, Iran)" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the present study was supported by the Italian Ministry of University and Research (MIUR, PON01_01226/1 - Decr. N.l/ Ric 18-1-2010)" Trial name/Trial reg istry number: NCT02369536 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "financial support and sponsorship: Food Security Research Centre, School of Nutrition and Food Science, Isfahan University of Medical sciences, Isfahan, Iran" Trial name/Trial registry number: IRCT2013122811763N15 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was supported by a teaching and research scholarship from the Faculty of Pharmacy of Tehran University of Medical Sciences" Trial name/Trial registry number: IRCT20121017011145N20 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "the EFFECT I study was funded by AstraZeneca" Trial name/Trial registry number: EFFECT 1 Attempts were made to contact study authors in December 2020

    Funding Information:
    Outcomes reported: serious adverse events (number of people), any adverse events (number of events), resolution of fatty liver disease Follow-up, months: 3 Source of funding (q uote): "this study was supported by the National Natural Science Foundation of China (No. 30972469; No. 81273059), the Science and Technolog y Key Project Foundation of Chong q ing (No. CSTC, 2011AB5040), and the National Science-technolog y Support Plan Projects Foundation of China (No. 2012BAI35B02)" Trial name/Trial reg istry number: ChiCTR-TRC-12002377 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was support by the National Centre for Scientific Research, as part of its research-development projects" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "the study was funded by a research g rant from Iran National Science Foundation (INSF) (Grant Number 97014520)" Trial name/Trial reg istry number: IRCT 20181005041238N1 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "we thank the Research Vice-Chancellor and Nutrition Research Center of Tabriz University of Medical Sciences, Tabriz, Iran, for the financial support" Trial name/Trial registry number: IRCT201511233664N16

    Funding Information:
    Source of funding (q uote): "we thank the Research Vice-Chancellor of Tabriz University of Medical Sciences, Tabriz, Iran, for the financial support" Trial name/Trial registry number: IRCT201406183664N12 Attempts were made to contact study authors in December 2020

    Funding Information:
    Outcomes reported: mortality, liver transplantation, cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, fibrosis score Follow-up, months: 12 Source of funding (q uote): "the synbiotic and placebo were provided at no cost by Chr. Hansen Holding.Chr.Hansenhadnoinputintoanyaspectofstudydesignorconductofthetrial.Furthermore,Chr. Hansen will have no input into data analysis or subseq uent reporting of the trial results. The INSYTE trial was funded by the National Institute for Heath Research Southampton Biomedical Research Centre and JKS is Funded by the Wellcome Trust (Grant Number 206453/Z/17/Z)" Trial name/Trial reg istry number: NCT01680640 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this work was financially supported by Vice Chancellor for Research, Iran University of Medical Sciences, Tehran, Iran" Trial name/Trial registry number: IRCT201701162709N39 Attempts were made to contact study authors in April 2021

    Funding Information:
    This project was funded by the National Institute for Health Research (NIHR) Systematic Reviews Programme (project number 16/114/17) and was supported by the Complex Reviews Support Unit; it was also funded by the National Institute for Health Research (project number 14/178/29).

    Funding Information:
    Source of funding (q uote): "this work was supported by Afimmune. Afimmune was involved in the design and conduct of the trial, collection, analysis, and interpretation of data; and preparation of this manuscript" Trial name/Trial reg istry number: NCT02941549 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this study is funded by the Armed Forces Institute of Patholog y, Rawalpindi and Higher Education Commission, Government of Pakistan, Islamabad" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was supported by a U.S. Department of Veterans Affairs Merit Award" Trial name/Trial reg istry number: NCT01002547 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was supported by Research Vice Chancellor of Tabriz University of Medical Sciences" Trial name/Trial registry number: IRCT201503163320N10 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was funded by research g rants from the Sapienza University Ate-neo Scientific Research (MGC, IB) and the Italian Minister of University and Research (MGC, MGB)" Trial name/Trial registry number: 2011-003010-17 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by the Sapienza University of Rome (Prog etti di Ricer-ca Universitaria 2011e2012)" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the study was supported by the cooperative research projects of Hungkuang UniversityandKuang-TienGeneralHospital(HK-102147)" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in April 2021

    Funding Information:
    Outcomes reported: mortality at maximal follow-up Follow-up, months: 3 Source of funding (q uote): "this study was supported by the National Natural Science Foundation of China (No. 30972469; No. 81273059), the Science and Technolog y Key Project Foundation of Chong q ing (No. CSTC, 2011AB5040), and the National Science-Technolog y Support Plan Projects Foundation of China (No. 2012BAI35B02)" Trial name/Trial registry number: CHICTR-TRC12002378 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "Nutrition and Food Security Research Center of Shahid Sadoug hi University of Medical Sciences funded this research. The corresponding author, Mozaffari-hassan, is an academ-

    Funding Information:
    Outcomes reported: mortality at maximal follow-up, serious adverse events (number of people), liver transplantation at maximal follow-up, decompensation (number of people), cirrhosis (number of people), resolution of fatty liver disease, hepatocellular carcinoma Follow-up, months: 6 Source of funding (q uote): "the study, funded by the Urmia University of Medical Sciences. The West Azarbaijan Peg ah Dairy Company (Urmia, Iran) supplied the synbiotic and conventional yog urts (author replies)" Trial name/Trial registry number: IRCT2017020932417N2 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by the University of Malaya Research Grant (Project Number: RG536-13HTM) and Meda Group" Trial name/Trial reg istry number: NCT02006498 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by Italian Ministry of University and Research, g rant number: Nutramed Project, PON 03PE000_78_1" Trial name/Trial reg istry number: ISRCTN12833814 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this work is supported by g rant No K/PBW/000495 from the Polish Ministry ofScienceandHigherEducation" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was supported by a research g rant from Nutrition Research center, Tabriz University of Medical Sciences, Iran" Trial name/Trial registry number: IRCT2014020516491N1 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "financial support was provided by Ahvaz Jundishapur University of Medical Sciences" Trial name/Trial registry number: IRCT2013071313984N1 Attempts were made to contact study authors in December 2020

    Funding Information:
    Outcomes reported: serious adverse events (number of people), any adverse events (number of people) Follow-up, months: 4 Source of funding (q uote): "the financial support provided by Isfahan University of Medical Sciences, Isfahan, Iran. The funder is not involved in the study desig n, data analysis and interpretation, or writing of the manuscript" Trial name/Trial registry number: IRCT2014110819853N1 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "this study was funded by Celltrion Pharm (Seoul, Korea)" Trial name/Trial reg istry number: KCT0000505 Attempts were made to contact study authors in December 2020

    Funding Information:
    Outcomes reported: mortality at maximal follow-up, serious adverse events (number of people), any adverse events (number of people), liver transplantation at maximal follow-up, decompensation (number of people), cirrhosis (number of people) Follow-up, months: 9 Source of funding (q uote): "this trial was funded by The University of Edinburg h ‘Liver Fund’. No external funding was applied for. No funding or support was received from the pharmaceutical industry" Trial name/Trial reg istry number: NCT01277237 Attempts were made to contact study authors in April 2021

    Funding Information:
    Source of funding (q uote): "the present study was supported by Isfahan University of Medical Sciences, Isfahan, Iran" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "the present study was supported by a g rant from Vice Chancellor for Research, Iran University of Medical Sciences, Tehran, Iran (no. 24996)" Trial name/Trial registry number: IRCT201410052394N13 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by the Italian Ministry of Health (Fondi di Ricerca Corrente and 5*1000) to Prof. Valerio Nobili. Prof. Anania is supported by US Public Health Service Grant DK062092 and Departments of Veterans’ Affairs Grant BX001746" Trial name/Trial reg istry number: NCT01650025 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by a g rant from the Istituto Biochimico Italiano, Lorenzini S.p.a., Italy" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was funded by Kyotsu Jig yo, Inc., Japan" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was supported by the Iran National Science Foundation" Trial name/Trial registry number: 201111082709N22 Attempts were made to contact study authors in December 2020

    Funding Information:
    We acknowledge the help and support of the Cochrane Hepato-Biliary Group, the Cochrane Central Editorial Unit, and copyeditors. We also thank Amanda Brand, researcher at the Centre for Evidence-based Health Care, Stellenbosch University, South Africa, and co-ordinator at Cochrane Nutrition, for comments on the review. Peer reviewers: Amanda Brand, South Africa (Cochrane Nutrition); Luca Giocaomelli, Italy; Kerry Dwan, UK.?Contact editor: Christian Gluud, Denmark.?Sign-off editor: Rachel Richardson, UK. Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato-Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Rigshospitalet, Copenhagen, Denmark. This project was funded by the National Institute for Health Research (NIHR) Systematic Reviews Programme (project number 16/114/17) and was supported by the Complex Reviews Support Unit; it was also funded by the National Institute for Health Research (project number 14/178/29). The views and opinions expressed therein are those of the review authors and do not necessarily reflect those of the 16/114/17 or 14/178/29 Programmes, the NIHR, the NHS, or the Department of Health. The views and opinions expressed in this protocol are those of the review authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.

    Funding Information:
    Source of funding (q uote): "this work was supported by g rants from the Major State Basic Research Development Prog ram of China (2012CB524906 to Gao X.; http// www.973.g ov.cn/Default_3.aspx), National Natural Science Foundation of China (81270933 to Gao X.), Major State Basic Research Development Prog ram of China (2011CB504004 to Gao X.), the Science and Technolog y Commission of Shang hai Municipality" Trial name/Trial reg istry number: NCT00633282 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study is funded by Tabriz University of Medical Sciences" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this work was partly funded by the Italian Ministry of University and Research (MIUR) PRIN 2005" Trial name/Trial reg istry number: not stated Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this article was supported financially by the Vice Chancellor for Research of Shiraz University of Medical Sciences (g rant number: 92-01-21-6352)" Trial name/Trial reg istry number: NCT02303314 ; IRCT2013102015083N1 Attempts were made to contact study authors in December 2020

    Funding Information:
    Source of funding (q uote): "this study was supported by the Vice Chancellor for research affairs of Ah-vaz Jundishapur University of Medical Sciences" Trial name/Trial registry number: IRCT2016042827652N1 Attempts were made to contact study authors in April 2021

    Publisher Copyright:
    Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    ASJC Scopus subject areas

    • Pharmacology (medical)

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